Pharmaceutical composition comprising stable, amorphous, hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component

Abstract

To provide a pharmaceutical composition with improved bioavailability containing a protein kinase inhibitor (PKI) being a poorly water-soluble compound.SOLUTION: A pharmaceutical compositions comprises amorphous solid dispersion particles of PKIs having an average particle diameter less than 1000 nm, and at least one polymeric stabilizing and matrix-forming component such as hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose and copolyvidone, and optionally further comprises 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. Specifically, the present invention relates to pharmaceutical compositions comprising stable amorphous hybrid nanoparticles of a protein kinase inhibitor (PKI) and a polymeric stabilizing matrix-forming component. Further, the present invention relates to a method for treating a proliferative disease in a patient in need of treatment, comprising administering a therapeutically effective amount of said composition.

Background Art

[0002] Components of cell signaling pathways that control normal cell growth and differentiation, when dysregulated, give rise to cell proliferative diseases 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 changes in cell-cell adhesion properties.

[0003] Many proliferative disorders, such as tumors and cancers, have been shown to involve the overexpression or upward regulation of protein kinase activity. Protein kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation usually alters the function of the target protein by changing enzyme activity, cellular site, or association with other proteins. Protein kinases can be subdivided or characterized by the amino acids of the target protein whose phosphorylation they regulate. Most kinases act on both serine and threonine, and tyrosine kinases act on tyrosine, but some (bispecific kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, such as histidine kinases that phosphorylate histidine residues. The human genome contains approximately 500 protein kinase genes, and up to 30% of all human proteins can be modified by protein kinases. Kinases are known to regulate a large portion of cellular pathways, particularly those involved in signal transduction. Dysregulation of protein kinases due to mutations in both receptors and ligands, gene rearrangements, gene amplification, and overexpression is involved in the development and progression of human cancers. Therefore, protein kinase inhibitors (PKIs) are useful in treating diseases caused or exacerbated by overexpression or upward regulation of protein kinases. For example, tyrosine kinase inhibitors (TKIs, also known as tylphostine) have been shown to be effective antitumor and antileukemia agents (Lowery A et al., Front Biosci. 2011 Jun 1;17:1996-2007).

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

[0005] PKIs are generally weak bases that dissolve only slightly at low pH (e.g., 100-1000 mg / L) and are 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-polypetide structure and have relatively low molecular weights, such as less than 10,000 daltons or less, or less than 5,000 daltons.

[0006] Several methods have been reported to improve the solubility of poorly water-soluble drugs, including particle formation, the development of salts or solvates, complexes, and microspheres. Furthermore, efforts have been made to improve the bioavailability provided by solid dosage forms by forming drug-containing particles or by mixing poorly water-soluble drugs with hydrophilic excipients. However, conventional methods have inherent limitations in terms of the physical stability of particles during storage, issues related to grinding, or the difficulty of removing solvents, which are often toxic. Moreover, since precipitation reduces bioavailability, it is important that the drug released from the solid phase does not precipitate in the gastrointestinal tract, that precipitation is minimized as much as possible, and that the drug remains water-soluble in the aqueous fluids of the gastrointestinal tract (see, for example, Herve J. et al. Pharm Dev Technol. 2011 Jun;16(3):278-86).

[0007] Since most drug absorption occurs in the small and large intestines where the pH is close to neutral, pH-dependent solubility is a well-known issue for many oral formulations of poorly water-soluble substances such as PKIs. Therefore, there is a constant need to develop oral solid dosage forms of PKI-based drugs and improve their solubility (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). Consequently, methods to improve the solubility of PKI-based drugs and other poorly water-soluble drugs at neutral (intestinal) pH are highly desirable.

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

[0009] Specification EP2105130 discloses a pharmaceutical formulation comprising a solid dispersion or solid solution containing a polymer and an active agent in amorphous form. Furthermore, the formulation includes an external polymer to stabilize 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 method for the manufacture of the above-mentioned formulation. [Overview of the project]

[0010] The present invention relates to a pharmaceutical composition comprising stable amorphous hybrid nanoparticles containing at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component. Optionally, one or more solubilizers present separately from or within the particles may be added to the particles. [Brief explanation of the drawing]

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

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

[0013] In this specification, the phrase “hybrid nanoparticles” means a group of particles typically having an average size range of 1 to 1000 nm, composed of at least two components, one of which is a PKI and the other is a polymeric stabilizing matrix-forming component. The particles may be crystalline, amorphous, or a mixture thereof. Typically, in the sense of this disclosure, the particles are “amorphous” or “basically amorphous.” This means that the contents of almost all, if not all, of the particles contain an amorphous protein kinase inhibitor and a polymeric stabilizing matrix-forming component. The level or degree of amorphousness is at least 60%, 70%, 80%, or 85%, preferably at least 90%, more preferably over 95%, and so on, where 100% represents that all the material in the particles is amorphous.

[0014] The quantification of crystalline PKI, or the absence of crystalline (crysalline) PKI, can be measured by X-ray powder diffraction (methods) as described in Saleki-Gerhardt A et al. Int J Pharm. 1994;101:237-247) or by 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" is related to the previously defined "hybrid nanoparticles," but solid dispersion particles are typically large or much larger in size (typically μm to mm, as described in Wu K. et al. J Pharm Sci. 2009 Jul;98(7):2422-3). The smaller size of hybrid nanoparticles contributes to further stabilizing PKI to prevent crystallization. Typically, hybrid nanoparticles have an average size range of 1 to 1000 nm, preferably less than 250 nm, such as less than 500 nm.

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

[0017] The term "protein kinase inhibitor" or "PKI" means a single 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, sediranib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, restaurtinib, motesanib, mbritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, semacsanib, sunitinib, tandunitib, tipifamib, vandetanib, and vemurafenib; or their salts, hydrates, or solvates, or combinations thereof.

[0018] The phrase "polymeric stabilizing matrix-forming component" refers to a component present in hybrid nanoparticles along with PKI. Typically, the polymeric stabilizing matrix-forming component is, for example, 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., Kollicoat VA 64), crospovidone (e.g., Kollicoat ME), copolymer of methacrylic acid and ethyl acrylate (e.g., Eudragit Polymer structures include, but are not limited to, L100, polyethylene glycol (PEG), DL-lactide / glycolide copolymer, poly-DL-lactide, cellulose acetate phthalate (CAP), aminoalkyl methacrylate copolymer (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 up of monomers that are bonded together to form a larger molecule. A polymer generally consists of 20 or more monomers bonded together, but fewer than 20 monomers bonded 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, and includes, but is not limited to, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus), d-α-tocopherolate 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 acid glycerides (e.g., Labrasol), and poloxamers (e.g., Pluronics, Kolliphor).

[0021] In this specification, the term “primary particles” refers to the smallest granular objects formed during the precipitation process. Particle boundaries are analyzed by SEM microscopy. Depending on process parameters, primary particles may together form denser or less dense porous networks, or larger clumps or bridging particles. Parameters influencing agglomeration include, for example, temperature, which can alter the softness of primary particles; precipitation time; solvent / reverse solvent ratio, which affects the concentration of the PKI solution; and the properties of polymeric stabilizing and matrix-forming agents(s). The average size of primary particles is typically 1 to 1000 nm, preferably less than 500 nm, and more preferably less than 250 nm.

[0022] In this specification, the terms "supercritical" and "supercritical fluid" refer to chemical substances that are set to both a critical temperature (Tc) or higher and a critical pressure (Pc) or higher.

[0023] In this specification, the terms “subcritical” and “subcritical fluid” mean that one of the critical temperature (Tc) and critical pressure (Pc) is set to a temperature or pressure higher than that critical temperature (Tc) or critical pressure (Pc), and the other of the critical temperature (Tc) and critical pressure (Pc) is set to a temperature or pressure lower than that critical temperature (Tc) or critical pressure (Pc).

[0024] The term "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 the concentration of the solubilized drug.

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

[0026] The term "supersaturated" is used herein to mean a solvent containing a substance in greater quantities than can be dissolved in the solvent or medium under normal circumstances.

[0027] In this specification, the term "Soluplus" means polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0028] In this specification, the term "TPGS" means d-α-tocopherolate polyethylene glycol 1000 succinate.

[0029] In this specification, the term "Chremophor RH40" refers to PEG-40 hydrogenated castor oil.

[0030] In this specification, the term "PVAP" means polyvinyl acetate phthalate.

[0031] In this specification, the term "PVP 90K" means polyvinylpyrrolidone K-90.

[0032] In this specification, the term "PVP 30K" means polyvinylpyrrolidone K-30.

[0033] In this specification, the term "HPMC-AS" means hydroxypropyl methylcellulose acetate succinate.

[0034] In this specification, the term "HPMCP HP55" means hydroxypropyl methylcellulose phthalate.

[0035] In this specification, the term "HPC" means hydroxypropylcellulose such as HPC EF and HPC LF.

[0036] In this specification, the term "Kollidon VA64" means copolividone.

[0037] In this specification, the term "CAP" means cellulose acetate phthalate.

[0038] The dissolution media used for testing the hybrid nanoparticles of the present invention include a fasting artificial intestinal fluid called FaSSIF, a feeding artificial intestinal fluid called FeSSIF, and an artificial gastric fluid called SGF. The FaSSIF medium is formulated to represent a fasting state and has a pH of approximately 6.5 and specific osmotic properties. The FeSSIF medium is formulated to represent a feeding state and has a pH of approximately 5 and specific osmotic properties. SGF is formulated to represent gastric fluid and has a pH of approximately 1.4 and specific osmotic properties. FaSSIF, FeSSIF, and SGF media are commonly used in in vitro models for the dissolution of poorly water-soluble drugs. The choice of medium will depend on the location and conditions (fasting or feeding) within the gastrointestinal tract where the particles are to be dissolved and 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. Ease of dissolution can be at least partially due to the amount of energy required to dissolve the component from its crystalline or amorphous solid phase. Amorphous particles require less energy to dissolve compared to crystalline particles of the same compound.

[0040] The composition of the present invention comprises particles containing PKI or a combination of two or more PKIs. However, the particles may contain 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 also includes hydrates, solvates (alcoates), pharmaceutically acceptable acidic salts, basic salts, or cocrystals of such protein kinase inhibitor compounds.

[0042] In this specification, the term "water-insoluble or poorly water-soluble (or hydrophobic) compound" means a compound whose solubility in water at 25°C is less than 1 g / 100 ml, and in particular less than 0.1 g / 100 ml in pure water at a neutral pH.

[0043] The stable amorphous hybrid nanoparticles contained in the compositions of the present invention are typically in the form of particles described elsewhere herein. There are several different methods for forming larger particles, such as granulation, melt extrusion, spray drying, and precipitation, but all of these typically involve starting with the formation of a mixture of a pharmaceutical active ingredient (API) and a polymeric stabilizing matrix-forming component. The particles contained in the compositions of the present invention are produced by a continuous process that generates hybrid nanoparticles. In this context, a continuous process means that particle formation proceeds continuously, and at the same time, the hybrid nanoparticles are continuously drawn, recovered, and stored from the mixture after their formation. In a preferred method, i.e., a precipitation method, this means that a fluid, which is a solution of the PKI, preferably in the form of a fluid flow, is mixed with a fluid of a reverse solvent, preferably in the form of a reverse solvent fluid flow. The polymeric stabilizing matrix-forming component may be present in one or both of the two fluids, depending on its solubility properties. The mixing of the two fluids is carried out in a mixing function, e.g., in a mixing chamber. When the process is continuous, i.e., when two fluids are fluid flows, the mixing function is typically associated with a particle-forming separation function, where hybrid nanoparticles are stored as the mixed fluid flow passes through. Agents that alter the properties of particles without being incorporated into them can be added to one or both of the two fluids before the mixing step. The fluids are typically conventional liquids or supercritical fluids, and supercritical fluids also include subcritical fluids (i.e., fluids where only one of the pressure or temperature exceeds its supercritical value). Typical combinations are a) conventional (i.e., non-supercritical) liquids for both the API solution and the reverse solvent, b) conventional liquid for the reverse solvent combined with a supercritical solution of API, c) supercritical fluid for the reverse solvent combined with a conventional liquid for the API solution, and d) supercritical fluids for both fluids. In certain variants, the reverse solvent can be omitted. The fluid flow, preferably supercritical, containing both the API and the polymeric stabilizing matrix-forming components, is then spread within the particle-forming function. In the precipitation method described above, it is preferable that at least one of the fluids is in a supercritical state.These types of precipitation methods are discussed in International Publication No. 2005061090 (Censdelivery AB), International Publication No. 2009072950 (XSpray Microparticles AB), International Publication No. 2009072953 (XSpray Microparticles AB), International Publication No. 2011159218 (XSpray Microparticles AB), and the references cited in these publications.

[0044] The term "solution" encompasses both true solute and minute particles smaller than the particles to be produced at colloidal dimensions (typically 1–1000 nm).

[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 internationally published patent application mentioned in the previous paragraph. A key characteristic of the system is that the flows of two fluids are integrated within the nozzle at an angle between 45° and 135°, preferably around 90°, and sprayed during the particle formation / separation function. In principle, the system can produce particles of a given size / shape. In this specification, the Right Size system and apparatus will be described using non-limiting examples of PKI as the drug and CO2 as the supercritical fluid reverse solvent.

[0046] The system consists of one pump transport configuration for PKI dissolved in a liquid solvent called API solution and one pump transport configuration for a reverse solvent, such as CO2, although other reverse solvents can be used as appropriate. Each pump transport configuration includes devices such as flow meters and pressure gauges used to control process conditions. These two pump transport configurations are fluidically connected by a spray nozzle.

[0047] A stream of liquid API solution is mixed with a stream of CO2 under flow conditions within a spray nozzle. Polymeric stabilizing matrix-forming components are present in either the API solution or the CO2 stream. These streams are sprayed at the nozzle outlet into a precipitation vessel under controlled conditions (typically pressure and temperature). The CO2 acts as a reverse solvent, precipitating the API along with the polymeric stabilizing matrix-forming components into fine particles. The particles are collected in the vessel by a filtration configuration. Typically, a back pressure relief valve is used to regulate the pressure within the precipitation vessel.

[0048] While not limited to this, for the preparation of hybrid nanoparticles of certain drugs, such as pazopanib and erlotinib, it may be advantageous to have an extra pump transport configuration for injecting an additional solvent, called a modifier, into CO2. Here, a pump transport configuration control unit is installed for the modifier, and the modifier is mixed with CO2 in a mixer before entering the nozzle.

[0049] When using the system, the system operator typically begins by equilibrating the system by pumping CO2, a "PKI-like solution" (a solution similar in composition to a PKI solution but without PKI or excipients), and modifiers (if used) through the system until the desired steady state is reached in terms of flow rate, pressure, and temperature. Key parameters for setting up the system are the PKI solution composition, PKI solution flow rate, CO2 flow rate, CO2 pressure and temperature, and, if used, the properties and flow rate of the modifiers.

[0050] Next, the "PKI-like solution" is replaced with the PKI solution to produce a solution, which is stored downstream of the mixing, for example, downstream of the nozzle outlet. The system is then washed, typically by pumping the "PKI-like solution" through the system. The particles are dried by flowing a large amount of CO2 through the stored particles to remove any remaining solvent. The precipitation container is then depressurized and the particles can be recovered.

[0051] The solution / solvent and the reverse solvent are typically miscible with respect to each other. The pressure and temperature upstream of the particle-forming function and / or mixing function can create a supercritical or subcritical state with respect to the reverse solvent.

[0052] The concentration of PKI in solution is typically below the saturation concentration, such as 50% or less, 60% or less, 75% or less, 85% or less, or 95% or less. Preferred concentrations are typically found in the range of 20% or less, with a lower limit of 0.05% or less, or 0.1%, such as 10% or less, or 5% or less, or 3% or less (all w / v%). The term "volatile" in relation to solvents means a boiling point of 200°C or less, such as 150°C or less, or 100°C or less, at atmospheric pressure. Examples include inorganic solvents and organic solvents, with dimethyl sulfoxide and trifluoroethanol and mixtures thereof being particularly emphasized. 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 acids, alkalis, buffering components, and / or other organic solvents.

[0053] Examples of fluids that can be used as reverse solvents are: a) Is it a gas at room temperature and atmospheric pressure, or b) It is a liquid at room temperature and atmospheric pressure.

[0054] The reverse solvent is typically selected based on its ability to readily disperse in small droplets and its ability to act as a reverse solvent for PKI in sprays and solutions.

[0055] The compounds / elements in 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), sulfur 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), as well as mixtures containing these compounds / elements. Pc represents the critical pressure and Tc represents the critical temperature. The compounds in group (b) are typically selected from conventional liquids of the same general type as those previously discussed regarding solvents, except that the PKI present in the solution must be sparingly soluble in the reverse solvent. Specific solvents in group (b) include methanol, ethanol, acetone, water, and mixtures containing one or more of these fluids.

[0056] The reverse solvents of group (a) above are typically used at pressures and temperatures that impart i) a supercritical state (supercritical fluid) or ii) a subcritical state (subcritical fluid) upstream of the particle formation function and / or the function, for example, the mixing function and upstream of the latter function.

[0057] Deformed form (i) typically refers to pressures and temperatures exceeding the critical pressure Pc and critical temperature Tc of the reverse solvent used. With respect to pressure, this is typically within the range of (1.0–7.0) × Pc, or within the range of 10 bar or more, preferably 20 bar or more, and preferably 30 bar or more, higher than Pc, with exemplary upper limits being 100 bar, 200 bar, and 300 bar above Pc. With respect to temperature, this is typically within (1.0–4.0) × Tc, or within the range of 5°C or more above Tc, preferably 10°C or more, and preferably 15°C or more, with exemplary upper limits being 10°C, 40°C, and 50°C above Tc.

[0058] Deformation (ii) means that at least one of the temperature and pressure, preferably only the temperature, is below the critical values ​​(Tc and Pc, respectively). Therefore, the temperature can be within the interval of (0.1-1)×Tc, (0.5-1)×Tc, or lower. Furthermore, the temperature can be as low as -10°C or -30°C. These temperatures can be combined with the pressure defined in the previous paragraph, or with a pressure lower than the Pc of the reverse solvent used. With respect to carbon dioxide, this means that the temperature during particle formation is below +31°C, around +25°C, or lower, and is combined with a pressure higher or lower than 74 bar.

[0059] The reverse solvents in group (b) above are typically used in a subcritical state, i.e., as subcritical fluids.

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

[0061] In one embodiment of this aspect, a pharmaceutical composition is provided comprising 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 pharmaceutically acceptable solubilizer. Typically, the solubilizer exists 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-polyvinyl acetate-polyethylene glycol copolymer, d-α-tocopherolate polyethylene glycol 1000 succinate, and hydrogenated castor oil such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. Furthermore, the solubilizer may be a poloxamer.

[0062] A composition comprising stable amorphous hybrid nanoparticles containing at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component exhibits an increased dissolution rate.

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

[0064] Typically, the dissolution rate is measured, for example, by a flow-through cell system under sink conditions, according to the United States Pharmacopeia (USP4). Dissolution measurement of hybrid nanoparticles under sink conditions can be performed by adding the desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), mounting the cell in the apparatus, and then pumping the powder through an appropriate medium (typically FaSSIF, FeSSIF, SGF). The temperature of the apparatus is typically set to 37°C. The amount of powder added to the cell depends on the drug-filled amount of the powder. The exact amount of powder can be calculated from the results obtained from the drug-filled amount 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. A 1 ml sample of the medium passing through the cell is collected at a predetermined time and subsequently analyzed by HPLC (e.g., C18 column Eclipse, 4.6 mm × 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 after the moment the medium exits the flow-through cell. The cumulative percentage of the amount of active substance added to the flow-through cell that is solubilized can be calculated and plotted against time (minutes). The initial slope of the graph ("initial dissolution rate," corresponding to 0-10 minutes) can be estimated and adopted as the dissolution rate of a substance in a given dissolution medium under 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 dissolution rate ratio of the stable amorphous hybrid nanoparticles to the untreated crystalline form of the protein kinase inhibitor. Preferably, the ratio is about 1.5:1 to about 500:1, about 10:1 to about 30:1, etc.

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

[0068] Typically, the dissolution rate is measured, for example, by a flow-through cell system under sink conditions. Dissolution measurement of stable amorphous hybrid nanoparticles under sink conditions can be performed by adding the desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), mounting the cell in the apparatus, and then pumping a suitable medium (typically FaSSIF, FeSSIF, SGF) through the powder. The apparatus temperature is typically set to 37°C. The amount of powder added to the cell depends on the drug-filled amount of the powder. The exact amount of powder can be calculated from the results obtained from the drug-filled amount 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. A 1 ml sample of the medium passing through the cell is collected at a predetermined time and subsequently analyzed by HPLC (e.g., C18 column Eclipse, 4.6 mm × 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 after the moment the medium exits the flow-through cell. The cumulative percentage of the amount of active substance added to the flow-through cell that is solubilized can be calculated and plotted against time (minutes). The initial slope of the graph ("initial dissolution rate," corresponding to 0-10 minutes) can be estimated and adopted as the dissolution rate of a substance in a given dissolution medium under sink conditions at 37°C.

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

[0070] The polymeric stabilizing 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), copolymer of methacrylic acid and ethyl acrylate (e.g., Kollicoat ME), copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit Examples include, but are not limited to, L100), polyethylene glycol (PEG), DL-lactide / glycolide copolymer, polyDL-lactide, cellulose acetate phthalate (CAP), carbomer homopolymer type A (e.g., Carbopol 971P), carbomer homopolymer type B (e.g., Carbopol 974P), aminoalkyl methacrylate copolymer (e.g., Eudragit RL100, RL PO, or RS PO), and poloxamers (e.g., Pluronics, Kolliphor).

[0071] Therefore, in other embodiments of this embodiment, the polymeric stabilizing matrix-forming component is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone, polyvinyl acetate phthalate, copolyvidone, crospovidone, copolymer of methacrylic acid and ethyl acrylate, copolymer of methacrylic acid and methyl methacrylate, polyethylene glycol, DL lactide / glycolide copolymer, polyDL-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 hydroxypropyl methylcellulose phthalate, hydroxypropylcellulose, copolyvidone, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, and polyvinylpyrrolidone.

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

[0073] In another embodiment of this aspect, a composition is provided 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 the stable amorphous hybrid nanoparticles remains stable at at least about 90% after storage at room temperature for six months or more.

[0074] In other embodiments of this model, 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, 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, sediranib, fostamatinib, imatinib, lenvatinib, restaurtinib, motesanib, mbritinib, pegaptanib, ruxolitinib, semacsanib, sunitinib, tandunitib, tipifamib, and vandetanib; or a salt, hydrate, or solvate thereof, or a combination thereof.

[0075] In other embodiments of this model, the stable amorphous hybrid nanoparticles have an average particle size of less than 1000 nm, preferably less than 250 nm, such as less than 500 nm.

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

[0077] The composition of the present invention is soluble, and the protein kinase inhibitor can be absorbed systemically in typically approximately equal amounts, independent of the pH of the surrounding environment, particularly at gastric pH, such as about pH 1.2 to about pH 2.1, preferably about 1.7, and at intestinal pH, such as about pH 4.5 to about pH 8, preferably about 6. Systemic absorption means that the protein kinase inhibitor is released from stable amorphous hybrid nanoparticles and absorbed by the systemic bloodstream. Thus, in other embodiments of this aspect, a composition is provided in which the protein kinase inhibitor is absorbed systemically in an independent of pH. Typically, the protein kinase inhibitor is absorbed systemically 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] Approximately equal amounts mean that the concentrations of protein kinase inhibitors in the bloodstream after exposure are approximately similar. This can be expressed by a ratio in which the concentration of the protein kinase inhibitor in the bloodstream, measured after administration under gastric pH conditions (A), is compared to the concentration of the protein kinase inhibitor in the bloodstream, measured after administration under 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), maximum concentration (Cmax), or bioavailability between 0 and 24 hours.

[0079] Accordingly, in other embodiments of this model, a composition is provided comprising stable amorphous hybrid nanoparticles containing at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component, wherein the systemic absorption ratio of the protein kinase inhibitor under gastric pH conditions to the systemic absorption ratio of the protein kinase inhibitor under intestinal pH conditions is about 0.75:1 to about 1.5:1, preferably about 1:1 to about 1.25:1. Typically, the gastric pH condition represents a pH of about 1.4, and the intestinal pH condition represents a pH of about 6. Typically, the concentration is measured as the area under the curve (AUC) during 0 to 24 hours of exposure to the composition, or as the maximum concentration (Cmax).

[0080] The amount of protein kinase inhibitor absorbed throughout the body can be measured by various methods. Example 14 of this disclosure provides a method for measuring the amount of protein kinase inhibitor absorbed throughout the body at various pH levels, i.e., under both acidic and neutral conditions.

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

[0082] 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 a suitable solution for the in vitro dissolution test. It is essential that the in vitro test conditions closely mimic the in vivo environment, such as pH and osmotic pressure. Typically, in intestinal uptake, the pH is between 6 and 7. Therefore, the solution may maintain a pH of approximately 6 to 7, such as approximately pH 6.5.

[0083] Therefore, in embodiments of the present invention, the test solution has a pH ranging from approximately pH 4.5 to approximately pH 8, such as approximately pH 6.5 or approximately pH 5. The solution may be either fasting rectal fluid (FaSSIF) or feeding rectal fluid (FeSSIF).

[0084] Typically, in gastric uptake, the pH is between 1 and 2. Therefore, the solution can maintain a pH of approximately 1 to 2, such as approximately 1.4. Thus, in embodiments of the present invention, the test solution may be artificial gastric juice (SGF).

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

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

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

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

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

[0090] Controlling particle properties can be advantageous for specific applications. The selection and ratio of particle size, particle aggregation, particle porosity, and polymeric stabilizing matrix-forming agents can be altered to increase or decrease the particle surface area-to-volume ratio or the behavior of particles in gastrointestinal fluids, resulting in an increase or decrease in dissolution rate. Such particle properties can be adapted according to the desired dissolution characteristics. Furthermore, particles with different properties can be present in the same pharmaceutical composition to provide initial and long-term or delayed doses of the active ingredient. Additionally, it may be advantageous to provide different PKIs and / or other active ingredients(s) with different primary particles having different properties adapted to give each active ingredient(s) a desired dissolution rate.

[0091] Another embodiment of the present invention provides a pharmaceutical composition comprising stable amorphous hybrid nanoparticles. Such a composition may further comprise at least one pharmaceutically acceptable solubilizer. The solubilizer may exist separately from the stable amorphous hybrid nanoparticles in the composition (i.e., physically mixed with 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 a multi-layer dosage form, such as a laminated tablet or multilayer tablet, such that the hybrid nanoparticles are separated from the solubilizer. The solubilizer can be selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-α-tocopherolate polyethylene glycol 1000 succinate, and hydrogenated castor oil such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. The solubilizer may also be poloxamer.

[0092] In other embodiments of this model, 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 other embodiments of this model, 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 model, the inhibitor is nilotinib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate; and the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherolate polyethylene glycol 1000 succinate.

[0095] In other embodiments of this model, the inhibitor is erlotinib, and the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose acetate succinate.

[0096] In other embodiments of this model, the inhibitor is erlotinib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose acetate succinate; and the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherolate polyethylene glycol 1000 succinate.

[0097] In other embodiments of this model, the inhibitor is pazopanib; and the polymeric stabilizing matrix-forming component is polyvinylpyrrolidone.

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

[0099] In other embodiments of this model, the inhibitor is lapatinib; and the polymeric stabilizing matrix-forming component is hydroxypropylcellulose.

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

[0101] In other embodiments of this model, the inhibitor is gefitinib; and the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, or polyvinylpyrrolidone.

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

[0103] In other embodiments of this model, the inhibitor is dasatinib; and the polymeric stabilizing matrix-forming component is copolividone.

[0104] In other embodiments of this model, the inhibitor is dasatinib; the polymeric stabilizing matrix-forming component is copolividone; and the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0105] In other embodiments of this model, the inhibitor is sorafenib; and the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate.

[0106] In other embodiments of this model, the inhibitor is sorafenib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate; and the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0107] In other embodiments of this model, the inhibitor is a nilotinib base; and the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate.

[0108] In other embodiments of this model, the inhibitor is a nilotinib base; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate; and the solubilizer is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0109] In other embodiments of this model, the inhibitor is axitinib; and the polymeric stabilizing matrix-forming component is copovidone or hydroxypropyl methylcellulose acetate succinate.

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

[0111] In other embodiments of this model, the inhibitor is crizotinib; and the polymeric stabilizing matrix-forming component is copolyvidone or polyvinylpyrrolidone.

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

[0113] In other embodiments of this model, the inhibitor is vemurafenib; and the polymeric stabilizing matrix-forming component is copolividone or cellulose acetate phthalate.

[0114] In other embodiments of this model, the inhibitor is vemurafenib; the polymeric stabilizing matrix-forming component is copolyvidone or cellulose acetate phthalate; and the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.

[0115] In other embodiments of this model, 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, a stable amorphous hybrid nanoparticle is provided comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component as defined herein.

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

[0118] In another embodiment of this aspect, a composition of the present invention is provided for use in the treatment of proliferative disorders. Typically, the proliferative disorders include, but are not limited to, tumors and cancers such as neurofibromatosis, tuberous sclerosis, hemangiomas and lymphangiogenesis, cervical cancer, anal cancer, and oral cancer, eye or ocular cancer, gastric cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, head and neck cancer, pharyngeal cancer, cutaneous melanoma, acute lymphoblastic 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, and multiple myeloma; cardiac hypertrophy, age-related macular degeneration, and diabetic retinopathy.

[0119] In another embodiment of this aspect, a composition of the present invention is provided which is given during the intake of food.

[0120] In another embodiment of the present invention, a method is provided for treating a proliferative disorder in a patient requiring treatment, comprising administering a therapeutically effective amount of the composition of the present invention. The aforementioned proliferative disorders are typically selected from tumors and cancers including, but not limited to, neurofibromatosis, tuberous sclerosis, hemangiomas and lymphangiogenesis, cervical cancer, anal cancer, and oral cancer, eye or eye cancer, gastric cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, head and neck cancer, pharyngeal cancer, cutaneous melanoma, acute lymphoblastic 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, and multiple myeloma; cardiac hypertrophy, age-related macular degeneration, and diabetic retinopathy.

[0121] It will be recognized that the amount of protein kinase inhibitor in the stable amorphous hybrid nanoparticles of the present invention required for therapeutic use will vary depending not only on the specific inhibitor selected, but also on the route of administration, the nature of the condition requiring treatment, and the patient's age, weight, and condition, and ultimately on the judgment of the attending physician. However, generally, a suitable dose may be in the range of about 0.005 to about 30 mg per kg of body weight per day, preferably in the range of 0.05 to 10 mg / kg / day.

[0122] The desired dose may be expressed simply 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 need for treatment and / or prevention, the desired dose may be, for example, once every two days, once every three days, or even once a week.

[0123] The composition is conveniently administered in unit dosage forms containing, for example, 0.5 to 1500 mg, 1 to 1000 mg, or most conveniently, 5 to 700 mg of the active ingredient per unit dosage form. The composition of the present invention is usually administered orally, parenterally, intravenously, intramuscularly, subcutaneously, or by other injectable methods via buccal, rectal, vaginal, transdermal and / or intranasal routes, and / or by inhalation, in pharmaceutically acceptable dosage forms. Depending on the disease to be treated, the patient, and the route of administration, the composition may be administered in various dosages.

[0124] Pharmaceutical compositions may be suitable for oral, rectal, intranasal, topical (including buccal and sublingual), transdermal, vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or for administration by inhalation or inhalation. Compositions may be conveniently presented in individual dose units as needed and prepared by any method well known in the field of compounding. Pharmaceutical compositions suitable for oral administration may conveniently be presented in individual 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 binders, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated by methods well known in the art.

[0126] The composition can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in the form of dosing units such as ampoules, pre-filled syringes, small-volume injectors, or multi-dose containers with added preservatives. The composition may also take the form of suspensions, liquids, or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants.

[0127] The above-described composition can be modified to provide sustained release of the inhibitory agent.

[0128] The following examples are given to illustrate various embodiments of the present invention and are not intended to limit its scope. [Examples]

[0129] The following are some non-limiting examples of compositions containing stable amorphous hybrid nanoparticles. In the table, the following abbreviations apply to “composition.”

[0130] "I" stands for protein kinase inhibitor (PKI); "P" represents a polymeric stabilizing matrix-forming component; "S" represents a solubilizer; "I+P" represents a physical mixture of the inhibitor and the polymeric stabilizing matrix-forming component, i.e., without further processing; "I+S" represents a physical mixture of an inhibitor and a solubilizer; "I+P+S" represents a physical mixture of an inhibitor, a polymeric stabilizing matrix-forming component, and a solubilizer; "I / P" represents stable amorphous hybrid nanoparticles of an inhibitor and a polymeric stabilizing matrix-forming component; "I / P+S" refers to stable amorphous hybrid nanoparticles comprising an inhibitor and a polymeric stabilizing matrix-forming component, to which a solubilizer has been added separately. "I / P / S" represents a stable amorphous hybrid nanoparticle comprising an inhibitor, a polymeric stabilizing matrix-forming component, and a solubilizer. "Exp" represents the experiment number.

[0131] Stable amorphous hybrid nanoparticles were prepared using the exemplary PKI, polymeric stabilizing matrix-forming components ("polymers"), solubilizers, solution concentrations, ratios, solvents, reverse solvents, temperatures, and pressures shown in Table A below.

[0132] A 3-6% w / v PKI / polymer solution in a solvent, with a PKI / polymer ratio of approximately 20-70% w / w, was pumped at a flow rate of 1 ml / min using a high-performance liquid chromatography pump, along with a 100 g / min flow of CO2 (supercritical or subcritical), through an XSpray RightSize nozzle. The pressure in the precipitation chamber was set to approximately 100-175 bar, and the temperature to approximately 10-50°C. Both flows came into contact within the nozzle, forming hybrid nanoparticles, which were then recovered in the recovery chamber. The CO2 and solvent passed through the filtration system of the recovery chamber and were discharged through a back pressure adjustment outlet that maintained the pressure in the precipitation and recovery chambers. After pumping the PKI / polymer solution and flushing the piping with the same solvent used to prepare the PKI / polymer solution, any remaining solvent in both the precipitation and recovery chambers was removed by flushing these chambers with a large volume of pure scCO2. After the large volume flushing process, the CO2 was slowly discharged from the recovery chamber. Once the CO2 was completely removed, the particles attached to 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 and dissolved, and then the solution was pumped through a nozzle for precipitation using the method described above.

[0134] For I / P+S type particles, a defined amount of solubilizer is added to stable amorphous hybrid nanoparticles in a glass vial. The glass vial is slowly rotated to mix the solubilizer with the hybrid nanoparticles. TIFF2023123773000001.tif166161

[0135] General explanation of dissolution measurement tests The method involves adding a desired amount of stable amorphous hybrid nanoparticle powder to a glass vial, followed by the addition of a suitable medium (typically FaSSIF, FeSSIF, or SGF). The medium was prepared according to the manufacturer's instructions. The amount of powder added depends on the desired "total PKI concentration." In some experiments testing and comparing high drug-filled powders, the actual amount of PKI in the stable amorphous hybrid nanoparticles was not taken into account. In other experiments, the drug-filled amount was first estimated by HPLC, and the amount of powder needed to obtain the drug concentration was then calculated.

[0136] Typically, the powder was added to an 8 mL glass bottle, and 7 mL of solution was added (typically FaSSIF, FeSSIF, or SGF). The glass bottle was placed in a shaker (approximately one rotation per minute) to dissolve. 500 μl samples were taken at different time points and then centrifuged at approximately 15,000 g for 3 minutes. The resulting supernatant was then analyzed by HPLC (C 18 Column: Eclipse, 4.6 mm × 15 cm, 1 mL / min, detection range: 254–400 nM. Generally, samples were collected at 5, 30, and 90 minutes, and finally at 150 minutes.

[0137] Example 1. Composition containing stable amorphous hybrid nanoparticles with nilotinib - solubility at pH 6.5 and pH 5 Several experiments were conducted using nilotinib base or nilotinib HCl as an example of a protein kinase inhibitor. The experiments involved measuring the concentration (mg / L) of solubilized PKI at 5, 30, and 90 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Further experiments were conducted in another solution with a pH of approximately 5, i.e., FeSSIF (feeding artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of protein kinase inhibitor was measured using the dissolution measurement test described above.

[0138] Representative results in FaSSIF solution are given in Tables 1 and 2 below. Table 1 shows the concentration (mg / L) of nilotinib HCl at 5, 30, and 90 minutes after dissolution, and Table 2 shows the percentage of solubilized nilotinib HCl at 30 minutes after dissolution, the area under the curve (AUC-mg / min / L) at 90 minutes after dissolution, and the AUC increase of stable amorphous hybrid nanoparticles compared to untreated crystalline nilotinib HCl added to the solution (Experiments 1-40). Tables 3 and 4 show the dissolution data in FeSSIF solution, similar to Tables 1 and 2 (Experiments 41-55). Table 5 shows the data from comparative experiments using similar stable amorphous hybrid nanoparticles conducted with FaSSIF and FeSSIF, respectively (Experiments 56-57). Table 6 shows further comparative data of the experiments conducted with FaSSIF and FeSSIF, respectively. TIFF2023123773000002.tif37128TIFF2023123773000003.tif250128TIFF202 3123773000004.tif69128TIFF2023123773000005.tif172151TIFF20231237730 00006.tif250151TIFF2023123773000007.tif182161TIFF2023123773000008. tif195161TIFF2023123773000009.tif51161TIFF2023123773000010.tif86170

[0139] Conclusion of Example 1 Experiments 17-23 demonstrate that increased solubility can be obtained with compositions containing nilotinib HCl and stable amorphous hybrid nanoparticles formed by polymeric stabilizing matrix-forming components. Specific increases are achieved with polymeric stabilizing matrix-forming components, hydroxypropyl methylcellulose phthalate (HPMCP HP55), and polyvinyl acetate phthalate (PVAP). These improvements are not obtained when nilotinib HCl is physically mixed with the polymeric stabilizing matrix-forming components. Experiments 24-36 clearly demonstrate that further increases in solubility can be obtained with stable amorphous hybrid nanoparticles formed by nilotinib HCl and polymeric stabilizing matrix-forming components, with the addition of independent solubilizers. Specific improvements are achieved by the addition of independent solubilizers such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) or d-α-tocopherolate polyethylene glycol 1000 succinate (TPGS). These improvements were not obtained when nilotinib HCl, a solubilizer, and / or a polymeric stabilizing matrix-forming component were physically mixed (I+S or I+P+S). No particular improvements were obtained with stable amorphous hybrid nanoparticles (I / P / S) formed by nilotinib HCl, a polymeric stabilizing matrix-forming component, and a solubilizer.

[0140] The results obtained in FaSSIF and FeSSIF, respectively, demonstrate that the stable amorphous hybrid nanoparticles of the present invention provide a similar increase in solubility. One problem with PKI formulations is the effect of food. Despite the fact that food increases the bioavailability of PKIs in most cases, some PKIs are indicated to be administered on an empty stomach. Low bioavailability may partly explain the digestive problems associated with PKIs. The similar dissolution rates in FaSSIF and FeSSIF indicate that the stable amorphous hybrid nanoparticles of the present invention (e.g., Experiments 56 / 57) can reduce the effect of food and patient digestive problems due to their improved solubility, thereby allowing for dose reduction. Thus, the stable amorphous hybrid nanoparticles of the present invention can be administered together with food intake.

[0141] Example 2. Composition containing stable amorphous hybrid nanoparticles with erlotinib HCl - solubility at pH 6.5 and pH 5. Several experiments were conducted using erlotinib HCl as an example of a PKI. The experiments involved dissolving erlotinib HCl in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid), and measuring the PKI concentration (mg / L) at 5, 30, and 90 minutes. Furthermore, experiments were conducted in another solution with a pH of approximately 5, i.e., FeSSIF (feeding artificial intestinal 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.

[0142] Representative results in FaSSIF solution are given in Tables 7 and 8 below. Table 7 shows the concentration (mg / L) of erlotinib HCl after 5, 30, and 90 minutes of dissolution, and Table 8 shows the percentage of solubilized erlotinib HCl after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) after 90 minutes of dissolution, and the AUC increase of stable amorphous hybrid nanoparticles compared to untreated crystalline erlotinib HCl added to the solution (Experiments 58-68). Tables 9 and 10 show the dissolution data in FeSSIF solution, similar to Tables 7 and 8 (Experiments 69-73). Table 11 shows the data from comparative experiments using similar stable amorphous hybrid nanoparticles conducted with FaSSIF and FeSSIF, respectively (Experiments 74-83). Table 12 shows further comparative data from experiments conducted with FaSSIF and FeSSIF, respectively. TIFF2023123773000011.tif144161TIFF2023123773000012.tif152161TIFF2023123773000013.tif88161 TIFF2023123773000014.tif100161TIFF2023123773000015.tif182161TIFF2023123773000016.tif106161

[0143] Conclusion of Example 2 Experiments demonstrate that increased solubility can be obtained with compositions containing erlotinib HCl and stable amorphous hybrid nanoparticles with polymeric stabilizing matrix-forming components. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Experiments 65-66 and 72 demonstrate that further increases in solubility can be obtained with stable amorphous hybrid nanoparticles containing erlotinib HCl and polymeric stabilizing matrix-forming components when an independent solubilizer is added. This particular improvement is achieved by the addition of an independent solubilizer, in which case the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherolate polyethylene glycol 1000 succinate (TPGS). This improvement was not observed when the solubilizer was incorporated into stable amorphous hybrid nanoparticles.

[0144] Physical mixing of erlotinib HCl with a solubilizer and / or HPMC AS also improves solubility in FaSSIF (Experiments 59, 60-61, 62-63), but not in FeSSIF (Experiments 69-72). One problem with PKI formulations is the effect of food. Despite the fact that food increases the bioavailability of PKIs in most cases, some PKIs are indicated to be administered on an empty stomach. Low bioavailability may partly explain the digestive problems associated with PKIs. Data show that stable amorphous hybrid nanoparticles can reduce the effect of food and patient digestive problems (Experiments 76 / 77 and 82 / 83) with their equal solubility improvement in both FaSSIF and FeSSIF, and further potentially allow for dose reduction. Thus, compositions containing these stable amorphous hybrid nanoparticles can be administered with food intake.

[0145] Example 3. Composition containing stable amorphous hybrid nanoparticles including pazopanib - solubility at pH 6.5 and pH 5 Several experiments were conducted to demonstrate pazopanib as an example of a PKI. The experiments involved measuring the concentration of PKI (mg / L) after dissolution in a solution with approximately pH 6.5, i.e., FaSSIF (fasting artificial intestinal fluid), at 5, 30, and 90 minutes. Furthermore, experiments were conducted in another solution with approximately pH 5, i.e., FeSSIF (feeding artificial intestinal 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.

[0146] Representative results in FaSSIF solution are given in Tables 13 and 14 below. Table 13 shows the concentration (mg / L) of pazopanib after 5, 30, and 90 minutes of dissolution, and Table 14 shows the percentage of solubilized pazopanib after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) after 90 minutes of dissolution, and the AUC increase with stable amorphous hybrid nanoparticles compared to untreated crystalline pazopanib added to the solution (Experiments 84-93). Tables 15 and 16 show the dissolution data in FeSSIF solution, similar to Tables 13 and 14 (Experiments 94-101). Table 17 shows the data from comparative experiments with similar stable amorphous hybrid nanoparticles conducted in FaSSIF and FeSSIF, respectively (Experiments 102-109). Table 18 shows further comparative data from experiments with stable amorphous hybrid nanoparticles conducted in FaSSIF and FeSSIF, respectively. TIFF2023123773000017.tif146161TIFF2023123773000018.tif155161TIFF2023123773000019.tif125161 TIFF2023123773000020.tif133161TIFF2023123773000021.tif163161TIFF2023123773000022.tif169161

[0147] Conclusion of Example 3 Experiments demonstrate that increased solubility can be obtained with compositions containing pazopanib and stable amorphous hybrid nanoparticles with polymeric stabilizing matrix-forming components. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, polyvinylpyrrolidone K-90 (PVP 90K). Experiments 91-92 demonstrate that further increases in solubility can be obtained with stable amorphous hybrid nanoparticles containing pazopanib and polymeric stabilizing matrix-forming components when an independent solubilizer is added. This particular improvement is achieved by the addition of an independent solubilizer, in which case the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherolate 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 obtained in FaSSIF and FeSSIF, respectively, demonstrate that the stable amorphous hybrid nanoparticles of the present invention provide a similar increase in solubility. One problem with PKI formulations is the effect of food. Despite the fact that food increases the bioavailability of PKIs in most cases, some PKIs are indicated to be administered on an empty stomach. Low bioavailability may partly explain the digestive problems associated with PKIs. The similar dissolution rates in FaSSIF and FeSSIF indicate that the stable amorphous hybrid nanoparticles, with their equal increase in solubility in both FaSSIF and FeSSIF, can mitigate the effect of food and the digestive problems of patients (e.g., experiments 89 / 100 and 104 / 105), and further allow for dose reduction. Thus, the stable amorphous hybrid nanoparticles of the present invention can be administered with food intake.

[0149] Example 4. Composition containing stable amorphous hybrid nanoparticles with lapatinib - solubility at pH 6.5 Several experiments were conducted using lapatinib base or lapatinib tosylate as examples of PKIs. The experiments involved measuring the concentration (mg / L) of the PKI after 5, 30, and 90 minutes of dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0150] Representative results for the FaSSIF solution are shown in Tables 19 and 20 below. Table 19 shows the concentration (mg / L) of lapatinib after 5, 30, and 90 minutes of dissolution, while Table 20 shows the percentage of solubilized lapatinib after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) after 90 minutes of dissolution, and the AUC increase due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated lapatinib tosylate added to the solution (Experiments 110-126). TIFF2023123773000023.tif207161TIFF2023123773000024.tif214161

[0151] Conclusion of Example 4 Experiments 122-125 clearly demonstrate that increased solubility is obtained with the stable amorphous hybrid nanoparticles of the present invention by lapatinib, particularly lapatinib base and polymeric stabilizing matrix-forming components, when an independent solubilizer is added to the composition. Special improvements are achieved with the polymeric stabilizing matrix-forming components, hydroxypropylcellulose EF and hydroxypropylcellulose LF. Further improvements are achieved by the addition of an independent solubilizer, in which case the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherolic acid polyethylene glycol 1000 succinate (TPGS).

[0152] Example 5. Composition containing stable amorphous hybrid nanoparticles with nilotinib HCl - solubility at pH 1.4 Several experiments were conducted using nilotinib HCl as an example of a PKI. The experiments involved measuring the concentration of PKI (mg / L) after 5, 30, and 90 minutes of dissolution in a solution with a pH of approximately 1.4, i.e., SGF (artificial gastric juice). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0153] Representative results in SGF solution are given in Table 21 below, which shows the percentage of solubilized nilotinib HCl from both the physical mixture with untreated crystalline nilotinib HCl and the stable amorphous hybrid nanoparticles of the present invention after 5, 30, and 90 minutes after dissolution. Nilotinib present in a physical mixture of untreated nilotinib HCl, polymeric stabilizing matrix-forming component PVAP, and solubilizer Soluplus (Experiment 129) was completely dissolved in SGF within 5 minutes, whereas nilotinib in the stable amorphous hybrid nanoparticles of the present invention was only partially dissolved in SGF after 90 minutes, where the component consists of stable amorphous hybrid nanoparticles with or without a solubilizer (Experiment 127). TIFF2023123773000025.tif79161

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

[0155] Example 6. Composition containing stable amorphous hybrid nanoparticles with gefitinib - solubility at pH 6.5 Several experiments were conducted to demonstrate gefitinib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0156] Representative results in the FaSSIF solution are shown in Tables 22 and 23 below. Table 22 shows the concentration (mg / L) of gefitinib at 3, 40, and 80 minutes after dissolution, while Table 23 shows the percentage of solubilized gefitinib at 40 minutes after dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the AUC increase due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated gefitinib added to the solution (Experiments 131-137). TIFF2023123773000026.tif109161TIFF2023123773000027.tif115161

[0157] Experiments 131-137 demonstrate that increased solubility can be achieved with compositions containing the stable amorphous hybrid nanoparticles of the present invention, particularly with gefitinib and polymeric stabilizing matrix-forming components, when independent solubilizers are added to the composition. Special improvements are achieved with polymeric stabilizing matrix-forming components, polyvinylpyrrolidone K-30 (PVP 30K) and hydroxypropyl methylcellulose phthalate (HPMCP HP55). Further improvements are achieved by the addition of independent solubilizers, in which case the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0158] Example 7. Composition containing stable amorphous hybrid nanoparticles with dasatinib - solubility at pH 6.5 Several experiments were conducted to demonstrate dasatinib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI at 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined using the dissolution measurement test described above.

[0159] Representative results in the FaSSIF solution are given in Tables 24 and 25. Table 24 shows the concentration (mg / L) of dasatinib after 3, 40, and 80 minutes of dissolution, while Table 25 shows the percentage of solubilized dasatinib after 40 minutes of dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the AUC increase due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated dasatinib added to the solution (Experiments 138-141). TIFF2023123773000028.tif88161TIFF2023123773000029.tif88161

[0160] Experiments 138-141 demonstrate that increased solubility can be achieved with compositions containing the stable amorphous hybrid nanoparticles of the present invention, particularly with dasatinib, and especially with dasatinib and polymeric stabilizing matrix-forming components, when an independent solubilizer is added to the composition. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, copolyvidone (Kollidon VA64). Further improvements can be achieved by adding an independent solubilizer, in which case the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0161] Example 8. Composition containing stable amorphous hybrid nanoparticles including sorafenib tosylate - solubility at pH 6.5 Several experiments were conducted using sorafenib tosylate as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI at 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0162] Representative results for the FaSSIF solution are given in Tables 26 and 27 below. Table 26 shows the concentration (mg / L) of sorafenib after 3, 40, and 80 minutes of dissolution, while Table 27 shows the percentage of solubilized sorafenib after 40 minutes of dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the AUC increase of the composition compared to unformulated sorafenib tosylate added to the solution (Experiments 142-145). TIFF2023123773000030.tif97161TIFF2023123773000031.tif106161

[0163] Experiments 138-141 demonstrate that increased solubility can be achieved with compositions comprising dasatinib, particularly dasatinib and polymeric stabilizing matrix-forming components, of the present invention, when an independent solubilizer is added to the composition. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, hydroxypropyl methylcellulose phthalate (HPMCP HP55). Further improvements can be achieved by adding an independent solubilizer, in which case the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0164] Example 9. Composition containing stable amorphous hybrid nanoparticles with nilotinib base - solubility at pH 6.5 Several experiments were conducted using nilotinib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI after 3, 40, and 80 minutes of dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0165] Representative results for the FaSSIF solution are shown in Tables 28 and 29 below. Table 28 provides data on the concentration (mg / L) of nilotinib base after 3, 40, and 80 minutes of dissolution, while Table 29 provides data on the percentage of solubilized nilotinib base after 40 minutes of dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the increase in AUC of the composition compared to the unformulated nilotinib base added to the solution (Experiments 146-149). TIFF2023123773000032.tif80161TIFF2023123773000033.tif88161

[0166] Example 10. Composition containing stable amorphous hybrid nanoparticles with crizotinib - solubility at pH 6.5 Several experiments were conducted using crizotinib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI at 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above. Representative results in the FaSSIF solution are shown in Tables 30 and 31 below. Table 30 shows the data for the concentration (mg / L) of crizotinib at 3, 40, and 80 minutes after dissolution, and Table 31 shows the percentage of solubilized crizotinib at 40 minutes after dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the data for the increase in AUC due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated crizotinib added to the solution (Experiments 150-156). TIFF2023123773000034.tif121161TIFF2023123773000035.tif125161

[0167] Experiments 150-156 demonstrate that increased solubility can be obtained with compositions containing the stable amorphous hybrid nanoparticles of the present invention, particularly with crizotinib and polymeric stabilizing matrix-forming components, when an independent solubilizer is added to the composition. Special improvements are achieved with polymeric stabilizing matrix-forming components, polyvinylpyrrolidone K-30 (PVP 30K) and copolyvidone (Kollidon VA64). Further improvements can be achieved by adding an independent solubilizer, in which case the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and PEG-40 hydrogenated castor oil (Cremophor RH40).

[0168] Example 11. Composition containing stable amorphous hybrid nanoparticles with axitinib - solubility at pH 6.5 Several experiments were conducted using axitinib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI at 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above. Representative results in the FaSSIF solution are shown in Tables 32 and 33 below. Table 32 shows the concentration (mg / L) of axitinib at 3, 40, and 80 minutes after dissolution, and Table 33 shows the percentage of solubilized axitinib at 40 minutes after dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the AUC increase due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated axitinib added to the solution (Experiments 157-163). TIFF2023123773000036.tif110161TIFF2023123773000037.tif121161

[0169] Experiments 157-163 demonstrate that increased solubility can be achieved with compositions containing axitinib, particularly axitinib and polymeric stabilizing matrix-forming components, of the present invention, when an independent solubilizer is added to the composition. Special improvements are achieved with polymeric stabilizing matrix-forming components, copolyvidone (Kollidon VA64) and hydroxypropyl methylcellulose acetate succinate (HPMC AS). Further improvements are achieved by the addition of an independent solubilizer, in which case the solubilizer is 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 conducted using vemurafenib as an example of a PKI. The experiments involved measuring the concentration (mg / L) of PKI at 3, 40, and 80 minutes after dissolution in a solution with a pH of approximately 6.5, i.e., FaSSIF (fasting artificial intestinal fluid). Samples of the solution were taken at various time intervals, and the amount of PKI was determined by the dissolution measurement test described above.

[0171] Representative results in the FaSSIF solution are shown in Tables 34 and 35 below. Table 34 provides data on the concentration (mg / L) of vemurafenib at 3, 40, and 80 minutes after dissolution, while Table 35 provides data on the percentage of solubilized vemurafenib at 40 minutes after dissolution, the area under the curve (AUC-mg / min / L) during dissolution at 80 minutes, and the increase in AUC due to the stable amorphous hybrid nanoparticles of the present invention compared to unformulated vemurafenib added to the solution (Experiments 164-170). TIFF2023123773000038.tif113161TIFF2023123773000039.tif117161

[0172] Experiments 164-170 demonstrate that increased solubility can be obtained with vemurafenib, particularly with compositions containing vemurafenib and polymeric stabilizing matrix-forming components of the present invention, when independent solubilizers are added to the composition. Special improvements are achieved with polymeric stabilizing matrix-forming components, copolyvidone (Kollidon VA64) and cellulose acetate phthalate (CAP). Further improvements are achieved by the addition of independent solubilizers, in which case the solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0173] Example 13. Measurement of the dissolution rate of the composition of the present invention under sink conditions. The dissolution of the composition of the present invention under sink conditions was measured by adding a desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), attaching the cell to the apparatus, and then passing a suitable medium (typically FaSSIF, FeSSIF, or SGF) through the powder using a pump. The temperature of the apparatus was set to 37°C. The amount of powder added to the cell depends on the drug content of the powder. The exact amount of powder was calculated from the results obtained from the drug content analysis of the powder.

[0174] Typically, 3.5 to 7 mg of PKI was added to a flow-through cell, and the powder was passed through it by pump at a flow rate of 8 to 16 ml of medium / min (preferably about 8 ml of medium / min). A 1 ml sample of the medium passing through the cell was collected at predetermined times. These samples were analyzed by HPLC (e.g., C18 column Eclipse, 4.6 mm × 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 exited the flow-through cell. The cumulative percentage of solubilized active substance added to the flow-through cell was calculated and plotted against time (minutes). The initial slope of the graph measured from 0 to 10 minutes ("initial dissolution rate") was estimated and adopted as the dissolution rate of the substance in a given dissolution medium under sink conditions of 37°C.

[0175] Each experiment involves comparing the untreated form of PKI with compositions containing the stable amorphous hybrid particles of the present invention, which include inhibitors and representative polymeric stabilizing matrix-forming components.

[0176] Example 13.1. Measurement of the dissolution rate of the composition of the present invention containing nilotinib HCl under sink conditions In experiments using nilotinib HCl, 4 mg was weighed in a flow-through cell (Experiment 500) and compared with the stable amorphous hybrid nanoparticles of the present invention (Experiment 501) using nilotinib base and the polymeric stabilizing matrix-forming component HPMCP HP55. The results are shown in Table 36 below. TIFF2023123773000040.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 untreated crystalline nilotinib HCl.

[0178] Example 13.2. Measurement of the dissolution rate of the composition of the present invention containing erlotinib HCl under sink conditions In the experiment using erlotinib HCl, 3.5 mg was weighed in a flow-through cell (Experiment 510) and compared with the stable amorphous hybrid nanoparticles of the present invention using erlotinib HCl and the polymeric stabilizing matrix-forming component HPMC AS (Experiment 511). The results are shown in Table 37 below. TIFF2023123773000041.tif184161

[0179] Experiments 510-511 demonstrate that the initial dissolution rate of the composition containing the stable amorphous hybrid nanoparticles of the present invention, with erlotinib HCl and the polymeric stabilizing matrix-forming component HPMC AS, is superior to the initial dissolution rate of untreated erlotinib HCl in its crystalline form.

[0180] Example 13.3. Measurement of the dissolution rate of the composition of the present invention containing pazopanib HCl under sink conditions In the experiment using pazopanib HCl, 3.5 mg was weighed in a flow-through cell (Experiment 520) and compared with the stable amorphous hybrid nanoparticles of the present invention using pazopanib HCl and the polymeric stabilizing matrix-forming component PVP90K (Experiment 521). The results are shown in Table 38 below. TIFF2023123773000042.tif179161

[0181] Experiments 520-521 demonstrate that the initial dissolution rate of the composition containing stable amorphous hybrid nanoparticles of the present invention, mediated by pazopanib HCl and the polymeric stabilizing matrix-forming component PVP90K, is superior to that of untreated crystalline pazopanib HCl.

[0182] Example 13.4. Measurement of the dissolution rate of the composition of the present invention containing lapatinib tosylate under sink conditions In experiments using lapatinib tosylate, 4 mg was weighed in a flow-through cell (Experiment 530) and compared with the stable amorphous hybrid nanoparticles of the present invention (Experiment 531) formed by lapatinib base and polymeric stabilizing matrix-forming component HPC lf. The results are shown in Table 39 below. TIFF2023123773000043.tif181161

[0183] Experiments 530-531 demonstrate that the initial dissolution rate of the composition containing the stable amorphous hybrid nanoparticles of the present invention, mediated by lapatinib base and polymeric stabilizing matrix-forming component HPC lf, is superior to the initial dissolution rate of untreated crystalline lapatinib tosylate.

[0184] Example 13.5. Measurement of the dissolution rate of the composition of the present invention containing gefitinib under sink conditions In the gefitinib experiment, 3.5 mg was weighed in a flow-through cell (Experiment 540) and compared with the stable amorphous hybrid nanoparticles of the present invention formed by gefitinib and the polymeric stabilizing matrix-forming component HPMCP HP55 (Experiment 541). The results are shown in Table 40 below. TIFF2023123773000044.tif181161

[0185] Experiments 540-541 demonstrate that the initial dissolution rate of the composition containing the stable amorphous hybrid nanoparticles of the present invention, mediated by gefitinib and the polymeric stabilizing matrix-forming component HPMCP HP55, is superior to that of untreated crystalline gefitinib.

[0186] Example 13.6. Measurement of the dissolution rate of the composition of the present invention containing dasatinib under sink conditions In the dasatinib experiment, 3.5 mg was weighed in a flow-through cell (Experiment 550) and compared with the stable amorphous hybrid nanoparticles of the present invention (Experiment 551) formed by dasatinib and the polymeric stabilizing matrix-forming component copolividone-Kollidon VA64. The results are shown in Table 41 below. TIFF2023123773000045.tif183161

[0187] Experiments 550-551 demonstrate that the initial dissolution rate of compositions containing the stable amorphous hybrid of the present invention, comprising dasatinib and the polymeric stabilizing matrix-forming component copolividone (Kollidon VA64), is superior to that of untreated crystalline dasatinib.

[0188] Example 13.7. Measurement of the dissolution rate of the composition of the present invention containing sorafenib tosylate under sink conditions In the experiment using sorafenib tosylate, 3.5 mg was weighed in a flow-through cell (Experiment 560) and compared with the stable amorphous hybrid nanoparticles of the present invention using sorafenib tosylate and the polymeric stabilizing matrix-forming component HPMCP HP55 (Experiment 561). The results are shown in Table 42 below. TIFF2023123773000046.tif182161

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

[0190] Example 13.8. Measurement of the dissolution rate of the composition of the present invention containing crizotinib under sink conditions In the experiment using crizotinib, 3.5 mg was weighed in a flow-through cell (Experiment 570) and compared with the stable amorphous hybrid nanoparticles of the present invention using crizotinib and the polymeric stabilizing matrix-forming component PVP 30K (Experiment 571). The results are shown in Table 43 below. TIFF2023123773000047.tif146161

[0191] Experiments 570-571 demonstrate that the initial dissolution rate of the composition containing stable amorphous hybrid nanoparticles of the present invention, crizotinib and the polymeric stabilizing matrix-forming component PVP 30K, is superior to the initial dissolution rate of untreated crystalline crizotinib.

[0192] Example 13.9. Measurement of the dissolution rate of the composition of the present invention containing axitinib under sink conditions In the axitinib experiment, 3.5 mg was weighed in a flow-through cell (Experiment 580) and compared with the stable amorphous hybrid nanoparticles of the present invention, which consist of axitinib and the polymeric stabilizing matrix-forming component Kollidon VA64 (Experiment 581) or HPMC AS (Experiment 582). The results are shown in Table 44 below. TIFF2023123773000048.tif151161

[0193] Experiments 580-582 demonstrate that the initial dissolution rate of the composition containing axitinib and the polymeric stabilizing matrix-forming component Kollidon VA64 or HPMC AS is superior to that of the untreated crystalline form of axitinib.

[0194] Example 13.10. Measurement of the dissolution rate of the composition of the present invention containing vemurafenib under sink conditions In the vemurafenib experiment, 3.5 mg was weighed in a flow-through cell (Experiment 590) and compared with the stable amorphous hybrid nanoparticles of the present invention, which were formed using vemurafenib and the polymeric stabilizing matrix-forming component Kollidon VA64 (Experiment 591) or CAP (Experiment 592). The results are shown in Table 45 below. TIFF2023123773000049.tif148161

[0195] Experiments 590-592 clearly demonstrate that the initial dissolution rate of the composition containing vemurafenib and the polymeric stabilizing matrix-forming component Kollidon VA64 or CAP is superior to that of the untreated crystalline form of vemurafenib.

[0196] Example 14. In vivo measurement of plasma levels after oral administration of the composition of the present invention. Several groups of four beagle dogs were administered a single oral dose (5 mg / kg) of a capsule composition containing nilotinib base and either PVAP or HPMCP HP55, a polymeric stabilizing matrix-forming component, to either a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (optionally added as a solubilizer), and compared to a commercially available formulation containing nilotinib HCl. The tested stable amorphous hybrid nanoparticles are described in Experiments 146-149 of Example 9. The stomach contents of the dogs were neutralized with sodium bicarbonate solution 5 minutes before capsule administration or acidified with an HCl-KCl buffer 10 minutes before administration. One group of dogs also received a single intravenous dose of nilotinib (1 mg / kg). Plasma levels of nilotinib were determined by selective LC-MS / MS. No adverse reactions were observed in any of the tested animals.

[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 according to the Grubbs test based on whether a value was a significant outlier from the others within a 95% confidence interval (α=5%). For n=4, the rejection limit Z for the Grubbs test in the 95% confidence interval is 1.48. Z = (mean - questionable value) / SD TIFF2023123773000050.tif71161

[0199] The T2500- 1 / 2 Since only two values ​​were obtained, we will treat them as an exception and express the values ​​as mean ± standard deviation.

[0200] Intravenous (IV) data were obtained by intravenously injecting a 0.2 mg / mL nilotinib solution in 10% HPβCD adjusted to pH 3.3 to 3.5 at a constant rate of 1 mg / kg. Co: 511±46 ng / mL;T 1 / 2: 3.3 ± 1.8 hours; AUC 0-24 hours: 1000 ± 300 ng* hours / mL. TIFF2023123773000051.tif75161

[0201] Values ​​are given as mean ± SD. Intravenous (IV) data were obtained by intravenously injecting a 0.2 mg / mL nilotinib solution in 10% HPβCD adjusted to pH 3.3 to 3.5 at a constant rate of 1 mg / kg. Co: 511 ± 46 ng / mL;T 1 / 2 : 3.3 ± 1.8 hours; AUC 0-24 hours: 1000 ± 300 ng* hours / mL.

[0202] Commercial nilotinib formulations administered to an acidified stomach showed approximately twice the plasma level compared to the same formulation administered to a neutralized stomach. Both formulations of the present invention, containing nilotinib base and PVAP and HPMCP HP55 as polymeric stabilizing matrix-forming components, showed a significant improvement in plasma exposure, reaching approximately twice the plasma level of the commercial formulations administered to an acidified stomach. Furthermore, combining the stable amorphous hybrid nanoparticles produced by the method of the present invention may provide plasma exposure that is, to varying degrees, independent of gastric pH.

[0203] Further improvements in oral availability were observed when the formulation of the present invention, comprising stable amorphous hybrid nanoparticles, was combined with the solubilizer polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer. Thus, compositions of the present invention comprising nilotinib base and PVAP and HPMCP HP55 as polymeric stabilizing matrix-forming components, to which the solubilizer polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer was added, and administered to an acidified stomach, resulted in plasma levels 2.3 to 3.1 times higher than those of commercially available formulations. In this study, high oral bioavailability was achieved when the stable amorphous hybrid nanoparticles of the present invention, comprising nilotinib base and HPMCP HP55 as a polymeric stabilizing matrix-forming component, to which the solubilizer polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer was added (I / P+S) and administered to neutralized stomach contents. In this study, exposure was approximately seven times higher than that of a commercially available 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 the present invention, with nilotinib base and PVAP as a polymeric stabilizing matrix-forming component, were administered to a neutralized stomach. However, this study also had the highest standard deviation.

[0204] The in vivo performance of the composition of the present invention, using nilotinib-stable amorphous hybrid nanoparticles, was improved based on enhanced absorption and bioavailability through optimization of the physical properties of the dosage form. Since there appears to be a close relationship between the drug absorption processes in the gastrointestinal tract of dogs and humans (Persson, EMet al. Pharm.Res. 2005, 22, 2141-2151), similar absorption of the stable amorphous hybrid nanoparticles of the present invention in patients can be predicted based on the results of in vivo studies in dogs. The advantageous absorption of the stable amorphous hybrid nanoparticles of the present invention also suggests that oral dosages currently used in clinical practice may be reduced. Furthermore, the stable amorphous hybrid nanoparticles of the present invention may reduce pH dependence in the absorption and bioavailability of PKIs.

[0205] Example 15. Measurement of the degree / level of stability of the composition using the hybrid nanoparticles of the present invention. In stability tests of compositions containing the hybrid nanoparticles of the present invention, the dissolution rate was measured by X-ray powder diffraction and AUC, demonstrating that the particles are stable at room temperature (18-25°C) for at least 11 months.

[0206] In a series of experiments using stable amorphous hybrid nanoparticles prepared by the present invention method containing nilotinib and HPMCP HP55, the resulting particles yielded stable amorphous hybrid nanoparticles with a drug-filled content of 40%, as measured by dissolution rates using XRPD and AUC (I / P nilotinib base / HPMCP HP55: Experiment 146). The material exhibited a single glass transition temperature at approximately 127°C, but it showed a single amorphous phase with intrinsic stability. Partially crystalline batches also showed similar intrinsic stability. Storage of partially crystalline hybrid nanoparticles, I / P nilotinib base / HPMCP HP55, with a drug-filled content of 40% for 6 months at room temperature (18-25°C) showed no signs of physical instability whatsoever.

[0207] Thermogravimetric analysis showed a 1.7% mass loss at 120°C above ambient temperature.

[0208] Dynamic water vapor absorption analysis at 25°C showed a relative mass increase of approximately 7% from 0 to 90% RH (three cycles from 0 to 90% RH were performed, but no phase change occurred).

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

[0210] Modulated differential scanning calorimetry (mDSC) Modulated differential scanning calorimetry (mDSC) analysis was performed on a TA Instruments Q200 (New Castle, USA) equipped with an RC90 refrigeration 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 amplitude of 1°C and modulation period of 40 seconds. Ultra-high purity nitrogen was used as a purge gas at a flow rate of 50 mL / min. All data analysis was performed using TA Universal Analysis software, version 4.7A. Cell constants and temperature calibration were performed using indium standards before instrument operation. DSC results were evaluated in terms of both forward and reverse components of the heat flow.

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

[0212] Dynamic water vapor sorption (DVS) The hygroscopicity of the samples was tested by dynamic water vapor sorbent gravimetric analysis (DVS) using a DVS-1 (Surface Measurement Ltd., UK). Approximately 10 mg of the substance was weighed into a glass cup. The relative weight was recorded at 20-second intervals as the target relative humidity (RH) on the sample increased stepwise from 0% to 90% at 10% RH per step, and then similarly decreased to 0% RH. Each sample was tested for three consecutive complete cycles. The condition for advancing to the next level of RH was a weight change of less than 0.002% within 15 minutes, with a maximum total time of 24 hours per step. Due to the slow equilibrium in this type of experiment, the obtained numbers should be considered a conservative estimate of water absorption. The temperature was maintained at 25°C.

[0213] X-ray powder diffraction (XRPD) XRD experiments were performed using an X'Pert Pro diffractometer (PANanalytical, Almelo, Netherlands) configured as a Bragg-Brentano type. The diffractometer was equipped with a 20 μm nickel filter and an X'Celerator RTMS detector with an active length of 2.122°²θ. A representative sample was placed on a zero-background quartz single crystal sample support (Siltronix, Archamps, France). The experiment was conducted at ambient temperature and humidity using Cu Kα radiation (45 kV and 40 mA). Scanning was performed in continuous mode, in the 2θ range of 4.5 to 40°, using an auto-divergence slit and a scattering prevention slit, with an observed length of 10 mm, a common counting time of 299.72 seconds, and a step size of 0.0167°²θ. Data collection was performed using application software, X'Pert Data Collector V.2.2j, and device 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, and Netherlands).

[0214] Dissolution rate measured by AUC Stable hybrid nanoparticles (I / P) described in Experiments 171 and 172 below were prepared according to Experiment 148 using nilotinib base, HPMCP HP55, and stored at room temperature for 11 months. Non-sink dissolution rates were tested at different time points, and the results are shown in Table 47 and Figure 26. Solubility was increased by adding polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer. A comparison of AUC over 80 minutes clearly showed that the particle dissolution rate profile had not changed practically after 11 months of storage; for example, the ratio of AUC of the prepared and tested particles to that of the prepared and tested particles stored for 11 months was over 97%. TIFF2023123773000052.tif61161

Claims

1. A tablet, comprising: (a) particles comprising (i) amorphous dasatinib and (ii) a copolymer of methacrylic acid and ethyl acrylate, copolyvidone, or a combination thereof, wherein the particles do not contain a pharma- ceutically acceptable solubilizer; and (b) one or more excipients tablets,

2. The tablet of claim 1, wherein the dasatinib is present in an amount of 10% to 70% by weight of the particles.

3. The tablet of claim 1, wherein the dasatinib is present in an amount of 5% to 50% by weight of the particles.

4. The tablet of claim 1, wherein the dasatinib is present in an amount of 10% to 50% by weight of the particles.

5. The tablet of claim 1, wherein the amorphous dasatinib comprises dasatinib, a dasatinib salt, a dasatinib hydrate, a dasatinib solvate, or a combination thereof.

6. The tablet of claim 1, wherein the amorphous dasatinib contains dasatinib.

7. The tablet of claim 1, comprising a copolymer of methacrylic acid and ethyl acrylate.

8. The tablet of claim 7, wherein the dasatinib is present in an amount of 10% to 70% by weight of the particles.

9. The tablet of claim 7, wherein the dasatinib is present in an amount of 5% to 50% by weight of the particles.

10. The tablet of claim 7, wherein the dasatinib is present in an amount of 10% to 50% by weight of the particles.

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