ES2854751T3 - A process for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component - Google Patents

Abstract

Process for producing stable amorphous solid dispersion particles comprising a protein kinase inhibitor selected from dasatinib, a salt of dasatinib, a hydrate of dasatinib, a solvate of dasatinib or a combination thereof and at least one stabilizing polymer component and matrix former, said solid dispersion particles have an amorphous degree of 100%, the process comprises ** (See formula) ** a) providing a first pressurized stream of said protein kinase inhibitor dissolved in a solvent; b) providing a second pressurized antisolvent stream comprising a supercritical or subcritical CO2 fluid, wherein said at least one matrix-forming and stabilizing polymer component is present in said first or second stream; and c) mixing said first and second streams, and spraying the mixed stream at the outlet of a nozzle, thereby forming said solid dispersion particles; followed by collecting said solid dispersion particles.

Description

DESCRIPTION

A process for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component

Field of the invention

The present invention relates to the field of processes for providing components of pharmaceutical compositions comprising drugs that are poorly soluble in water. In particular, the present invention relates to processes for providing hybrid protein kinase inhibitor (IPC) nanoparticles, to increase the dissolution rate and the resulting bioavailability of said IPCs, useful in pharmaceutical compositions. Background of the invention

Components of cellular signal transduction pathways that regulate the growth and differentiation of normal cells can, when deregulated, lead to the development of cancer and cell proliferative disorders. Mutations in cell signaling proteins can cause these proteins to be expressed or activated at inappropriate levels or at inappropriate times during the cell cycle, which in turn can lead to uncontrolled cell growth or changes in cell binding properties. -cell.

Many proliferative disorders, such as tumors and cancers, have been shown to be involved in the overexpression or up-regulation of protein kinase activity. Protein kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). In general, phosphorylation results in a functional change of the target protein by changing enzymatic activity, cell location, or association with other proteins. The amino acids of the target protein can subdivide or characterize protein kinases, whose phosphorylation they control: most kinases act on both serine and threonine, tyrosine kinases act on tyrosine, and a number (double specificity kinases) act about three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues. The human genome contains approximately 500 protein kinase genes, and protein kinases can modify up to 30% of all human proteins. Kinases are known to regulate most cellular pathways, especially those involved in signal transduction. Dysregulation of protein kinases by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated in the development and progression of cancers in humans. Protein kinase inhibitor compounds or protein kinase inhibitors (IPCs) are therefore useful for treating diseases caused or aggravated by overexpression or upregulation of protein kinases. For example, tyrosine kinase inhibitors (ITCs also known as thyphostins) have been shown to be effective antitumor and antileukemic agents (Lowery A et al., Front Biosci. 2011 Jun 1; 17: 1996-2007).

A primary goal of formulation chemistry is to improve drug efficacy and safety, for example, by improving bioavailability and stability, as well as patient comfort. Bioavailability means the rate and degree to which an active or therapeutic substance is absorbed from a pharmaceutical form and becomes available at the site of action. The most common and preferred method of administration due to its comfort, ease of ingestion, and high patient compliance with treatment is the oral route of drug administration. However, for certain drugs, absorption of the drug from the gastrointestinal tract is limited by poor water solubility and / or poor membrane permeability of drug molecules.

In general, IPCs are weak bases that dissolve only slightly at low pH (eg 100-1000 mg / l) and are practically insoluble at neutral pH (eg 0.1-10 mg / l). Therefore, it is important to improve the solubility and dissolution rate of IPC-based drugs to improve the bioavailability and efficacy of most of these drugs. Typical IPCs exhibit a non-polypeptide structure and have relatively low molecular weights, such as <10,000 daltons or <5,000 daltons.

Various methods for improving dissolution characteristics of poorly water soluble drugs have been documented, including micronization, salt or solvate formation, complexes, and microspheres. Additionally, attempts have been made to improve the bioavailability provided by solid dosage forms by forming particles comprising the drug or by mixing the poorly water soluble drug with hydrophilic excipients. However, traditionally, these processes carry inherent limitations with respect to the physical stability of the particles during storage, grinding problems, or difficulty in removing the frequently toxic solvent. Furthermore, it is important that the drug released from the solid phase does not precipitate in the gastrointestinal tract, or that it precipitates as little as possible, but remains soluble in water in the aqueous fluids of the gastrointestinal tract, since such precipitation leads to a low bioavailability (see, for example, Herve J. et al., Pharm Dev Technol. 2011 Jun; 16 (3): 278-86).

PH-dependent solubility is a well-known problem for many oral formulations of poorly water-soluble substances, such as IPCs, since most of the absorption of the drug occurs in the small and large intestine, where the pH is found. close to neutral. Therefore, there is a continuing need for develop and improve the dissolution characteristics of oral solid galenic forms of IPC-based drugs. (Budha ^{n R,} Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, Holden SN, Benet LZ, Ware JA. Clin Pharmacol Ther. 2012 Aug; 92 (2): 203-13). Therefore, methods for improving dissolution of IPC-based drugs, as well as other poorly water-soluble drugs, at neutral (intestinal) pH are highly desirable. Document US20090203709 describes 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 describes processes for preparing the aforementioned pharmaceutical dosage form, which comprise preparing the homogeneous orodispersible tablet of at least one tyrosine kinase inhibitor, at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable solubilizer, and allowing the solidify orodispersible tablet to obtain a solid dispersion product.

EP2105130 describes pharmaceutical formulations comprising a solid dispersion or a solid solution, containing a polymer and an active agent in amorphous form. Furthermore, the formulation comprises an external polymer to stabilize the solution, so that the% by weight of the external polymer is less than 20% of the total weight of the pharmaceutical formulation. Additionally, the reference describes a hot melt extrusion process for the production of the aforementioned formulation. Other relevant prior techniques include WO 2008/008733 A2, WO 2008/055966 A1, WO 2011/159218 A1, WO 2007/133750 A2, WO 2009/072953 A1 and ARASALI SULAIMAN ZARENA et al.,: "Design of submicron and nanoparticle delivery systems using supercritical carbon dioxide-mediated processes: an overview ", THERAPEUTIC DELIVERY, vol. 2, no. 2, 1 February 2011.

Summary of the invention

The present invention relates to processes for producing stable amorphous hybrid nanoparticles comprising dasatinib as a protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component. Optionally, one or more solubilizers may be added to the particles, present separately from the particles or within the particles.

Brief description of the drawings

Figure 1 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising nilotinib HCl produced by the methods of the invention. In Example 1, additional experimentation with both nilotinib base and nilotinib HCl is found. Details of the particles are described in Example 1, Table 1, for Experiments 3, 30, and 37, respectively. Briefly, experiment 30 represents hybrid nanoparticles comprising nilotinib HCl and HPMCP HP55 and where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately with respect to the hybrid nanoparticles. Experiment 3 represents crude crystalline nilotinib HCl and experiment 37 represents hybrid nanoparticles of nilotinib HCl, HpMCP HP55 and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, present within the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.

Figure 2 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising erlotinib produced by the methods of the invention. In Example 2, you will find additional experimentation with erlotinib. The details of the hybrid nanoparticles are described in Example 2, Table 7, for experiments 58, 65 and 67, respectively. Briefly, experiment 65 represents hybrid nanoparticles with erlotinib HCl and HPMCP-AS, where the solubilizing polyvinyl caprolactamaacetate polyvinyl polyethylene glycol copolymer is present separately with respect to the hybrid nanoparticles. Experiment 58 represents crude crystalline erlotinib HCl and experiment 67 represents hybrid nanoparticles of erlotinib HCl, HPMCP-AS and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, present within the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 3 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising pazopanib produced by the methods of the invention. In Example 3, additional experimentation with pazopanib is found. The details of the hybrid nanoparticles are described in Example 3, Table 13, for experiments 84, 91 and 93, respectively. In a nutshell, experiment 91 represents hybrid nanoparticles comprising pazopanib and PVP 90K and where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately with respect to hybrid nanoparticles, experiment 93 represents hybrid nanoparticles comprising pazopanib , PVP 90K and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, present within the hybrid nanoparticles. Experiment 84 represents crude crystalline pazopanib. The experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.

Figure 4 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising lapatinib base produced by the methods of the invention. In Example 4, additional experimentation with both lapatinib base and lapatinib ditosylate salt is found. The details of the hybrid nanoparticles are described in Example 4, Table 19, for experiments 110, 122 and 126, respectively. Briefly, experiment 122 represents hybrid nanoparticles comprising lapatinib base and HPC EF, where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately from the hybrid nanoparticles. Experiment 110 represents crude lapatinib base and experiment 126 represents hybrid nanoparticles of lapatinib base, HPC LF and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, present within the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 5 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising nilotinib produced by the methods of the invention. The details of the hybrid nanoparticles are described in Example 5, Table 21, for experiments 127, 128 and 129, respectively. Briefly, Experiment 129 represents a physical mixture of crude crystalline nilotinib HCl, HPMCP HP55, and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Experiment 128 represents hybrid nanoparticles comprising nilotinib HCl and HPMCP HP55, where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately from the hybrid nanoparticles. Experiment 127 represents hybrid nanoparticles of nilotinib HCl and HPMCP HP55. The experiments illustrated in the graphs were carried out at pH 1.4 in SGF.

Figure 6 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising gefitinib produced by the methods of the invention. In Example 6, you will find additional experimentation with gefitinib. Details of the compositions are described in Example 6, Table 22, for Experiments 131, 133, 135, and 137, respectively. Simply put, Experiment 131 represents crude crystalline gefitinib. Experiment 133 represents a mixture of crude crystalline gefitinib, HPMCP HP55, and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Experiment 135 represents hybrid nanoparticles of gefitinib and HPMCP HP55. Experiment 137 represents hybrid nanoparticles of gefitinib and HPMCP HP55 where the solubilizing polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymer is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 7 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising dasatinib produced by the methods of the invention. The details of the hybrid nanoparticles are described in Example 7, Table 24, for Experiments 138-141. Simply put, Experiment 138 represents crude crystalline dasatinib. Experiment 139 represents a mixture of crude crystalline dasatinib, Kollidon VA64, and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Experiment 140 represents hybrid nanoparticles of dasatinib and Kollidon VA64. Experiment 141 depicts dasatinib and Kollidon VA64 hybrid nanoparticles where the solubilizing polyvinyl caprolactamaacetate polyvinyl polyethylene glycol copolymer is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 8 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising sorafenib produced by the methods of the invention. The details of the hybrid nanoparticles are described in Example 8, Table 26, for experiments 142-145. Briefly, Experiment 142 represents crude crystalline sorafenib tosylate. Run 143 depicts a mixture of crude crystalline sorafenib tosylate, HPMCP HP55, and the solubilizing polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymer. Experiment 144 represents hybrid nanoparticles of sorafenib tosylate and HPMCP HP55. Experiment 145 represents hybrid nanoparticles of sorafenib tosylate and HPMCP HP55 where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 9 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising crizotinib produced by the methods of the invention. In Example 10, more experimentation with crizotinib is found. Details of the compositions are described in Example 10, Table 30, for Experiments 150, 152, 153, and 156, respectively. Simply put, Experiment 150 represents crude crystalline crizotinib. Run 152 represents a mixture of crude crystalline crizotinib, PVP 30K, and the solubilizer Cremophor RH40. Experiment 153 represents hybrid nanoparticles of crizotinib and PVP 30K. Experiment 156 represents hybrid nanoparticles of crizotinib and PVP 30K where the solubilizer Cremophor RH40 is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 10 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising axitinib produced by the methods of the invention. In Example 11, you find further experimentation with axitinib. Details of the compositions are described in Example 11, Table 32, for Experiments 157, 158, 160, and 162, respectively. Simply put, experiment 157 represents axitinib crude crystalline. Run 158 represents a mixture of crude crystalline axitinib, Kollidon VA64, and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Experiment 160 represents hybrid nanoparticles of axitinib and Kollidon VA64. Experiment 162 depicts axitinib and Kollidon VA64 hybrid nanoparticles where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 11 provides a graph showing the apparent solubility of stable amorphous hybrid nanoparticles comprising vemurafenib produced by the methods of the invention. In Example 12, more experimentation with vemurafenib is found. Details of the compositions are described in Example 12, Table 34, for Experiments 164, 166, 168, and 170, respectively. Simply put, Experiment 164 represents crude crystalline vemurafenib. Run 166 depicts a mixture of crude crystalline vemurafenib, CAP, and the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Experiment 168 represents hybrid nanoparticles of vemurafenib and CAP. Experiment 170 depicts hybrid nanoparticles of vemurafenib and CAP where the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer is present separately from the hybrid nanoparticles. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 12 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising nilotinib base produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.1, and in Table 36 for Runs 500 and 501. In a nutshell, Run 500 represents crude nilotinib HCl. Experiment 501 represents hybrid nanoparticles based on nilotinib and HPMC ^p HP55. The experiments illustrated in the graphs were carried out at pH 6.5 in FaSSIF.

Figure 13 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising erlotinib HCl produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.2, Table 37 for Run 510 and 511. Briefly, Run 510 represents crude erlotinib HCl. Experiment 511 represents hybrid nanoparticles of erlotinib HCl and HPMC AS.

Figure 14 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising pazopanib HCl produced by the methods of the invention, measured in a low concentration state. Details are in Examples 13 and 13.3, Table 38 for Experiments 520 and 521. Briefly, Experiment 520 represents crude pazopanib HCl Experiment 521 represents hybrid nanoparticles of pazopanib HCl and PVP90K.

Figure 15 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising lapatinib base produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.4, Table 39 for Runs 530 and 531. Briefly, Run 530 represents crude lapatinib ditosylate. Experiment 531 represents hybrid nanoparticles based on lapatinib and HPMCP If.

Figure 16 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising gefitinib produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.5, Table 40 for Experiments 540 and 541. Briefly, Experiment 540 represents crude gefitinib. Experiment 541 represents hybrid nanoparticles of gefitinib and HPMCP HP55.

Figure 17 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising dasatinib produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.6, Table 41 for Runs 550 and 551. Simply put, Run 550 represents crude dasatinib. Experiment 551 represents hybrid nanoparticles of dasatinib and Kollidon VA64.

Figure 18 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising sorafenib tosylate produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.7, Table 42 for Runs 560 and 561. Briefly, Run 560 represents crude sorafenib tosylate. Experiment 561 represents hybrid nanoparticles of sorafenib tosylate and HPMCP HP55.

Figure 19 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising crizotinib produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.8, Table 43 for Experiments 570 and 571. Briefly, Experiment 570 represents crude crizotinib. Experiment 571 represents hybrid nanoparticles of crizotinib and PVP 30K.

Figure 20 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising axitinib produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.9, Table 44 for Experiments 580, 581, and 582. Briefly, Experiment 580 represents crude axitinib. Experiment 581 represents hybrid nanoparticles of axitinib and Kollidon VA64 and experiment 582 represents hybrid nanoparticles of axitinib and HPMC AS.

Figure 21 provides a graph showing the dissolution rate of stable amorphous hybrid nanoparticles comprising vemurafenib produced by the methods of the invention, measured in the low concentration state. Details are in Examples 13 and 13.10, Table 45 for Experiments 590, 591, and 592. Briefly, Experiment 590 represents crude vemurafenib. Experiment 591 represents hybrid nanoparticles of vemurafenib and Kollidon VA64 and experiment 592 represents hybrid nanoparticles of vemurafenib and CAP.

Figure 22 provides graphs showing the in vivo measurement of plasma concentrations after oral administration to beagle dogs of compositions, represented by formulations comprising stable amorphous hybrid nanoparticles of nilotinib base and the stabilizing and matrix-forming polymeric components PVAP and HPMCP HP55, respectively (I / P), called PVAP and HP55, as well as where the solubilizing copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (I / P + S), called HP55 and PVAP, respectively, was added. The experiments were carried out on beagle dogs pretreated to have a neutral stomach content. Hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9) and details of the in vivo experiments are set out in Example 14. The experiments used a commercial formulation comprising nilotinib HCl ("Tasigna") as a reference.

Figure 23 provides graphs showing the in vivo measurement of plasma concentrations after oral administration to beagle dogs of compositions, represented by formulations comprising stable amorphous hybrid nanoparticles of nilotinib base and the stabilizing and matrix-forming polymeric components PVAP and HPMCP HP55, respectively (I / P), called PVAP and HP55, produced by the processes of the invention, as well as where the solubilizing copolymer of polyvinyl caprolactamaacetate-polyethylene glycol (I / P + S), called PVAP and HP55 was added , respectively. The experiments were carried out on beagle dogs pretreated for acid stomach content. Hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9) and details of the in vivo experiments are set out in Example 14. The experiments used a commercial formulation comprising nilotinib HCl ("Tasigna") as a reference.

Figure 24 provides graphs showing the in vivo measurement of plasma concentrations after oral administration to beagle dogs of compositions, represented by formulations comprising stable amorphous hybrid nanoparticles of nilotinib base and the stabilizing and matrix-forming polymeric components PVAP and HPMCP HP55, respectively (I / P), called PVAP and HP55, produced by the processes of the invention, as well as where, after the formation of the hybrid nanoparticles, the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer was added (I / P + S), called HP55 and PVAP, respectively. The experiments were carried out on beagle dogs pretreated to have an acidic or neutral stomach content. Hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9) and details of the in vivo experiments are set out in Example 14.

Figure 25 provides graphs showing the in vivo measurement of plasma concentrations after oral administration to beagle dogs of compositions, represented by formulations comprising stable amorphous hybrid nanoparticles of nilotinib base and the stabilizing and matrix-forming polymeric components PVAP and HPMCP HP55, respectively (I / P), produced by the processes of the invention, called PVAP and HP55. The experiments were carried out on beagle dogs pretreated to have an acidic or neutral stomach content. Hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9) and details of the in vivo experiments are set out in Example 14.

Figure 26 provides a graph showing apparent solubility for stable amorphous hybrid nanoparticles produced by the methods of the invention, before and after 11 months of storage at room temperature. The experiment provides stable amorphous hybrid nanoparticles comprising nilotinib base, HPMCP HP55 and the addition of the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (I / P + S) copolymer as Exp 171 and Exp 172 with more details set forth in the example fifteen.

Figure 27 provides overlapping X-ray powder diffraction patterns (DRXP) of stable hybrid nanoparticles at 40% drug loading, I / P based on nilotinib / HPMCP HP55. Initial storage (top) and after 12 months at room temperature (bottom). The DRXP patterns are offset to improve visual comparison. In Example 15, more details are provided.

Detailed description of the invention

All patents, patent applications and publications mentioned in this application are incorporated herein in their entirety by reference.

As used herein, the phrase "hybrid nanoparticles" refers to a group of particles, typically in the average size range of 1 to 1000 nm, made up of at least two components, one of which is the IPC and the other a stabilizing and matrix-forming polymeric component. The particles can be crystalline or amorphous, or a mixture thereof. Typically, in the sense of the present description, the particles are "amorphous" or "essentially amorphous". This means that almost all, if not all, of the content of the particles comprises a protein kinase inhibitor and an amorphous matrix-forming and stabilizing polymer component. The level or degree of amorphousness is at least 60%, such as 70%, such as 80% or 85%, preferably, at least 90%, and more preferably> 95%, where 100% represents that all material is amorphous in particles. The quantification of crystalline IPC or the absence of crystalline IPC can be measured by X-ray powder diffraction procedures 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. April 2002; 91 (4): 983-90.

The term "solid dispersion particles" refers to "hybrid nanoparticles" as defined above, however, solid dispersion particles are typically larger or much larger in size (typically | jm-mm, as described in Wu K . et al., J Pharm Sci. 2009 Jul; 98 (7): 2422-3). The smaller size of the hybrid nanoparticles further helps stabilize the IPC against crystallization. Typically, the hybrid nanoparticles are in the average size range of 1 to 1000 nm, such as below 500 nm, preferably below 250 nm.

The term "stable" refers to the level of stability of the particles produced by the processes of the present invention and can be measured as the ability of the hybrid nanoparticles to remain in their physical state during 6-12 months of storage at room temperature ( for example, 20-25 ° C). The level of stability can be measured by measurements of the AUC of the dissolution rate during, for example, 80 minutes of the particles, after such storage.

The phrase "protein kinase inhibitor" or "IPC" refers to a type of enzyme inhibitor that specifically blocks the action of one or more protein kinases. IPCs include, but are not limited to, protein kinase inhibitors and tyrosine kinase inhibitors, such as axitinib, afatinib, bosutinib, crizotinib, cediranib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lestauvatinib, letauvatinib motesanib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, semaxanib, sunitinib, tandunitib, tipifamib, vandetanib, and vemurafenib; or salts or hydrates or solvates thereof, or combinations thereof.

By the phrase "stabilizing and matrix-forming polymeric component" is meant the component present in the hybrid nanoparticles together with the IPC. Typically, such a stabilizing and matrix-forming polymeric component exhibits a polymeric structure, such as, but not limited to, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg, HPC ef, HPC If, and HPC jf), hydroxypropylmethylcellulose (eg, Methocel E3 and E15 and Pharmacoat), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (for example, HPMCP-HP55), polyvinylpyrrolidone (for example, PVP 30K and PVP 90K), polyvinyl acetate phthalate ^{(P v A-pyl) ,} copolyvidone (for example, Kollidon VA 64), crospovidone (for example, Kollidon CL), copolymer of methacrylic acid and ethyl acrylate (for example, Kollicoat ME), copolymer of methacrylate acid and methyl methacrylate (for example, Eudragit L100 ), polyethylene glycol (PEG), DL lactide / glycolide copolymer, poly DL-lactide, cellulose acetate phthalate (CAP), aminoalkyl methacrylate copolymers (e.g. Eudragit RL100, RL PO or RS PO), homopo Type A carbomer polymer (eg, Carbopol 971 P), type B carbomer homopolymer (eg, Carbopol 974P), and poloxamers (eg, Pluronics, Kolliphor).

The term "polymer" or "polymeric" is used herein to mean a compound that is made up of monomers connected together to form a larger molecule. In general, a polymer consists of 20 or more monomers connected to each other, however, less than 20 monomers connected to each other are here also referred to as polymers.

The term "solubilizer" is used herein to mean a compound that increases the solubility of a substance, such as, but not limited to, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus), da-tocopherol succinate polyethylene glycol 1000 ( TPGS), PEG-40 hydrogenated castor oil (Cremophor RH40), PEG-35 castor oil (Cremophor EL), PEG-40 stearate (MYRJ 540), hard fat (for example, Gelucire 33/01), polyoxylglycerides (for eg, Gelucire 44/14), stearoyl polyoxyglycerides (eg, Gelucire 50/13), PEG-8 caprylic / capric glycerides (eg, Labrasol), and poloxamers (eg, Pluronics, Kolliphor).

As used in this application, the phrase "primary particles" refers to the smaller particle entities formed during the precipitation process. The boundaries of the particles are analyzed by SEM microscopy. Depending on the process parameters, the primary particles may together form a more or less dense and porous network that forms larger, agglomerated or bridging particles. The parameters that affect agglomeration are, for example, the temperature that can modify the plasticity of the primary particles; the solvent / antisolvent ratio affecting the precipitation time, the concentration of the IPC solution; and the nature of the polymeric stabilizing and matrix-forming agent (s). The average size of the primary particles is typically between 1 and 1000 nm, preferably below 500 nm, more preferably below 250 nm.

As used in this application, the phrases "supercritical" and "supercritical fluid" refer to a chemical that is fixed at a temperature greater than or equal to its critical temperature (Tc) and to a pressure greater than or equal to its critical pressure ( Pc).

As used in this application, the phrases "subcritical" and "subcritical fluid" refer here to that a critical temperature (Tc) or critical pressure (Pc) is set at a temperature or pressure greater than its critical temperature (Tc) or critical pressure (Pc), respectively, and the other of critical temperature (Tc) or critical pressure (Pc) is set at a temperature or pressure lower than its critical temperature (Tc) or critical pressure (Pc), respectively.

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

The phrase "apparent solubility" refers to the concentration of material at apparent equilibrium. See more information in the examples section.

The term "supersaturation" is used herein to mean that a solution contains more dissolved substance than the solvent or medium could dissolve under normal circumstances.

As used in this application, the term "Soluplus" or "soluplus" refers to a polyvinyl caprolactamaacetate-polyethylene glycol copolymer.

As used in this application, the term "TPGS" refers to d-α-tocopherol polyethylene glycol 1000 succinate.

As used in this application, the term "Chremophor RH40" refers to PEG-40 hydrogenated castor oil. As used in this application, the term "PVAP" refers to polyvinyl acetate phthalate.

As used in this application, the term "PVP 90K" refers to polyvinylpyrrolidone K-90.

As used in this application, the term "PVP 30K" refers to polyvinylpyrrolidone K-30.

As used in this application, the term "HPMC-AS" refers to hydroxypropylmethylcellulose acetate succinate. As used in this application, the term "HPMC HP55" refers to hydroxypropylmethylcellulose phthalate.

As used in this application, the term "HPC" refers to hydroxypropyl cellulose, such as HPC EF and HPC LF. As used in this application, the term "Kollidon VA64" refers to copolyvidone.

As used in this application, the term "CAP" refers to cellulose acetate phthalate.

The dissolution media used for the purpose of testing the hybrid nanoparticles produced by the methods of the present invention include stimulated intestinal fluid in the fasting state, termed FaSSIF, stimulated intestinal fluid in the fed state, termed FeSSIF, and simulated gastric fluid, termed SGF. FaSSIF medium is designed to represent a fasting state and has a pH of approximately 6.5, as well as particular osmotic properties. The FeSSIF medium is designed to represent a fed state and has a pH of approximately 5, as well as specific osmotic properties. SGF medium is designed to represent gastric fluid and has a pH of approximately 1.4, as well as particular osmotic properties. FaSSIF, FeSSIF and SGF media are generally used in in vitro models for the dissolution of drugs that are poorly soluble in water. The choice of medium will depend on the site of the intestinal tube and under what conditions (fasting or fed) it is desired that the particles dissolve and absorb. More details regarding these fluids are described in, for example, Hervé J. et al, Pharm Dev Technol. June 2011; 16 (3): 278-86 and Jantratid, E. and Dressman, J. Dissolut. Technol. 20098, 21-25.

The phrase "amorphous form" means a non-crystalline solid form. Ease of dissolution can be attributed at least in part to the amount of energy required for dissolution of the components of a crystalline or amorphous solid phase. Amorphous particles require less energy for dissolution compared to crystalline particles of the same compound.

The inventive processes produce hybrid nanoparticles comprising one IPC or a combination of two or more IPCs. However, the particles can comprise a combination of one or more IPCs and at least one additional active ingredient, such as one or more drugs. Various types of IPCs can be used effectively.

The term IPC (protein kinase inhibitors), as used in this application, is also intended to include the pharmaceutically acceptable hydrates, solvates (alcoholates), acid salts, basic salts or cocrystals of said protein kinase inhibitor compounds.

As used in this application, the term "water insoluble or poorly soluble (or hydrophobic) compounds" refers to compounds whose solubility in water at 25 ° C is less than 1 g / 100 ml, especially less than 0.1 g / 100 ml in pure water at neutral pH.

Hybrid nanoparticles generated by the methods of the present invention are typically in particulate form as described elsewhere in this specification. There are a number of different processes for the formation of larger particles, for example granulation, melt extrusion, spray drying, precipitation, etc., all of which generally encompass starting with the formation of a mixture between the active ingredient ( PA) and the stabilizing and matrix-forming polymeric component. The inventive processes of the present invention are continuous processes for generating hybrid nanoparticles. In this context, continuous processes mean that particle formation is ongoing continuously while at the same time hybrid nanoparticles are continuously extracted / collected / retained from the mixture after their formation. In preferred processes, ie, precipitation processes, this means that a fluid which is a solution of the IPC, preferably in the form of a fluid stream, is mixed with an antisolvent fluid, preferably in the form of an antisolvent fluid stream. The stabilizing and matrix-forming polymeric component may be present in one or both of the two fluids depending on their solubility characteristics. The mixing of the two fluids takes place in a mixing function, for example a mixing chamber. In the case where the process is continuous, that is, the two fluids are fluid streams, the mixing function is typically associated with a particle formation and separation function where the mixed fluid stream can pass while retaining the hybrid nanoparticles. . Agents that modify the characteristics of the particles without being incorporated into the particles can be added to one or both fluids prior to the mixing step. Typically the fluids are conventional liquids or supercritical fluids, where supercritical fluids also include subcritical fluids (that is, fluids for which only one of the pressure and temperature is above its supercritical value). Typical combinations are, a) conventional (i.e. non-supercritical) liquids for both the PA solution and the antisolvent, b) supercritical PA solution combined with conventional liquid for the antisolvent, c) conventional liquid for the PA solution combined with supercritical fluid for the antisolvent, and d) supercritical fluids for both fluids. In certain variants, the antisolvent can be omitted. Next, a fluid stream, preferably supercritical, containing both the PA and the matrix-forming and stabilizing polymer component, is allowed to expand into the particle-forming function. It is preferred that at least one of the fluids is in a supercritical state in the precipitation procedures described above. These types of precipitation procedures are discussed in WO 2005061090 (Censdelivery AB), WO 2009072950 (XSpray Microparticles AB), WO 2009072953 (XSpray Microparticles AB), WO 2011159218 (XSpray Microparticles AB) and the references cited in these publications.

The term "solution" encompasses that the solute is both a true solute and minute particles of colloidal dimensions (typically 1-1000 nm) and smaller than the particles to be produced.

A preferred particle formation system is the "Right Size System" developed by XSpray Microparticles AB, Sweden. A detailed description of the technology can be found in the WO publications provided in the preceding paragraph. An important feature of the system is that the two fluid streams must be fused within one nozzle at an angle in the range of 45-135 °, preferably about 90 °, and sprayed in a formation / separation function. particles. In principle, the system makes it possible to produce particles of predetermined size and / or morphology. Here the Right Size system and apparatus will be described using the non-limiting example of an IPC as a drug and CO ² as a supercritical fluid antisolvent.

The system consists of a pump setup for IPC dissolved in a liquid solvent, referred to as a PA solution, and a pump setup for an antisolvent, for example CO ² , however other antisolvent may also be used as appropriate. Each pump setup includes instruments such as a flowmeter and a pressure gauge that are used to monitor procedure conditions. These two pump configurations are fluidly connected to a spray nozzle.

A liquid PA solution stream is mixed with a CO ² stream under flow conditions within the spray nozzle. The stabilizing and matrix-forming polymeric component is present in the PA solution or in the CO ² stream. These streams are sprayed out of the nozzle into a beaker under controlled conditions (typically pressure and temperature). The CO ² acts as an antisolvent and causes the PA to precipitate together with the stabilizing and matrix-forming polymer component into fine particles. The particles are retained in the glass by a filtration system. Typically, a back pressure regulator is used to control the pressure within the beaker.

To prepare the hybrid nanoparticles of certain drugs, for example, but not limited to, Pazopanib and Erlotinib, it may be advantageous to have an additional pump configuration to inject an additional solvent, called modifier, in CO ² . Here a pump setting control is set for the modifier and the modifier is mixed with the CO ² in a mixer before being fed into the nozzle.

When using the system, the system operator typically begins by balancing the system by pumping CO ² , an "IPC-like solution" (a solution similar in composition to the IPC solution but containing no IPC or excipient), and the modifier (if used) through the system until flow rates, pressure, and temperature have reached the desired steady state. Critical parameters for configuring the system are the solution composition of the CPI, the flow of the solution of the CPI, the flow of CO ^2, the pressure and temperature of the CO ^2, the nature of the modifier and the flow modifier, if uses.

The "IPC-like solution" is then exchanged for the IPC solution and the particles are produced and retained below the mix, eg below the nozzle outlet. The system is then typically cleaned by pumping the "IPC-like solution" through the system. The particles are dried by passing CO ² through the retained particles to remove any remaining solvent. The beaker is then depressurized and the particles can be collected.

The solution / solvent and the antisolvent are typically miscible with each other. Pressure and temperature in the particle formation function and / or prior to this function, such as in the mixing function, provide supercritical or subcritical conditions with respect to the antisolvent.

The IPC concentration in the solution is typically below its saturation concentration, such as <50%, such as <60%, such as <75%, such as <85%, or such as <95% of the concentration. saturation. Suitable concentrations are typically in the range <20%, such as <10% or <5% or <3%, the lower limits are <0.005% or 0.1% (all% w / v). The term "volatile" for solvents typically means boiling points of <200 ° C, such as <150 ° C or <100 ° C, at atmospheric pressure. Examples are inorganic solvents and organic solvents with special emphasis on dimethylsulfoxide and trifluoroethanol and mixtures thereof. The term solvent includes mixtures of liquids that are miscible with each other. The solutions may contain agents that improve or decrease the solubility of the IPC, for example acidic, alkaline and / or other organic solvent buffers.

Illustrative fluids that can be used as an antisolvent are

a) gaseous at ambient temperature and atmospheric pressures, or

b) liquids at room temperature and atmospheric pressure.

The antisolvent is typically selected for its ability to easily disperse into small droplets and for its ability to act as an atomizing and antisolvent agent against IPC present in solution.

Compounds / elements according to group (a) can be selected from carbon dioxide (Pc = 74 bar and Tc = 31 ° C) (preferred), nitrous oxide (Pc = 72 bar and Tc = 36 ° C), hexafluoride sulfur (Pc = 37 bar and Tc = 45 ° C), ethane (Pc = 48 bar and Tc = 32 ° C), ethylene (Pc = 51 bar and Tc = 10 ° C), xenon (Pc = 58 bar and Tc = 16 ° C), trifluoromethane (Pc = 47 bar and Tc = 26 ° C), chlorotrifluoromethane (Pc = 39 bar and Tc = 29 ° C) and nitrogen (Pc = 34 bar and Tc = -147 ° C) and mixtures containing these compounds / elements. Pc means critical pressure and Tc critical temperature. The compounds according to group (b) are typically selected from among conventional liquids of the same general types as those discussed above for solvents, but with the difference that the IPC present in the solution must be poorly soluble in the antisolvent. Group (b) particular liquids include methanol, ethanol, acetone, water, and mixtures containing one or more of these fluids.

The antisolvents of group (a) above are typically used at pressures and temperatures that provide i) supercritical conditions (supercritical fluid) or ii) subcritical conditions (subcritical fluid) in the particle formation function and / or prior to this function, such as in the mix function and before the latter function.

Variant (i) means pressures and temperatures that are typically above the critical pressure Pc and the critical temperature Tc of the antisolvent used. For pressure, this typically means pressures in the range (1.0-7.0) x Pc or in the range> 10 bar, suitably> 20 bar preferably over> 30 bar, higher than Pc with limits Illustrative upper bars which are 100 bar, 200 bar and 300 bar higher than the Pc. For temperature, this typically means temperatures within (1.0-4.0) x Tc or in the range of> 5 ° C, suitably> 10 ° C preferably> 15 ° C above the Tc with illustrative upper limits of 10 ° C, 40 ° C, and 50 ° C above Tc.

Variant (ii) means that at least one temperature and pressure, preferably only for temperature, is / is below the critical value. (Tc and Pc, respectively). Therefore, the temperature can be in the range of (0.1-1) x Tc, such as (0.5-1) x Tc or less. Also, the temperature can be low, such as -10 ° C or -30 ° C. These temperatures can be combined with the pressures defined in the previous paragraph or with pressures lower than the Pc of the antisolvent used. For carbon dioxide, this means that the temperature in the particle formation function is <+31 ° C, such as about 25 ° C or less combined with a pressure above or below 74 bar.

The antisolvents of group (b) above are typically used in the subcritical state, that is, as a subcritical fluid.

For the processes of the invention using subcritical conditions in the particle formation chamber. This includes that the pressure in the mixing function and in the antisolvent fluid is always higher than in the particle formation function.

In one aspect of the invention, there is provided a process for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, comprising

a) providing a first stream, preferably pressurized, of said protein kinase inhibitor dissolved in a solvent;

b) providing a second stream of antisolvent, preferably pressurized; wherein said at least one matrix-forming and stabilizing polymer component is present in said first or second stream; and c) mixing said first and second streams, and spraying the mixed stream at the outlet of a nozzle, thereby forming said hybrid nanoparticles; followed by the collection of said hybrid nanoparticles.

In one embodiment of this aspect, said matrix-forming and stabilizing polymeric component is present in said solvent.

In another embodiment of this aspect, said stabilizing and matrix-forming polymeric component is present in said antisolvent.

In another embodiment of this aspect, at least one of said fluid streams is a supercritical fluid stream, preferably a CO ² supercritical or subcritical fluid stream.

In another embodiment of this aspect, said antisolvent stream is a supercritical or subcritical fluid stream of CO ² .

In another embodiment of this aspect, said solvent stream is a CO ² supercritical or subcritical fluid stream.

In another embodiment of this aspect, said at least one matrix-forming and stabilizing polymeric component is present in said CO ² supercritical or subcritical fluid stream.

In another embodiment of this aspect, said solvent stream is a CO ² subcritical fluid stream. Said supercritical or subcritical fluid stream of CO ² is preferably provided at about 25 ° C or less, at a pressure of about 100 to about 150 bar. However, said solvent stream may comprise, for example, nitrogen, methane, ethane, propane, ethylene, methanol, ethanol, acetone, water or a mixture of these compounds such as a mixture of CO ² and nitrogen. Also, an additional solvent such as an organic solvent (eg methanol, acetone) or an aqueous solution (eg water) can be added as a modifier in a supercritical / subcritical solvent.

In another embodiment of this aspect, said antisolvent stream is a supercritical or subcritical fluid stream of CO ² . Said supercritical or subcritical fluid stream of CO ² is preferably provided at about 25 ° C or less, at a pressure of about 100 to about 150 bar. However, said antisolvent stream can comprise, for example, nitrogen, methane, ethane, propane, ethylene, methanol, ethanol, acetone, water or a mixture of these compounds such as a mixture of CO ² and nitrogen. Also, a solvent, such as an organic solvent (eg, methanol, acetone) or an aqueous solution (eg, water) can be added as a modifier in a supercritical or subcritical antisolvent.

The stabilizing and matrix-forming polymer component of the invention includes, but is not limited to, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg, HPC ef, HPC If, and HPC jf), hydroxypropylmethylcellulose (eg, Methocel E3 and E15 and Pharmacoat), hydroxypropylmethylcellulose acetate succinate (HPMc AS), hydroxypropylmethylcellulose phthalate (for example, HPMC HP55), polyvinylpyrrolidone (for example, PVP 30K and PVP 90K), polyvinyl acetate phthalate (PVAP), polyvinyl acetate phthalate (for example, Kollidon VA 64), crospovidone (for example, Kollidon CL), copolymer of methacrylic acid and ethyl acrylate (for example, Kollicoat ME), copolymer of methacrylate acid and methyl methacrylate (for example, Eudragit L100), polyethylene glycol (PEG), DL lactide / glycolide copolymer, poly DL-lactide, cellulose acetate phthalate (CAP), carbomer homopolymer type A (Carbopol 971 P), carbomer homopolymer type B (Carbopol 97 4P), aminoalkyl methacrylate copolymers (eg Eudragit RL100, RL PO or RS PO) and poloxamers (eg Pluronics, Kolliphor).

Accordingly, in another embodiment of this aspect, said stabilizing and matrix-forming polymeric component is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropyl acetate, polyvinyl cellulose phthalate, polyvidone polyvinyl cellulose phthalate. methacrylic acid / ethyl acrylate copolymer, acid methacrylate / methyl methacrylate copolymer, polyethylene glycol, DL lactide / glycolide copolymer, poly DL-lactide, cellulose acetate phthalate, type B carbomer homopolymer, carbomer homopolymer type A , aminoalkyl methacrylate copolymers and poloxamers. Preferably, said stabilizing and matrix-forming polymeric component is selected from hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate and polyvinyl pyrrolide.

In another embodiment of this aspect, a solubilizer is added to the hybrid nanoparticles obtained in step c. In this context, the solubilizer will be present separately from the particles. Said solubilizer can be selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, da-tocopherol succinate polyethylene glycol 1000 and a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. Furthermore, said solubilizer can be a poloxamer.

The processes of the invention provide stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, which exhibit a higher dissolution rate.

Consequently, in another embodiment of this aspect, a process is provided for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, wherein said hybrid nanoparticles show a speed of increased dissolution of said protein kinase inhibitor, compared to the dissolution rate of said protein kinase inhibitor in crude crystalline form.

Typically, said dissolution rate is measured by a reading cuvette system under low concentration conditions, for example, according to the United States Pharmacopeia (USP4). The measurement of the dissolution under conditions of low concentration of hybrid nanoparticles can be measured in a procedure that consists of adding the desired amount of powder in a reading cuvette system (SOTAX, Allschwill, Switzerland), mounting the cuvette in your apparatus and then pump the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the apparatus is typically set at 37 ° C. The amount of powder added to the cuvette depends on the drug loading of the powder: the exact amount of powder can be calculated from the results obtained from the analysis of the drug loading of the powders. The IPC can be added to the reading cuvette and pumped through the powder at a flow rate of 5 to 25 ml of medium / min. One ml samples of the medium passing through the cuvette at predetermined times are collected and subsequently analyzed by HPLC (e.g. C18 Eclipse column, 4.6 mm x 15 cm, 1 ml / min, detection of 254 to 400 nm). Samples are typically taken after 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 when the medium exits the reading cell. The cumulative% solubilize of the amount of active substance added in the reading cuvette can be calculated and plotted against time (min). The initial slope ("initial dissolution rate", representing 0 to 10 minutes) of the graph can be estimated and taken as the dissolution rate of the material under conditions of low concentration at 37 ° C in the given dissolution medium.

Preferably, the dissolution rate is measured in the initial 0 to 10 minutes of dissolution.

The increased dissolution rate is preferably measured in a solution as a dissolution rate ratio of said hybrid nanoparticles and said protein kinase inhibitor in crude crystalline form. Preferably, said ratio is from about 1.5: 1 to about 500: 1, such as from about 10: 1 to about 30: 1.

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

Typically, said dissolution rate is measured by a reading cuvette system, for example, under low concentration conditions. The measurement of the dissolution under conditions of low concentration of hybrid nanoparticles can be measured in a procedure that consists of adding the desired amount of powder in a reading cuvette system (SOTAX, Allschwill, Switzerland), mounting the cuvette in your apparatus and then pump the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the apparatus is typically set at 37 ° C. The amount of powder added to the cuvette depends on the drug loading of the powder: The exact amount of powder can be calculated from the results obtained from the analysis of the drug loading of the powders. The IPC can be added to the reading cuvette and pumped through the powder at a flow rate of 5 to 25 ml of medium / min. One ml samples of the medium passing through the cuvette at predetermined times are collected and subsequently analyzed by HPLC (e.g. C18 Eclipse column, 4.6 mm x 15 cm, 1 ml / min, detection of 254 to 400 nm). Samples are typically taken after 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 when the medium exits the reading cell. The cumulative% solubilize of the amount of active substance added in the reading cuvette can be calculated and represent versus time (min). The initial slope ("initial dissolution rate", representing 0 to 10 minutes) of the graph can be estimated and taken as the dissolution rate of the material under conditions of low concentration at 37 ° C in the given dissolution medium.

In another embodiment of this aspect, a method is provided for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, which produces particles that provide an increase in the solubility of the inhibitor in a solution, said increase measured as the area under the curve (AUC) for from about 40 minutes to about 90 minutes, in said solution compared to the AUC of the inhibitor in crude crystalline form. Preferably, said increase is from about 2: 1 to about 10,000: 1, where 1 represents the AUC of the inhibitor in crude crystalline form. Preferably, said increase is measured in a solution with gastric pH, such as SGF, or it is measured in a solution with intestinal pH, such as FaSSIF or FeSSIF. The processes can produce particles that provide an increase in the solubility of the inhibitor in a solution until supersaturation, said increase measured as the area under the curve (AUC) for from about 40 minutes to about 90 minutes, in said solution compared to the Inhibitor ABC in crude crystalline form. In another embodiment of this aspect, a method is provided for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one stabilizing and matrix-forming polymer component, characterized by the provision of a ray diffraction pattern. X in amorphous powder.

In another embodiment of this aspect, a method is provided for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, where the dissolution rate of said stable amorphous hybrid nanoparticles remains stable to at least about 90%, after 6 months of storage or more, at room temperature.

In another embodiment of this aspect, said protein kinase inhibitor is dasatinib.

In another embodiment of this aspect, said hybrid nanoparticles have an average particle diameter size of less than about 1000 nm, such as less than about 500 nm, preferably less than 250 nm.

In another embodiment of this aspect, said 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 / acetate. ethyl. In another embodiment of this aspect, said particles further comprise a solubilizer within the particles. Said solubilizer can be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-α-tocopherol succinate polyethylene glycol 1000 or a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil.

In another embodiment of this aspect, the method further comprises formulating the retained particles in step (c) as a pharmaceutical composition containing the particles and, optionally, other pharmaceutically acceptable excipients.

In another aspect of the invention, stable amorphous hybrid nanoparticles are provided comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, obtainable by the procedures described above.

The hybrid nanoparticles produced by the methods of the present invention can also be dissolved and the protein kinase inhibitor can be absorbed systemically and independently of the pH in the surrounding environment, and typically in approximately equal amounts, especially both at gastric pH, such as from about pH 1.2 to about pH 2.1, preferably from about 1.7 as at an intestinal pH such as from about pH 4.5 to about pH 8, preferably at a pH of about 6. To be absorbed systemically , means that the protein kinase inhibitor is released from the hybrid nanoparticles and absorbed into the systemic bloodstream. Therefore, in another embodiment of this aspect, a method is provided, wherein said protein kinase inhibitor is absorbed systemically and independently of pH. Typically, said protein kinase inhibitor is systemically absorbed in approximately equal amounts both at gastric pH and at intestinal pH. Preferably said acidic pH is about pH 1.4 and preferably said neutral pH is about pH 6.5.

With approximately equal amounts it is understood that the concentration of protein kinase inhibitor in the bloodstream, after exposure, is approximately similar. This can be illustrated by a relationship, where the concentration of protein kinase inhibitor in the bloodstream is measured after administration under gastric pH conditions (A) and compared to the concentration of protein kinase inhibitor in the bloodstream. blood measured after administration under intestinal pH conditions (N). Typically, the A: N ratio is from about 0.75: 1 to about 1.5: 1, and preferably from about 1: 1 to about 1.25: 1. Measurement of the protein kinase inhibitor concentration in the bloodstream can be carried out as area under the curve (AUC) for 0-24 hours, the maximum concentration (Cmax) or as bioavailability.

Consequently, in another embodiment of this aspect, a method is provided for producing stable amorphous hybrid nanoparticles, comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymeric component, where the concentration of inhibitor of the Protein kinase systemically absorbed under gastric pH conditions compared to the concentration of protein kinase inhibitor systemically absorbed under intestinal pH conditions is in a ratio of about 0.75: 1 to about 1.5: 1, preferably, of about 1: 1 to about 1.25: 1. Typically, said gastric pH condition represents a pH of about 1.4 and said intestinal pH condition represents a pH of about 6. Typically, the concentration is measured as area under the curve (AUC) during 0-24 hours of exposure of the composition or as the maximum concentration (Cmax).

The amounts of systemically absorbed protein kinase inhibitor can be measured in a number of ways. In Example 14 of the present disclosure, a method is provided for measuring systemically absorbed protein kinase inhibitors at various pHs, ie, under both acidic and neutral conditions.

In another embodiment of this aspect, a method is provided for producing stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, which produces an increase in the solubility of the inhibitor in a solution to supersaturation, said increase is measured as the area under the curve (AUC) for approximately 90 minutes, in said solution compared to the AUC of the inhibitor in crystalline form. Said increase can be from about 2: 1 to about 1000: 1, where 1 represents the AUC of the inhibitor in crystalline form. To understand how the hybrid nanoparticles produced by the methods of the invention will dissolve in vivo in the different environments of the stomach, small intestine, large intestine, and colon, it is important to choose an appropriate solution for in vitro dissolution testing. It is essential that the in vitro test conditions mimic the in vivo environment as closely as possible, eg pH and osmolarity. Typically, for intestinal absorption, the pH is between 6 and 7. Therefore, the solution can maintain a pH of about pH 6 to about pH 7, such as about pH 6.5.

Therefore, in embodiments of the invention, the test solution has a pH of about pH 4.5 to about pH 8, such as about pH 6.5 or such as about pH 5. The solutions may represent intestinal fluid. simulated in the fasting state (FaSSIF) or simulated intestinal fluid in the fed state (FeSSIF).

Typically, for gastric absorption, the pH is between 1 and 2. Therefore, the solution can maintain a pH of about pH 1 to about pH 2, such as about pH 1.4. Therefore, in embodiments of the invention, the test solution may represent simulated gastric fluid (SGF).

The choice of medium will depend on the site of the intestinal tube and under what conditions (fasting or fed) the composition is desired to dissolve and absorb. Recipes and preparation of these solutions can be obtained from the manufacturer (Biorelevant, Croydon, UK). More details are also described in Jantratid, E. and Dressman, J. (2009) Dissolut. Technol. 8, 21-25).

In another embodiment of this aspect, a process for producing stable amorphous hybrid nanoparticles is provided, comprising at least one protein kinase inhibitor and at least one stabilizing and matrix-forming polymer component and, furthermore, a solubilizer selected from copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, da-tocopherol succinate polyethylene glycol 1000, poloxamers (eg, Pluronics, Kolliphor) and a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. Preferably, said solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer or a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil.

It may also be advantageous to use different dispersing agents and / or other excipients to achieve different dissolution profiles. For example, the use of Nilotinib HCl powder with HPC EF, HPMC (eg Methocel) and poloxamer (eg Lutrol® F127) results in hybrid nanoparticles with different dissolution profiles.

The amount of IPC in the hybrid nanoparticles produced by the processes of the present invention can be less or more, such as when the amount of IPC in the hybrid nanoparticles is from about 0.01% by weight to about 99.9%. % in weigh.

In another embodiment of this aspect, hybrid nanoparticles produced by the methods of the present invention are provided, where the amount of IPC in the hybrid nanoparticles is approximately one 10 % by weight to about 70 % by weight.

In another embodiment of this aspect, hybrid nanoparticles produced by the methods of the present invention are provided, where the amount of IPC in the hybrid nanoparticles is from about 10% by weight to about 50% by weight.

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

Control of particle characteristics may be suitable for specific applications. The size of the particles, the agglomeration of the particles, the porosity of the particles and the choice and proportion of the polymeric stabilizing and matrix forming agent could be modified to increase or decrease the ratio between the surface area and the volume of the particles or the behavior of the particles in gastrointestinal fluids, leading to an increase or decrease in the dissolution rate. Depending on the desired dissolution characteristics, said characteristics of the particles can be adapted. Furthermore, particles with different characteristics may be present in the same pharmaceutical composition to provide an initial dose and a prolonged or delayed dose of active ingredient. Additionally, it may be advantageous to provide different IPCs and / or other active ingredient (s) in different primary particles with different characteristics adapted to provide desired dissolution rates for each active ingredient (s).

Other embodiments of the invention provide pharmaceutical compositions comprising the hybrid nanoparticles obtainable by the methods of the invention. Said composition may further comprise a pharmaceutically acceptable solubilizer. Said solubilizer can be present separately from the hybrid nanoparticles in the composition or randomly intermixed with the hybrid nanoparticles in the pharmaceutical composition. The pharmaceutical composition can also be in a galenic form consisting of several layers, for example laminated or multilayer tablets, so that the hybrid nanoparticles are separated from the solubilizer. The solubilizer can be selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-a-tocopherol succinate polyethylene glycol 1000, and a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. Said solubilizer can also be a poloxamer.

In another embodiment of this aspect, stable amorphous hybrid nanoparticles are provided comprising at least one protein kinase inhibitor and at least one matrix-forming and stabilizing polymer component, obtainable by the methods of the present invention.

In another embodiment of this aspect, a method of the present invention is provided, further comprising formulating the retained particles in step (c) as a pharmaceutical composition containing the particles and optionally other pharmaceutically acceptable excipients.

It will be appreciated that the amount of a protein kinase inhibitor in the hybrid nanoparticles produced by the methods of the present invention required for use in treatment will vary not only with the particular inhibitor selected, but also with the route of administration, nature of the condition for which the treatment is required and the age, weight and condition of the patient and, ultimately, at the discretion of the responsible physician. In general, however, a suitable dose may be in the range of about 0.005 to about 30 mg / kg of body weight per day, preferably in the range of 0.05 to 10 mg / kg / day.

The desired dose is conveniently presented in a single dose or as a divided dose administered at appropriate intervals, eg, of two, three, four or more doses per day. Depending on the need for treatment and / or prevention, the desired dose can also be, for example, once every two days, once every three days or even once a week.

The composition can be conveniently administered in unit dosage form, for example, containing from 0.5 to 1500 mg, conveniently, from 1 to 1000 mg, more conveniently, from 5 to 700 mg of active principle per unit dosage form. Typically, the compositions of the invention will be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or other injectable routes, orally, rectally, vaginally, transdermally and / or nasal, and / or via inhalation, in a pharmaceutically acceptable galenic form. Depending on the disorder and the patient to be treated and the route of administration, the compositions can be administered in varying doses.

Pharmaceutical compositions include, but are not limited to, those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration or in a form suitable for administration by inhalation or insufflation. As appropriate, the compositions may be conveniently presented in discrete dosage units and may be prepared by any of the procedures well known in the art of pharmacy. Pharmaceutical compositions suitable for oral administration are conveniently presented as discrete units such as as capsules, wafers or tablets, each contains a predetermined amount of the active ingredient.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. Tablets can be coated according to procedures well known in the art.

The compositions may be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion, or in multidose containers with a added preservative. The compositions may take forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

The compositions described above can be adapted to provide sustained release of the active inhibitor.

Examples

The following is a series of non-limiting examples of hybrid nanoparticles produced by the processes of the present invention. In the tables, the following abbreviations for "compositions" apply: "I" represents protein kinase inhibitor (IPC);

"P" represents the stabilizing and matrix-forming polymer component;

"S" represents the solubilizer;

"I + P" represents a physical mixture of the inhibitor with the stabilizing and matrix-forming polymer component, ie, without additional processing;

"I + S" represents a physical mixture of the inhibitor with the solubilizer;

"I + P + S" represents a physical mixture of the inhibitor, the stabilizing and matrix-forming polymeric component and the solubilizer;

"I / P" represents hybrid nanoparticles with the inhibitor and the stabilizing and matrix-forming polymer component;

"I / P + S" represents hybrid nanoparticles with the inhibitor and the stabilizing and matrix-forming polymer component and a separate solubilizer added;

"I / P / S" represents hybrid nanoparticles with the inhibitor and the stabilizing and matrix-forming polymer component and the solubilizer.

"Exp" represents the experiment number.

Hybrid nanoparticles were produced with exemplary IPCs, stabilizing and matrix-forming polymeric components ("Polymers"), solubilizers, solution concentrations, ratios, solvents, antisolvents, temperatures and pressures as set forth below and in Table A.

A 3-6% w / v IPC / polymer solution in solvent, with an IPC / polymer ratio of approximately 20-70% w / w, was pumped through an XSpray RightSize nozzle at a flow rate of 1 ml. / min using a high performance liquid chromatography pump, together with a stream of CO ² (supercritical or subcritical) of 100 g / min. The pressure in the precipitation chamber was set at about 100-175 bar and the temperature was set at about 10 to 50 ° C. Both streams were in contact within the nozzle and the hybrid nanoparticles were formed and subsequently collected on the particle in the collection chamber. The ^{sc CO 2} and solvent passed through the collection chamber filtration system and drained through the outlet of the back pressure regulator that maintains pressure within the collection and precipitation chambers. After pumping out the IPC / polymer solution and cleaning the tubes with the same solvent used to prepare the IPC / polymer solution, the residual solvents that remained within both the precipitation and collection chambers were removed by washing these chambers with Pure CO ^2. After the washing process, the CO ² slowly drained out of the collection chamber. Once the CO ^{2 was} completely removed, the particles were collected from the filter system for analysis.

For type I / P / S particles, a defined amount of solubilizer is added and dissolved in the IPC / polymer solution before pumping the solution through the precipitation nozzle according to the procedures described above.

For type I / P + S particles, a defined amount of solubilizer is added to the hybrid nanoparticles in a glass bottle. The glass bottle is slowly rotated to mix the solubilizer with the hybrid nanoparticles.

Table A Stable Amorphous Hybrid Nanoparticles with Exemplary IPCs, Stabilizing and Matrix Forming Polymer Components, Solvents, Antisolvents, and Conditions

Dissolution measurement test overview

The procedure consists of adding the desired amount of hybrid nanoparticle powder to a glass bottle and then pouring the appropriate medium (typically FaSSIF, FeSSIF or SGF) into it. The medium was prepared according to the manufacturer's instructions. The amount of powder added depends on the desired "total IPC concentration". For some experiments where powders with high drug loadings were tested and compared, the actual amount of IPC in the hybrid nanoparticles was not taken into account. For other experiments, first, the drug loading was estimated by HPLC and the amount of powder was calculated to obtain the drug concentration. Typically, the powder was added to an 8 ml glass bottle and 7 ml of solution (usually FaSSIF, FeSSIF or SGF) was added. The glass bottle was placed on a shaker (approximately 1 rotation per minute) to dissolve. 500 µl samples were taken after different times and subsequently centrifuged at approximately 15,000 g for 3 minutes. The resulting supernatant was then analyzed by HPLC (Ci8 Eclipse column, 4.6 mm x 15 cm, 1 ml / min, detection at 254-400 nM. In general, samples were taken after 5, 30 and 90 minutes and , finally, 150 minutes.

Comparative

Example 1. Stable amorphous hybrid nanoparticles with nilotinib: solubility at pH 6.5 and pH 5

A number of experiments were carried out, where nilotinib base or nilotinib HCl represented the protein kinase inhibitor. The experiments were carried out by measuring the concentration of solubilized IPC (mg / l) after 5, 30 and 90 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting simulated intestinal fluid) . In addition, experiments were carried out in an alternative solution at about pH 5, namely FeSSIF (simulated intestinal fluid in fed state). The solution was sampled at various time intervals and the amount of protein kinase inhibitor was measured by the dissolution measurement assay described above.

Representative results in the FaSSIF solution are provided below in Table 1 and 2, where Table 1 provides data on the concentration of nilotinib HCl (mg / L) after 5, 30 and 90 minutes of dissolution, while Table 2 provides data on the% of nilotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in the AUC of the hybrid nanoparticles, in comparison with nilotinib HCl in crude crystalline form added to the solution (experiments 1-40). In Tables 3 and 4, dissolution data in the FeSSIF solution are provided, presented similarly to Table 1 and 2 (Experiments 41-55). Table 5 provides data from a comparative experiment with similar hybrid nanoparticles, carried out in FaSSIF and FeSSIF, respectively (experiments 56-57). Table 6 presents additional comparative data for experiments carried out in FaSSIF and FeSSIF, respectively, with hybrid nanoparticles produced by the methods of the invention.

Table 1. Nilotinib: concentration of nilotinib HCl (mg / l) after 5, 30 and 90 minutes of dissolution in FaSSIF H 6.5 solution

Table 2. Percentage of nilotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC of stable amorphous hybrid nanoparticles produced by the procedures of the invention, compared to nilotinib in crude crystalline form added to FaSSIF H 6.5 solution

Table 3. Nilotinib: concentration of nilotinib HCl (mg / l) after 5, 30 and 90 minutes of dissolution in FeSSIF H 5 solution

Table 4. Percentage of nilotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC:

mg / min / l) during 90 minutes of dissolution and the increase of the AUC of stable amorphous hybrid nanoparticles produced by the methods of the invention, compared to crude nilotinib in curd crystalline form added to the FeSSIF H 5 solution

Q- CO co _X c ^co LU co

LoO L rLa h LO- L 0L Conclusions Example 1

Experiments 17-23 show that an increase in solubility is obtained with the stable amorphous hybrid nanoparticles produced by the methods of the invention with nilotinib HCl and a stabilizing and matrix-forming polymer component. Particular improvements are achieved with the stabilizing and matrix-forming polymeric components hydroxypropylmethylcellulose phthalate (HPMCP HP55) and polyvinyl acetate phthalate (PVAP). These improvements are not obtained when nilotinib HCl is physically mixed with a stabilizing and matrix-forming polymer component. Experiments 24-36 clearly show that an increase in solubility is obtained with the hybrid nanoparticles produced by the processes of the invention with nilotinib HCl and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added. Particular improvements are achieved by the addition of a separate solubilizer such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) or d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). These improvements were not obtained when nilotinib HCl was physically mixed with a solubilizer and / or a stabilizing and matrix-forming polymer component (I + S or I + P + S). No particular improvements were obtained with hybrid nanoparticles with nilotinib HCl, a stabilizing and matrix-forming polymer component and a solubilizer (I / P / S).

The results carried out on FaSSIF and FeSSIF, respectively, indicate that the stable amorphous hybrid nanoparticles produced by the methods of the invention provide a similar increase in solubility. One problem with the IPC formulation is the effect of food. Several of the IPCs are indicated for administration in a fasting state despite the fact that food in most cases increases its bioavailability. The low bioavailability could partly explain the digestive problems associated with CPIs. The similar dissolution rate in FaSSIF and FeSSIF indicates that the hybrid nanoparticles produced by the methods of the invention (e.g. 56/57 experiments) can reduce the effect of food and digestive problems of the patient by improving the solubility that allows to reduce the dose. Thus, the hybrid nanoparticles produced by the methods of the invention can be administered in conjunction with food intake.

Comparative

Example 2. Stable amorphous hybrid nanoparticles with erlotinib HCl: solubility at pH 6.5 and pH 5

A number of experiments were carried out, where erlotinib HCl represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 5, 30 and 90 minutes of dissolution in a solution at approximately pH 6.5, namely, FaSSIF (fasting state simulated intestinal fluid). In addition, experiments were carried out in an alternative solution at about pH 5, namely FeSSIF (simulated intestinal fluid in fed state). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 7 and 8, where Table 7 provides erlotinib HCl concentration data (mg / L) after 5, 30 and 90 minutes of dissolution, while Table 8 provides data on the% erlotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in the AUC of the hybrid nanoparticles produced by the methods of the invention , compared to erlotinib HCl in crude crystalline form added to the solution (experiments 58-68). In Tables 9 and 10, dissolution data in the FeSSIF solution are provided, presented similarly to Table 7 and 8 (Experiments 69-73). In Table 11, data from a comparative experiment with similar hybrid nanoparticles produced by the methods of the invention, carried out in FaSSIF and FeSSIF, respectively (experiments 74-83), are presented. Table 12 presents additional comparative data for experiments carried out in FaSSIF and FeSSIF, respectively, with stable amorphous hybrid nanoparticles produced by the methods of the invention.

Table 7. Erlotinib: concentration of erlotinib HCl (mg / l) after 5, 30 and 90 minutes of dissolution in FaSSIF H 6.5 solution

Table 8. Percentage of erlotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC of stable amorphous hybrid nanoparticles produced by the procedures of the invention, compared to erlotinib in crude crystalline form added to FaSSIF H 6.5 solution

Table 9. Erlotinib: concentration of erlotinib HCl (mg / l) after 5, 30 and 90 minutes of dissolution in FeSSIF H 5 solution

Table 10. Percentage of erlotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC of stable amorphous hybrid nanoparticles produced by the procedures of the invention, compared to erlotinib in crude crystalline form added to FeSSIF H 5 solution

Table 11. Erlotinib: concentration of erlotinib HCl after 5, 30 and 90 minutes of dissolution in FaSSIF and FeSSIF solution, respectively

Table 12. Erlotinib: concentration of erlotinib HCl (mg / l) after 5, 30 and 90 minutes of dissolution in solution F IF F IF r ivm n r r n m m r iv

Conclusions Example 2

Experiments show that an increase in solubility is obtained with the stable amorphous hybrid nanoparticles produced by the methods of the invention with erlotinib HCl and a stabilizing and matrix-forming polymer component. Particular improvements are achieved with the stabilizing and matrix-forming polymeric component hydroxypropylmethylcellulose acetate succinate (HPMC-AS). Experiments 65-66 and 72 show that an increase in solubility is obtained with the hybrid nanoparticles produced by the methods of the invention with erlotinib HCl and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added. Improvements are achieved by adding a separate solubilizer, wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). This improvement was not observed when the solubilizer was incorporated into the hybrid nanoparticles produced by the methods of the invention.

Physical mixtures of erlotinib HCl with a solubilizer and / or HPMC AS also improve the solubility in FaSSIF (experiments 59, 60-61, 62-63) but not in FeSSIF (experiment 69-72). One problem with the IPC formulation is the effect of food. Several of the IPCs are indicated for administration in a fasting state despite the fact that food in most cases increases its bioavailability. The low bioavailability could partly explain the digestive problems associated with CPIs. The data indicate that the hybrid nanoparticles produced by the methods of the invention can reduce the effect of food and digestive problems of the patient by their equal improvement in solubility in both FaSSIF and FeSSIF (experiments 76/77 and 82/83). which can also potentially allow the dose to be reduced. Thus, the stable amorphous hybrid nanoparticles produced by the methods of the invention can be administered in conjunction with food intake.

Comparative

Example 3. Pazopanib Stable Amorphous Hybrid Nanoparticles: Solubility at pH 6.5 and pH 5

A number of experiments were carried out, where pazopanib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 5, 30 and 90 minutes of dissolution in a solution at approximately pH 6.5, namely, FaSSIF (fasting state simulated intestinal fluid). In addition, experiments were carried out in an alternative solution at about pH 5, namely FeSSIF (simulated intestinal fluid in fed state). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 13 and 14, where Table 13 provides data on the concentration of pazopanib (mg / L) after 5, 30, and 90 minutes of dissolution, while Table 14 provides data on the% of pazopanib solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC with the hybrid nanoparticles produced by the methods of the invention, in comparison with pazopanib in crude crystalline form added to the solution (experiments 84-93). In Tables 15 and 16, dissolution data in the FeSSIF solution are provided, presented similarly to Table 13 and 14 (Experiments 94-101). In Table 17, the data of a comparative experiment with similar hybrid nanoparticles produced by the methods of the invention, carried out in FaSSIF and FeSSIF, respectively (experiments 102-109) are presented. Table 18 presents additional comparative data for experiments carried out in FaSSIF and FeSSIF, respectively, with hybrid nanoparticles produced by the methods of the invention.

Table 13. Pazopanib: concentration of pazopanib (mg / l) after 5, 30 and 90 minutes of dissolution in FaSSIF H 6.5 solution

Table 14. Percentage of pazopanib solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to pazopanib in crude crystalline form added to FaSSIF H 6.5 solution

Table 15. Pazopanib: concentration of pazopanib (mg / l) after 5, 30 and 90 minutes of dissolution in FeSSIF H 5 solution

Table 16. Percentage of pazopanib solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the processes of the invention , compared to crude pazopanib in crystalline form added to FeSSIF H 5 solution

Table 17. Pazopanib: concentration of pazopanib after 5, 30 and 90 minutes of dissolution in FaSSIF FeSSIF solution, resectively

Table 18. Pazopanib: concentration of pazopanib (mg / l) after 5, 30 and 90 minutes of dissolution in solution F IF F IF r ivm n r r n m m r iv

Conclusions Example 3

The experiments show that an increase in solubility is obtained with the stable amorphous hybrid nanoparticles produced by the processes of the invention with pazopanib and a stabilizing and matrix-forming polymer component. Particular improvements are achieved with the polymeric stabilizer and matrix-forming component polyvinylpyrrolidone K-90 (PVP 90K). Experiments 91-92 show that an increase in solubility is obtained with the hybrid nanoparticles produced by the methods of the invention with pazopanib and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added. Improvements are achieved by adding a separate solubilizer, wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). This improvement was not observed when the solubilizer was incorporated into the hybrid nanoparticles produced by the methods of the invention.

The results carried out on FaSSIF and FeSSIF, respectively, indicate that the hybrid nanoparticles produced by the methods of the invention provide a similar increase in solubility. One problem with the IPC formulation is the effect of food. Several of the IPCs are indicated for administration in a fasting state despite the fact that food in most cases increases its bioavailability. The low bioavailability could partly explain the digestive problems associated with CPIs. The similar dissolution rate in FaSSIF and FeSSIF indicates that the hybrid nanoparticles produced by the methods of the invention can reduce the effect of food and digestive problems of the patient by their equal improvement in solubility in both FaSSIF and FeSSIF (Experiments 89 / 100 and 104/105) that also allow reducing the dose. Thus, the stable amorphous hybrid nanoparticles produced by the methods of the invention can be administered in conjunction with food intake.

Comparative

Example 4. Lapatinib Stable Amorphous Hybrid Nanoparticles:

solubility at pH 6.5

A number of experiments were carried out, where lapatinib base or lapatinib ditosylate salt represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 5, 30 and 90 minutes of dissolution in a solution at approximately pH 6.5, namely, FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 19 and 20, where Table 19 provides lapatinib concentration data (mg / L) after 5, 30, and 90 minutes of dissolution, while Table 20 provides data on the% of lapatinib solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC with the hybrid nanoparticles produced by the methods of the invention, in comparison to added unformulated lapatinib ditosylate salt to solution (experiments 110-126).

Table 19. Lapatinib: concentration of lapatinib (mg / l) after 5, 30 and 90 minutes of dissolution in FaSSIF H 6.5 solution

Table 20. Percentage of lapatinib solubilized after 30 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 90 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the processes of the invention , compared to unformulated lapatinib ditosylate salt added to FaSSIF H 6.5 solution

Conclusions Example 4

Experiments 122-125 clearly show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the processes of the invention, with lapatinib, in particular lapatinib base and a stabilizing and matrix-forming polymer component, where a solubilizer separated to the composition. Particular improvements are achieved with the polymeric stabilizer and matrix forming component hydroxypropylcellulose EF and hydroxypropylcellulose LF. Furthermore, improvements are achieved by adding a separate solubilizer, where said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherol succinate polyethylene glycol 1000 (TPGS).

Comparative

Example 5. Stable amorphous hybrid nanoparticles with nilotinib HCl: solubility at pH 1.4

A number of experiments were carried out, where nilotinib HCl represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 5, 30 and 90 minutes of dissolution in a solution at about pH 1.4, namely SGF (simulated gastric fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the SGF solution are provided below in Table 21, which provides the percentage of solubilized nilotinib HCl from both a physical mixture with nilotinib HCl in crude crystalline form and from hybrid nanoparticles produced by the methods of the invention after 5, 30 and 90 minutes of dissolution. The nilotinib present in the physical mixture of crude nilotinib HCl with the stabilizing and matrix-forming polymeric component PVAP and the solubilizer Soluplus (Exp.129) dissolves completely in 5 minutes in SGF, while nilotinib only partially dissolves after 90 minutes in SGF with hybrid nanoparticles produced by the methods of the invention, where the components are comprised as hybrid nanoparticles, with the addition of a solubilizer (Exp. 128) or without the addition of a solubilizer (Exp. 127).

Conclusions Example 5

Experiments 127-129 show that a stable amorphous hybrid nanoparticle nilotinib HCl produced by the methods of the invention (exp 127 and 128) is partially solubilized at pH 1.4. The stable amorphous hybrid nanoparticles produced by processes with an enteric coating polymer such as PVAP are partially protected from the acidic environment.

Comparative

Example 6. Gefitinib Stable Amorphous Hybrid Nanoparticles: Solubility at pH 6.5

A number of experiments were carried out, where gefitinib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 22 and 23, where Table 22 provides gefitinib concentration data (mg / L) after 3, 40 and 80 minutes of dissolution, while Table 23 provides data on the% of gefitinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with the hybrid nanoparticles produced by the methods of the invention, in comparison with unformulated gefitinib added to the solution (experiments 131-137).

Table 22. Gefitinib: gefitinib concentration (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF solution

H 6.5

Table 23. Percentage of gefitinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated gefitinib added to FaSSIF H 6.5 solution

Experiments 131-137 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the processes of the invention, with gefitinib, in particular gefitinib and a polymeric stabilizing and matrix-forming component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the polymeric stabilizer and matrix-forming component polyvinylpyrrolidone K-30 (PVP 30K) and hydroxypropylmethylcellulose phthalate (HPMCP HP55). Furthermore, the improvements are achieved by the addition of an added separate solubilizer, wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

Example 7. Stable amorphous hybrid nanoparticles with dasatinib: solubility at pH 6.5

A number of experiments were carried out, where dasatinib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 24 and 25, where Table 24 provides dasatinib concentration data (mg / L) after 3, 40, and 80 minutes of dissolution, while Table 25 provides data on the% dasatinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with the hybrid nanoparticles produced by the methods of the invention, in comparison with unformulated dasatinib added to the solution (experiments 138-141).

Table 24. Dasatinib: dasatinib concentration (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF H 6.5 solution

Table 25. Percentage of dasatinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated dasatinib added to FaSSIF H 6.5 solution

Experiments 138-141 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the processes of the invention, with dasatinib, in particular dasatinib and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the copolyvidone matrix-forming and stabilizing polymer component (Kollidon VA64). Furthermore, the improvements are achieved by the addition of an added separate solubilizer, wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

Comparative

Example 8. Stable amorphous hybrid nanoparticles with sorafenib tosylate: solubility at pH 6.5

A number of experiments were carried out, where sorafenib tosylate represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 26 and 27, where Table 26 provides sorafenib concentration data (mg / L) after 3, 40, and 80 minutes of dissolution, while Table 27 provides data of the% of sorafenib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase of the AUC of the compositions, compared to unformulated sorafenib tosylate added to the solution (experiments 142-145).

Table 26. Sorafenib tosylate: sorafenib concentration (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF H 6.5 solution

Table 27. Percentage of sorafenib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated sorafenib tosylate added to FaSSIF H 6.5 solution

Experiments 138-141 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the processes of the invention, with dasatinib, in particular dasatinib and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the polymeric stabilizer and matrix forming component hydroxypropylmethylcellulose phthalate (HPMCP HP55). Furthermore, the improvements are achieved by the addition of an added separate solubilizer, wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymer (Soluplus).

Comparative

Example 9. Stable amorphous hybrid nanoparticles based on nilotinib: solubility at pH 6.5

A number of experiments were carried out, where nilotinib base represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 28 and 29, where Table 28 provides nilotinib base concentration data (mg / L) after 3, 40, and 80 minutes of dissolution, while Table 29 provides data on the% of nilotinib base solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in the AUC of the compositions, compared to base of Non-formulated nilotinib added to the solution (experiments 146-149).

Table 28. Nilotinib base: concentration of nilotinib base (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF H 6.5 solution

Table 29. Percentage of nilotinib base solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the procedures of the invention, compared to unformulated nilotinib base added to FaSSIF H 6.5 solution

Comparative

Example 10. Crizotinib Stable Amorphous Hybrid Nanoparticles: Solubility at pH 6.5

A number of experiments were carried out, where crizotinib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above. Representative results in the FaSSIF solution are provided below in Table 30 and 31, where Table 30 provides crizotinib concentration data (mg / L) after 3, 40 and 80 minutes of dissolution, while Table 31 provides data on the% of crizotinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with the stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated crizotinib added to the solution (experiments 150-156).

Table 30. Crizotinib: crizotinib concentration (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF H 6.5 solution

Table 31. Percentage of crizotinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated crizotinib added to FaSSIF H 6.5 solution

Experiments 150-156 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the methods of the invention, with crizotinib, in particular crizotinib and a stabilizing and matrix-forming polymer component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the stabilizing and matrix-forming polymeric component polyvinylpyrrolidone K-30 (PVP 30K) and copolyvidone (Kollidon ^v A64). Furthermore, improvements are achieved by adding a separate solubilizer, wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymer (Soluplus) and PEG-40 hydrogenated castor oil (Cremophor RH40).

Comparative

Example 11. Stable amorphous hybrid nanoparticles with axitinib: solubility at pH 6.5

A number of experiments were carried out, where axitinib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above. Representative results in the FaSSIF solution are provided below in Table 32 and 33, where Table 32 provides axitinib concentration data (mg / L) after 3, 40, and 80 minutes of dissolution, while Table 33 provides data of the% axitinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with the stable amorphous hybrid nanoparticles produced by the methods of the invention , in comparison with Unformulated axitinib added to the solution (experiments 157-163).

Table 32. Axitinib: axitinib concentration (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF solution

H 6.5

Table 33. Percentage of axitinib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated axitinib added to FaSSIF H 6.5 solution

Experiments 157-163 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the methods of the invention, with axitinib, in particular axitinib and a stabilizing and matrix-forming polymeric component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the copolyvidone matrix-forming and stabilizing polymer component (Kollidon VA64) and hydroxypropylmethylcellulose acetate succinate (HPMC AS). Furthermore, improvements are achieved by adding a separate added solubilizer, wherein said solubilizer is polyvinyl caprolactam-acetate copolymer. polyvinyl-polyethylene glycol (Soluplus).

Comparative

Example 12. Stable Amorphous Hybrid Nanoparticles with Vemurafenib: Solubility at pH 6.5

A number of experiments were carried out, where vemurafenib represented the IPC. The experiments were carried out by measuring the IPC concentration (mg / l) after 3, 40 and 80 minutes of dissolution in a solution at approximately pH 6.5, namely FaSSIF (fasting state simulated intestinal fluid). The solution was sampled at various time intervals and the amount of IPC was measured by the dissolution measurement test described above.

Representative results in the FaSSIF solution are provided below in Table 34 and 35, where Table 34 provides vemurafenib concentration data (mg / L) after 3, 40, and 80 minutes of dissolution, while Table 35 provides data on the% of vemurafenib solubilized after 40 minutes of dissolution, the area under the curve (AUC: mg / min / l) during 80 minutes of dissolution and the increase in AUC with the stable amorphous hybrid nanoparticles produced by the methods of the invention , compared to unformulated vemurafenib added to the solution (experiments 164-170).

Table 34. Vemurafenib: concentration of vemurafenib (mg / l) after 3, 40 and 80 minutes of dissolution in FaSSIF H 6.5 solution

Experiments 164-170 show that an increase in solubility is obtained with stable amorphous hybrid nanoparticles produced by the processes of the invention, with vemurafenib, in particular vemurafenib and a stabilizing and matrix-forming polymeric component, where a separate solubilizer is added to the composition. Particular improvements are achieved with the copolyvidone matrix-forming and stabilizing polymeric component (Kollidon VA64) and cellulose acetate phthalate (CAP). Furthermore, the improvements are achieved by the addition of an added separate solubilizer, wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

Example 13. Measurement of the dissolution rate under conditions of low concentration, stable amorphous hybrid nanoparticles produced by the methods of the invention

The measurement of the dissolution under conditions of low concentration of stable amorphous hybrid nanoparticles produced by the processes of the invention were measured in a procedure that consists of adding the desired amount of powder in a reading cuvette system (SOTAX, Allschwill, Switzerland) , mount the cuvette on your apparatus, and then pump the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the apparatus was set at 37 ° C. The amount of powder added to the cuvette depends on the drug loading of the powder: the exact amount of powder was calculated from the results obtained from the analysis of the drug loading of the powders.

Typically 3.5 to 7 mg of the IPC was added to the reading cuvette and pumped at a flow rate of 8 to 16 ml of medium / min (preferably about 8 ml of medium / min) through the powder. One ml samples were collected from the medium passing through the reading cuvette at predetermined times. These samples were analyzed by HPLC (eg C18 Eclipse column, 4.6 mm x 15 cm, 1 ml / min, detection 254-400 nm). Samples were taken after 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 when the medium exits the reading cell. The cumulative% solubilize of the amount of active substance added in the reading cuvette was calculated and plotted against time (min). The initial slope ("initial dissolution rate") from the graph was estimated, as measured over 0-10 minutes, and the dissolution rate of the material was taken under low concentration conditions at 37 ° C in the given dissolution medium.

Each experiment comprises a comparison between crude IPC with stable amorphous hybrid nanoparticles produced by the methods of the invention with the inhibitor and a representative matrix-forming and stabilizing polymer component.

Comparative

Example 13.1. Measurement of dissolution rate under low concentration conditions with stable, amorphous hybrid nanoparticles produced by the methods of the invention, comprising nilotinib HCl

In the experiments with nilotinib HCl, 4 mg was weighed into the reading cuvette (experiment 500) and compared with stable amorphous hybrid nanoparticles produced by the methods of the invention based on nilotinib and the stabilizing and matrix-forming polymeric component HPMCP HP55 (experiment 501). The results are represented in Table 36 below.

T l. Nil ini H l n n i i n n nr i n n F IF

Experiments 500-501 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the processes of the invention, based on nilotinib, is higher than the initial dissolution rate of nilotinib HCl in crude crystalline form.

Comparative

Example 13.2. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles, produced by the methods of the invention, comprising erlotinib HCl

In the erlotinib HCl experiments, 3.5 mg was weighed into the reading cuvette (experiment 510) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with erlotinib HCl and the matrix-forming and stabilizing polymer component HPMCP AS (experiment 511). The results are represented in Table 37 below.

T l 7. Erl ini H l n n i i n n nr i n n F IF

Experiments 510-511 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with erlotinib HCl, is higher than the initial dissolution rate of erlotinib HCl in crude crystalline form.

Comparative

Example 13.3. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles, produced by the methods of the invention, comprising pazopanib HCl

In the experiments with pazopanib HCl, 3.5 mg was weighed into the reading cuvette (experiment 520) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with pazopanib HCl and the stabilizing and matrix-forming polymeric component PVP90K (experiment 521). The results are represented in Table 38 below.

Table 38. Pazo anib HCl under conditions of low concentration in FaSSIF

Experiments 520-521 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with pazopanib HCl, is higher than the initial dissolution rate of pazopanib HCl in crude crystalline form.

Comparative

Example 13.4. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles produced by the methods of the invention, comprising lapatinib ditosylate

In the experiments with lapatinib ditosylate, 4 mg was weighed into the reading cuvette (experiment 530) and compared with stable amorphous hybrid nanoparticles produced by the methods of the invention based on lapatinib and the stabilizing and matrix-forming polymeric component HPC If (experiment 531). The results are represented in Table 39 below.

T l. L ini i il n n i i n n nr i n n F IF

Experiments 530-531 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, based on lapatinib, is higher than the initial dissolution rate of lapatinib ditosylate in crude crystalline form.

Comparative

Example 13.5. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles produced by the methods of the invention, comprising gefitinib

In the gefitinib experiments, 3.5 mg was weighed into the reading cuvette (experiment 540) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with gefitinib and the matrix-forming and stabilizing polymer component HPMCP HP55 ( experiment 541). The results are represented in Table 40 below.

T l 4. fiini n n i i n n nr i n n F IF

Experiments 540-541 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with gefitinib, is higher than the initial dissolution rate of gefitinib in crude crystalline form.

Example 13.6. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles, produced by the methods of the invention, comprising dasatinib

In the dasatinib experiments, 3.5 mg was weighed into the reading cuvette (experiment 550) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with dasatinib and the Kollidon VA64 copolyvidon matrix-forming and stabilizing polymer component. (experiment 551). The results are represented in Table 41 below.

T l 41. D ini n n i i n n nr i n n F IF

Experiments 550-551 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with dasatinib, is higher than the initial dissolution rate of dasatinib in crude crystalline form.

Comparative

Example 13.7. Measurement of the dissolution rate of low concentration conditions with stable amorphous hybrid nanoparticles produced by the methods of the invention, comprising sorafenib ditosylate

In the sorafenib ditosylate experiments, 3.5 mg was weighed into the reading cuvette (experiment 560) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with sorafenib ditosylate and the matrix-forming and stabilizing polymeric component HPMCP HP55 (experiment 561). The results are represented in table 42 below.

T l 42. r f ni i il n n i i n n nr i n n F IF

Experiments 560-561 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with sorafenib ditosylate, is higher than the initial dissolution rate of sorafenib ditosylate in crude crystalline form.

Comparative

Example 13.8. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles produced by the methods of the invention, comprising crizotinib

In the crizotinib experiments, 3.5 mg was weighed into the reading cuvette (experiment 570) and compared with stable amorphous hybrid nanoparticles produced by the methods of the invention with crizotinib and the stabilizing and matrix-forming polymeric component PVP 30 ^k (experiment 571). The results are represented in table 43 below.

T l 4. riz ini n n i i n n nr i n n F IF

Experiments 570-571 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with crizotinib, is higher than the initial dissolution rate of crizotinib in crude crystalline form.

Comparative

Example 13.9. Measurement of the dissolution rate of low concentration conditions with stable, amorphous hybrid nanoparticles produced by the methods of the invention, comprising axitinib

In the axitinib experiments, 3.5 mg was weighed into the reading cuvette (experiment 580) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with axitinib and the matrix-forming and stabilizing polymer component Kollidon VA64 ( Run 581) or HPMCP AS (Run 582). The results are represented in Table 44 below.

T l 44. Axiini n n i i n n nr i n n F IF

Experiments 580-582 show that the initial dissolution rate of the stable amorphous hybrid nanoparticles produced by the methods of the invention, with axitinib, is higher than the initial dissolution rate of axitinib in crude crystalline form.

Comparative

Example 13.10. Measurement of the dissolution rate under conditions of low concentration of stable, amorphous hybrid nanoparticles produced by the methods of the invention comprising vemurafenib

In the vemurafenib experiments, 3.5 mg was weighed into the reading cuvette (experiment 590) and compared to stable amorphous hybrid nanoparticles produced by the methods of the invention with vemurafenib and the matrix-forming and stabilizing polymer component Kollidon VA64 ( experiment 591) or CAP (experiment 592). The results are represented in Table 45 below.

Table 45. Vemurafenib under conditions of low concentration in FaSSIF

Experiments 590-592 clearly show that the initial dissolution rate of hybrid nanoparticles Stable amorphous produced by the processes of the invention, with vemurafenib, is greater than the initial dissolution rate of vemurafenib in crude crystalline form.

Comparative

Example 14. Measurement in vivo of plasma concentrations after oral administration of stable amorphous hybrid nanoparticles produced by the methods of the invention

Groups of four male beagle dogs received single oral doses (5 mg / kg) of capsule compositions comprising stable amorphous hybrid nanoparticles produced by the methods of the invention based on nilotinib and any of the stabilizing and matrix-forming polymeric components PVAP or HPMCP HP55, optionally, with the addition of the solubilizing polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymer, and compared to a commercial formulation comprising nilotinib HCl. The stable amorphous hybrid nanoparticles tested are those set out in Experiments 146-149, in Example 9. The stomach contents of the dogs were neutralized with a sodium bicarbonate solution 5 min before capsule dosing or acidified with HCl-KCl buffer 10 min before dosing. A group of dogs also received a single intravenous dose (1 mg / kg) of nilotinib. Plasma nilotinib concentrations were determined with a selective LC-MS / MS procedure. No side effects were observed in any animal studied. Results and conclusions

Nilotinib base time-mean plasma concentration profiles ± SEM are shown in Figures 22-25, and pharmacokinetic parameters and results are shown in Tables 46A and 46B.

Outliers were calculated and excluded based on whether one value is a significant outlier relative to the rest at 95% confidence intervals (alpha = 5%) according to the Grubb test. The critical value Z for the Grubb test in the 95% confidence interval with n = 4 is 1.48. Z = (Average - Questionable value) / DT

Table 46A. Pharmacokinetic data after single oral administration of different nilotinib compositions comprising stable amorphous hybrid nanoparticles produced by the methods of the invention, in male dogs

by AP

utro

utro

Values are given as mean ± SD, except for T A of the commercially available nilotinib formulation administered on an overly acidic stomach, where only two values were obtained.

Intravenous (IV) data were obtained by constant rate 1 mg / kg IV infusion of a 0.2 mg / ml nilotinib solution in a 10% HPpCD, pH adjustment to pH 3.3 to 3.5. Co: 511 ± 46 ng / ml; RT: 3.3 ± 1.8 h; AUC0-24 h: 1000 ± 300 ng * h / ml.

Table 46B. Armature data after single oral administration of different nilotinib formulations comprising stable amorphous hybrid nanoparticles produced by the methods of the invention, in male dogs

Values are given as average ± SD

Intravenous (IV) data were obtained by constant rate 1 mg / kg IV infusion of a 0.2 mg / ml nilotinib solution in a 10% HPpCD, pH adjustment to pH 3.3 to 3.5. Co: 511 ± 46 ng / ml; T /: 3.3 ± 1.8 h; AUC0-24h: 1000 ± 300 ng * h / ml.

The marketed nilotinib formulation administered to an acidified stomach showed plasma concentrations approximately 2 times higher than those of the same formulation administered to a neutralized stomach. Both formulations comprising stable amorphous hybrid nanoparticles produced by the methods of the invention based on nilotinib with PVAP and HPMCP HP55 as stabilizing and matrix-forming polymeric components showed significant improvements in plasma exposure, with plasma concentrations approximately 2 times higher than those of the commercialized formulation administered to an acidified stomach. Furthermore, the combination of hybrid nanoparticles produced by the methods of the invention could give a plasma exposure that is more or less independent of the pH of the stomach.

Additional improvements in oral availability were observed when stable amorphous hybrid nanoparticle formulations produced by the processes of the invention were combined with the solubilizing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer. Therefore, the hybrid nanoparticles produced by the processes of the invention based on nilotinib with PVAP and HPMCP HP55 as stabilizing and matrix-forming polymer components, where the solubilizing copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol was added and administered to an acidified stomach resulted in plasma concentrations 2.3 to 3.1 times higher than those of the commercial formulation. In this study, a high oral bioavailability was achieved with the stable amorphous hybrid nanoparticles produced by the processes of the invention based on nilotinib with HPMCP HP55 as stabilizing and matrix-forming polymeric components, where the solubilizing polyvinyl caprolactam-acetate copolymer was added. of polyvinyl-polyethylene glycol (I / P + S) and administered to the neutralized stomach contents. In this case, the exposure increased approximately 7-fold over that of the commercially available oral formulation administered under the same neutralized conditions. In this study, the highest bioavailability, 36 ± 24%, was achieved when stable amorphous hybrid nanoparticles produced by the methods of the invention based on nilotinib with PVAP as stabilizing and matrix-forming polymeric components were administered to a neutralized stomach. However, this study group was also accompanied by the highest standard deviation in the study.

There was an improvement in the in vivo performance of the innovative formulations of nilotinib with the stable amorphous hybrid nanoparticles produced by the processes of the invention, which are based on improving absorption and bioavailability by optimizing the solid state properties of the galenic form. . The results of the in vivo study in dogs can predict similar absorption properties of hybrid nanoparticles produced by the methods of the invention, in patients, since there appears to be a close correlation in the absorption processes of gastrointestinal drugs between dogs and humans (Persson, EM et al., Pharm. Res. 2005, 22, 2141-2151). The hybrid nanoparticles produced by the methods of the invention, with advantageous absorption properties, also predict that the oral doses used in clinical practice today can be reduced. Furthermore, the stable amorphous hybrid nanoparticles produced by the processes of the invention can cause a lower pH dependence on the absorption and bioavailability of IPCs.

Comparative

Example 15. Measurement of the degree / level of stability of the stable amorphous hybrid nanoparticles produced by the processes of the invention

In stability tests of the stable amorphous hybrid nanoparticles produced by the procedures of the In the invention, the particles were shown to be stable for at least 11 months at room temperature (18-25 ° C), as measured by X-ray powder diffraction and dissolution rate by AUC measurement. In a series of experiments with hybrid nanoparticles comprising nilotinib and HPMCP HP55 produced by the methods of the invention, the resulting particles provided stable amorphous hybrid nanoparticles at 40% drug loading (I / P based on nilotinib / HPMCP HP55: exp 146 ), measured by DRXP as well as the dissolution rate by measurement of AUC. The material exhibited a glass transition temperature at approximately 127 ° C, indicating a single amorphous phase with inherent stability. Partially crystalline batches also processed similar inherent stability. 6 months storage at room temperature (18-25 ° C) of partially crystalline hybrid nanoparticles at 40% drug loading, I / P based on nilotinib / HPMCP HP55 did not show any sign of physical instability.

Thermogravimetric analysis provided a 1.7% mass loss from room temperature at 120 ° C. Dynamic vapor absorption analysis at 25 ° C gave a relative mass increase of approximately 7% from 0 to 90% RH (three cycles of 0 to 90% RH, did not induce a phase change) .

The high glass transition temperature, 1.7% mass loss from room temperature at 120 ° C, and moderate hygroscopicity suggest inherent stability. This is supported by multi-batch stability tests under various conditions. The longest stability point is 12 months at room temperature (18-25 ° C). No lot or condition has shown signs of physical instability (figure 27).

Modulated Differential Scanning Calorimetry ( CDBm)

Modulated Differential Scanning Calorimetry (CDBm) analysis was run on a TA Instruments model Q200 (New Castle, USA), equipped with a RC90 refrigerated refrigeration system (Home Automation, New Orleans, USA). Samples were weighed at 7 ± 2 mg into Tzero low mass aluminum containers and sealed with Tzero lids. They were then heated at a heating rate of 3 ° C / min from 0 to 170 ° C with a conventional modulation temperature span of 1 ° C and a modulation period of 40 seconds. Ultra-high purity nitrogen was used as the purge gas at a flow rate of 50 ml / min. All data analyzes were carried out using TA Universal Analysis software, version 4.7A. The temperature and cuvette constant calibrations were performed with the use of an indium standard before using the instrument. The CBD results were evaluated in terms of direct and inverse components of heat flux.

Thermogravimetry (TG) was performed on a Seiko TG / DTA 6200 and 90 µl open Pt-pan with approximately 10 to 20 mg of sample and a nitrogen flow of 200 ml / min. The temperature program was from room (20 ° C) to 400 ° C with a heating rate of 10 ° C / min. A blank was subtracted and TG data was normalized to sample size and analyzed using Muse Standard Analysis software, version 6.1 U.

Dynamic Vapor Sorption ( DVS)

The hygroscopicity of the samples was studied by dynamic vapor absorption gravimetry (DVS), using a DVS-1 (Surface Measurement Ltd., UK). Approximately 10 mg of the substance was weighed into a glass beaker. Relative weight was recorded over a 20 second interval when the target relative humidity (RH) over the sample gradually increased from 0% to 90% and then similarly decreased again to 0% RH , with 10% RH per stage. Each sample was analyzed in three consecutive full cycles. The condition for going to the next Hr level was a weight change of less than or equal to 0.002% in 15 minutes, with a maximum total time per stage of 24 hours. Due to the slow equilibrium in experiments of this type, the figures obtained should be considered as lower estimates of water absorption. The temperature was kept at 25 ° C.

X-ray powder diffraction ( DRXP)

The XRD experiments were run on an X'Pert Pro diffractometer (PANanalytical, Almelo, The Netherlands) configured in Bragg-Brentano geometry. The diffractometer was equipped with a 20 pm nickel filter and an X'Celerator RTMS detector with an active length of 2.122 ° 20. A representative sample was placed on a zero-quart bottom single crystal sample holder (Siltronix, Archamps , France). The experiments were processed using Cu Ka radiation (45 kV and 40 mA) at ambient temperature and humidity. Scans were processed in continuous mode in the range of 4.5-40 ° 20 using automatic divergence and anti-scattering gratings with an observed length of 10 mm, a common count time of 299.72 seconds, and a step size of 0. , 0167 ° 20. Data collection was performed using X'Pert Data Collector V.2.2j application software and V.2.1E instrument control software, while pattern analysis was performed using X'Pert Data Viewer V.1.2c (all softwares are from PANanalytical, Almelo, The Netherlands).

Dissolution rate by AUC measurement

The stable amorphous hybrid nanoparticles described in Exp 171 and Exp172 (I / P), as indicated below, were produced according to Exp 148, based on nilotinib, HPMCP HP55 and stored at room temperature for 11 months. The dissolution rate under conditions other than low concentration was tested at different time points and the results are presented in Table 47 and Figure 26. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer was added to improve solubility. . A comparison of the AUC over 80 minutes clearly shows that the dissolution rate profile of the particles is practically unchanged after 11 months of storage, for example the ratio of the AUC of the particles produced and tested, compared to the particles produced, tested and stored for 11 months is more than 97%.

T l 47.

Claims (12)

1. Process for producing stable amorphous solid dispersion particles comprising a protein kinase inhibitor selected from dasatinib, a salt of dasatinib, a hydrate of dasatinib, a solvate of dasatinib or a combination thereof and at least one polymeric component stabilizer and matrix former, said solid dispersion particles have an amorphous degree of 100%, the process comprises a) providing a first pressurized stream of said protein kinase inhibitor dissolved in a solvent; b) providing a second pressurized antisolvent stream comprising a supercritical or subcritical CO2 fluid, wherein said at least one matrix-forming and stabilizing polymer component is present in said first or second stream; and c) mixing said first and second streams, and spraying the mixed stream at the outlet of a nozzle, thereby forming said solid dispersion particles; followed by collecting said solid dispersion particles. The process according to claim 1, wherein said second pressurized antisolvent stream comprises a subcritical CO2 fluid with a pressure above or below 74 bar and a temperature of -30 ° C to 31 ° C. 3. The process according to any of claims 1 or 2, wherein the amount of protein kinase inhibitor is 10 to 70% by weight of the solid dispersion particles formed. The process according to any of the preceding claims, wherein said at least one matrix-forming and stabilizing polymeric component is present in said supercritical or subcritical CO2 fluid. The process according to any one of the preceding claims, wherein said stabilizing and matrix-forming polymeric component is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl cellulose phthalate, crospovidone, ethyl acrylate-methacrylic acid copolymer, methyl methacrylate-acid methacrylate copolymer, polyethylene glycol, polyvinyl caprolactamaacetate-polyvinyl acetate-polyethylene glycol copolymer, DL-lactide / acetylene glycolide copolymer, DL-cellulto-lactose polypropylene Type A carbomer homopolymer, Type B carbomer homopolymer, aminoalkyl methacrylate copolymers and poloxamers. The process according to any of the preceding claims, wherein said stabilizing and matrix-forming polymeric component is selected from hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, and cellulose acetate phthalate. polyvinylpyrrolidone. 7. The process according to any of the preceding claims, wherein a solubilizer is added to the solid dispersion particles obtained in step c. The process of claim 7, wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, da-tocopherol polyethylene glycol 1000 succinate and a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. The method according to any of the preceding claims, wherein said solid amorphous dispersion particles are characterized by providing an amorphous powder X-ray diffraction pattern. 10. The process according to any of the preceding claims, wherein said solvent is an organic solvent selected from DMSO and trifluoroethanol (TFE), or a mixture thereof. The process according to any one of the preceding claims, wherein said particles further comprise a solubilizer, within the particles. The method of claim 11, wherein said solubilizer is polyvinyl caprolactamaacetate-polyvinyl polyethylene glycol copolymer, da-tocopherol succinate polyethylene glycol 1000 or a hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or hydrogenated castor oil PEG-35.