Solid dispersions of HER2 inhibitors

Abstract

A solid dispersion of an HER2 inhibitor. The present invention relates to solid dispersions of HER2 inhibitors and pharmaceutically acceptable dispersion carriers. Also provided herein are pharmaceutical compositions and kits comprising the solid dispersions, their use, inter alia, for the treatment and / or prevention of cancer and methods of making the solid dispersions.

Description

Technical Field

[0001] The present invention relates to a solid dispersion of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide.

Background Art

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide (also referred to herein as compound (1) or zongertinib) is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. Zongertinib is an effective and selective wild-type and mutant HER2 tyrosine kinase inhibitor that does not affect wild-type epidermal growth factor receptor (EGFR). Thus, it can be used to treat and / or prevent diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly tumors and / or hyperproliferative diseases (such as cancer).

[0003] It has been found that the solubility of compound (1) in aqueous media is limited and strongly pH-dependent, with increased solubility under acidic conditions. Specifically, a decrease in solubility of approximately 10 5 -fold was observed between pH 1.2 and pH 6.8. Thus, the in vivo absorption of compound (1) is affected by gastric pH. Specifically, low gastric pH is associated with increased absorption of compound (1), while increased gastric pH results in decreased serum levels of compound (1). This pH-dependence is undesirable as it can reduce the bioavailability and / or bioaccessibility of compound (1). Due to the variability of gastric pH among patients, this reduction can occur to different extents in different patients.

[0004] In addition, the gastric pH of cancer patients can be altered by therapeutic agents in their treatment regimens (such as protein pump inhibitors (PPIs), antacids, or antihistamines, which are acid-lowering agents known to increase gastric pH). The therapeutic agents are typically administered to cancer patients to (for example) mediate gastrointestinal side effects caused by pharmaceuticals (especially those that lower gastric pH), and are also used to manage the effects of tumors in the gastric region. Thus, co-administration of an acid-lowering agent and compound (1) can reduce the absorption and systemic exposure of compound (1).

[0005] Therefore, there is still a need to reduce the pH-dependence of compound (1) to improve its bioavailability and / or bioaccessibility.

Description of the Drawings

[0006] Figure 1 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) having 75 wt% HPMCAS-M (top curve) and 50 wt% HPMCAS-M (bottom curve) obtained from Example 1 herein, compared to the XRPD of the crystalline Compound (1).

[0007] Figure 2 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) having 75 wt% PVP-VA (top curve) and 50 wt% PVP-VA (bottom curve) obtained from Example 1 herein, compared to the XRPD of the crystalline Compound (1).

[0008] Figure 3 Shows compared to the XRPD of the crystalline Compound (1), the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) having 75 wt% L100 (top curve) and 50 wt% L100 (bottom curve) obtained from Example 1 herein.

[0009] Figure 4 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) having 75 wt% HPMCHME 15LV (top curve) and 50 wt% HPMC HME 15LV (bottom curve) obtained from Example 1 herein, compared to the XRPD of the crystalline Compound (1).

[0010] Figure 5 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) obtained from Example 3.3 herein. From the top curve to the bottom curve: Sample 3.3-A (top curve), Sample 3.3-B (middle curve), and Sample 3.3-C (bottom curve).

[0011] Figure 6 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) obtained from Example 3.4 herein. From the top curve to the bottom curve: Sample 3.4-A (top curve) and Sample 3.4-B (bottom curve).

[0012] Figure 7X-ray powder diffraction patterns (XRPD) of amorphous solid dispersions of Compound (1) with HPMCAS-M (50 wt%:50 wt%) after exposure for three weeks at 75 °C / 79% relative humidity and 80 °C / 76% relative humidity. From the top curve to the bottom curve: stress-free sample (top), stressed sample at 75 °C / 79% relative humidity (middle), and stressed sample at 80 °C / 76% relative humidity (bottom).

[0013] Figure 8 Comparison of log solubility values measured in aqueous media at different pH: amorphous solid dispersions of Compound (1) with HPMCAS-M (50 wt%:50 wt%) (circles), crystalline Form III of Compound (1) (squares), and crystalline Form IV of Compound (1) (triangles).

[0014] Figure 9 In vitro dissolution profiles of various amorphous solid dispersions (25 wt%:75 wt% Compound (1): polymer) including different polymers in simulated intestinal fluid after transfer from simulated gastric fluid in the two-stage gastric transfer test of Example 5.2, compared to the dissolution profile of crystalline Compound (1). From the top curve to the bottom curve (relative to the first measurement point): HPMCHME 15LV, PVP-VA, HPMCAS-M, L100, and crystalline Compound (1).

[0015] Figure 10 In vitro dissolution profiles of various amorphous solid dispersions (50 wt%:50 wt% Compound (1): polymer) including different polymers in simulated intestinal fluid after transfer from simulated gastric fluid in the two-stage gastric transfer test of Example 5.2, compared to the dissolution profile of crystalline Compound (1). From the top curve to the bottom curve (relative to the first measurement point): HPMCAS-M, HPMC HME 15LV, PVP-VA, L100, and crystalline Compound (1).

[0016] Figure 11 Results of in vitro dissolution comparison of tablets containing crystalline Compound (1) (squares) and solid dispersions of Compound (1) (circles) at pH 2.0.

[0017] Figure 12 Results of in vitro dissolution comparison of conventional tablets containing crystalline Compound (1) (circles) and tablets containing solid dispersions of Compound (1) (squares Example 6.2-A, triangles Example 6.2-C) at pH 6.8.

[0018] Figure 13Schematic diagram showing a dynamic in vitro gastrointestinal tract model for simulating physiological processes occurring in a human gastric and small intestine mini-TIM model. A: Dietary inlet; B: Body of stomach; C: Proximal antrum; D: Distal antrum; E: Pyloric valve; F: Peristaltic valve; G: Small intestine compartment; H: Filtration system; I: Gastric secretion; J: Intestinal secretion; K: pH electrode; L: Liquid level sensor.

[0019] Figure 14 Results of in vitro determination of the bioaccessibility of a solid dispersion (“SDD”) of compound (1) over time compared to a conventional tablet (“Conv.”) of a crystalline compound (1) after administration of a proton pump inhibitor (PPI) at a 100 mg dose under fasting conditions (usually low gastric pH) and under conditions simulating a higher gastric pH.

[0020] Figure 15 Shows the X-ray powder diffraction pattern (XRPD) of the formulation disclosed in Example 6.1-C.

[0021] Figure 16 Shows the X-ray powder diffraction pattern (XRPD) of the formulation disclosed in Example 6.2-C.

Summary of the Invention

[0022] According to a first aspect, there is provided a solid dispersion comprising compound (1) as defined below or a pharmaceutically acceptable salt thereof:

[0023]

[0024] and a pharmaceutically acceptable dispersion carrier.

[0025] Another aspect relates to a pharmaceutical composition comprising the solid dispersion as set forth herein and one or more pharmaceutically acceptable excipients.

[0026] Another aspect relates to the solid dispersion as set forth herein or the pharmaceutical composition as set forth herein for use as a medicament.

[0027] Another aspect relates to the solid dispersion as set forth herein or the pharmaceutical composition as set forth herein for the treatment and / or prevention of tumors and / or hyperproliferative diseases.

[0028] In one embodiment of all aspects disclosed herein, the tumor and / or hyperproliferative disease is cancer.

[0029] Another aspect relates to a method for preparing the solid dispersion as set forth herein, the method comprising the following steps:

[0030] a) Providing a mixture of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier and adding a solvent to obtain a solution or suspension; and

[0031] b) Removing the solvent from the solution or suspension to form the solid dispersion as described.

[0032] On the other hand, it relates to the use of the solid dispersion as described herein for the preparation of the pharmaceutical composition as described herein.

[0033] On the other hand, it relates to a kit comprising:

[0034] - the solid dispersion or pharmaceutical composition as described herein; and

[0035] - a component containing the solid dispersion or pharmaceutical composition; and

[0036] - an optional desiccant. DETAILED DESCRIPTION OF THE INVENTION

[0038] The object of the present invention is to reduce the pH-dependence of compound (1) to improve its bioavailability and / or bioaccessibility.

[0039] Surprisingly, it has been found that compared with administering a formulation comprising the crystalline form of compound (1), a formulation of compound (1) as a solid dispersion can achieve sustained bioavailability and / or bioaccessibility and overcome the gastric pH variability among patients.

[0040] Specifically, the administration of the solid dispersion of compound (1) provides high absorption not only when administered to individuals who typically have a low gastric pH but also when administered in combination with agents that increase gastric pH (such as proton pump inhibitors, antacids or antihistamines). The surprising results shown in the examples described herein, especially the excellent in vitro and in vivo performance of the solid dispersion of the present invention compared to the formulations comprising crystalline compound (1) shown in Examples 5.1, 5.2 and 7.1 to 7.4 herein, indicate that a formulation of compound (1) as a solid dispersion provides sustained high absorption that is not affected by pH changes (such as those induced by co-medications that cause an increase in gastric pH value), thus making it possible to include in the treatment of compound (1) patient populations who are using combination medications such as proton pump inhibitors, antacids or antihistamines.

[0041] It has also been surprisingly found that compound (1) can remain in the amorphous state (such as in the solid dispersion), even when subjected to extended temperature and moisture stress as shown in Example 4 herein.

[0042] Compound (1)

[0043] As used herein, the term "compound (1)" refers to the compound or its pharmaceutically acceptable salt as defined below:

[0044]

[0045] The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. In the event of any inconsistency between the IUPAC name and the depicted formula, the formula shall prevail. Compound (1) is also known as zolotinib. Compound (1) was disclosed as Example Compound I-01 in WO 2021 / 213800. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines (such as compound (1)) as HER2 inhibitors and provides the synthetic procedures for compound (1). The properties of compound (1) and evidence of its inhibitory effect on HER2 wild type and YVMA kinase activity without affecting EGFR are also disclosed in WO2021 / 213800, which is incorporated herein by reference.

[0046] As used herein, the term "compound (1)" also encompasses any tautomer of the compound and pharmaceutically acceptable salts and all solid forms thereof, as well as solvates (including hydrates and solvates) of pharmaceutically acceptable salts thereof.

[0047] In an embodiment, compound (1) is the free base. Thus, in any aspect or embodiment, the term "compound (1) or a pharmaceutically acceptable salt thereof" may be replaced by "compound (1)" without reference to its pharmaceutically acceptable salts. In an embodiment, a pharmaceutically acceptable salt of compound (1) is used. As used herein, the term "pharmaceutically acceptable" refers to a compound, material, composition, and / or dosage form that, within the scope of sound medical judgment, is suitable for contact with human tissues without excessive toxicity, irritation, allergic response, or other problems or complications and is commensurate with a reasonable benefit / risk ratio.

[0048] As used herein, a "pharmaceutically acceptable salt" of compound (1) refers to compound (1) modified by preparing its acid or base salt. As used herein, the term pharmaceutically acceptable salt generally includes acid and base addition salts. Pharmaceutically acceptable acid addition salts refer to those salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, which are formed with inorganic or organic acids. Pharmaceutically acceptable base addition salts include salts derived from inorganic bases or organic non-toxic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines), basic or organic salts of acidic residues (such as carboxylic acids); and so on. For example, these salts include salts of benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. In an embodiment, the pharmaceutically acceptable salt is selected from chloride and fumarate.

[0049] Pharmaceutically acceptable salts can be synthesized from compound (1) by conventional chemical methods. Generally, these salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of an appropriate acid or base in water or an organic diluent or solvent (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile or a mixture thereof).

[0050] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0051] Solid dispersion

[0052] Provided herein is a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier.

[0053] Also provided herein is a solid dispersion consisting essentially of compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier. As used herein, the terms "consisting essentially of" and "consisting essentially of" have the meanings given to them in the art. Specifically, it indicates that another component may be present, particularly another component that does not substantially affect the properties of the individual dispersion, composition, or formulation. These other components may be, for example, residual solvents.

[0054] Also provided herein is a solid dispersion consisting of compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier.

[0055] As used herein, the term "solid dispersion" refers to a solid system comprising at least two components, wherein one component (e.g., compound (1) or generally an active pharmaceutical ingredient (API), preferably in an amorphous state) is dispersed in another component (e.g., a pharmaceutically acceptable solid dispersion carrier, particularly a dispersion polymer).

[0056] As used herein, the term "dispersion carrier" refers to the carrier component that allows the API (e.g., compound (1)) to be dispersed to form a solid dispersion. In an embodiment, compound (1) is molecularly dispersed in a pharmaceutically acceptable dispersion carrier.

[0057] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Accordingly, the present invention provides a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer. The polymer dispersion carrier is also referred to as a "dispersion polymer". Polymers are widely used in solid dispersion formulations. Different polymer carriers can produce solid dispersions with different properties in terms of physical stability, phase behavior, and drug release rate and extent. Due to the complexity of the carriers in solid dispersion formulations, it is necessary to test the carriers most suitable for a given API. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer.

[0058] In other embodiments, the pharmaceutically acceptable dispersion carrier is an enteric or non-enteric polymer, preferably enteric. In other embodiments, the polymer is enteric or non-enteric, preferably enteric. The term "enteric polymer" refers to a pH-dependent acidic polymer that is insoluble or only slightly soluble at low pH (e.g., about pH 1 to but less than pH 3) but soluble at higher pH (e.g., pH 5 and above). In certain embodiments, the pH-dependent polymer can become soluble in a pH range of about pH 5 and above (e.g., about pH 6 to about pH 9, about pH 6 to about pH 8, about pH 5 to about pH 7, or about pH 5 to about pH 6), which is generally less acidic than the gastric environment and roughly corresponds to the pH values in the small intestine. Examples of enteric polymers include but are not limited to copolymers of methyl acrylate-methacrylic acid, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), copolymers of methyl methacrylate-methacrylic acid ( L100), shellac, cellulose acetate trimellitate, sodium alginate, and zein. The term "non-enteric polymer" refers to neutral polymers that do not exhibit pH-dependent solubility characteristics. Examples of non-enteric polymers include (but are not limited to) cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), copovidone (e.g., polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA)), poly(ethylene glycol) PEG, starch derivatives (such as cyclodextrin), (an amphiphilic copolymer composed of polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate).

[0059] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group consisting of hydroxypropylmethylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylate and its copolymers. The pharmaceutically acceptable dispersion carrier may contain a mixture of two or more polymers.

[0060] In one embodiment, hydroxypropylmethylcellulose and its esters are selected from the group consisting of hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, hydroxyethyl ethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and carboxymethylcellulose acetate butyrate (CMCAB). In one embodiment, hydroxypropylmethylcellulose and its esters are selected from the group consisting of hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose (especially hot melt extrusion grade hydroxypropylmethylcellulose).

[0061] In one embodiment, polyvinylpyrrolidone and its copolymers are selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP) is also commonly referred to as polyvidone or povidone. In an embodiment, polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA).

[0062] In one embodiment, the polymethacrylate and its copolymer are selected from the group consisting of ethyl acrylate - methacrylic acid copolymer, methyl methacrylate - methacrylic acid copolymer, methyl methacrylate, and methacrylic acid copolymer. The polymethacrylate and its copolymer are (for example) available under the trade name obtained from Evonik Industries AG. The methyl methacrylate - methacrylic acid copolymer is (for example) available under the trade name L100. In certain embodiments, the polymethacrylate and its copolymer are methyl methacrylate - methacrylic acid copolymer.

[0063] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone - vinyl acetate copolymer (PVP - VA), methyl methacrylate - methacrylic acid copolymer (for example L100), and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0064] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hydroxypropyl methylcellulose acetate succinate. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinyl groups into the hydroxyl groups of the hydroxypropyl methylcellulose (HPMC) (also known as hydroxypropyl methylcellulose) backbone. This operation can be carried out by known methods, for example, by treating HPMC with acetic anhydride and / or succinic anhydride. Acetic anhydride and succinic anhydride can react with hydroxypropyl methylcellulose (HPMC) under specific controlled conditions to produce HPMCAS with different degrees of substitution of acetyl and succinyl groups.

[0065] HPMCAS is available in grades (L, M, and H) with different degrees of substitution of several acetyl and succinyl groups (based on the content of acetyl and succinyl (wt%) in the HPMCAS molecule). Any grade of HPMCAS can be used in the solid dispersions of the present invention. Preferably, HPMCAS of grade L, M, or H is used. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade L. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade M. HPMCAS grade M may include an acetyl content of 7–11 wt%; a succinyl content of 10–14 wt%; a methoxy content of 21–25 wt%; and a hydroxypropoxy content of 5–9 wt%. Preferably, HPMCAS grade M (HPMCAS-M) is soluble at pH ≥ 6. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade H. Preferably, particulate HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used for any grade of HPMCAS, especially for grade G, thus using HPMCAS-MG.

[0066] In certain embodiments, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA). Polyvinylpyrrolidone-vinyl acetate copolymer is a linear, random copolymer that can be obtained by free radical polymerization of the monomers in a ratio of vinyl acetate to vinylpyrrolidone of 70 / 30 to 30 / 70.

[0067] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methyl methacrylate-methacrylic acid copolymer, such as L100. As used herein, "methylacrylic acid methylmethacrylate copolymer" may be used interchangeably with "methacrylic acid methyl methacrylate copolymer".

[0068] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME). HPMC HME refers to a modified grade of hydroxypropyl methylcellulose with a low glass transition temperature and melt viscosity, which can be used to prepare solid dispersions via hot melt extrusion. HPMC HME is a water-soluble amorphous polymer (usually provided as white to off-white) that can be obtained in three grades with different molecular weights (HPMC HME 15LV, HPMC HME 100LV, and HPMC HME 4M). Preferably, the molecular weight (M W) HPMC HME 15LV with a molecular weight lower than 100 kDa. Further preferably, HPMC HME 100LV with a molecular weight (M W ) lower than 200 kDa is used.

[0069] By dispersing compound (1) (preferably at the molecular level) in a pharmaceutically acceptable dispersion carrier such as a polymer, the amorphous state can be maintained (even when exposed to elevated temperature and / or humidity conditions), and the solid dispersion can reliably provide compound (1) in an amorphous form. In an embodiment, compound (1) is amorphous. The preferred feature that compound (1) is amorphous can be applied to any of the embodiments disclosed herein to provide other embodiments of the present invention. In particular, it can be applied to any of the embodiments of the solid dispersions (including embodiments regarding the properties of the pharmaceutically acceptable dispersion carrier, the amounts of the components of the solid dispersion, etc.), pharmaceutical compositions, kits, uses, and methods described herein.

[0070] As used herein, the term "amorphous" refers to a condensed phase in which the molecules are randomly oriented and is characterized by the absence of any microscopic ordering, where XRPD shows no diffraction peaks; an amorphous solid system can consist of a single chemical entity or can be a multi-component system containing, for example, an API, a polymer, and other excipients without a stoichiometric composition. Amorphous solids generally have a short-range molecular arrangement similar to that of crystals, but without the long-range ordering of molecular packing found in crystalline solids. The solid state form of a solid can be determined, for example, by X-ray powder diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0071] In an embodiment, the solid dispersion comprises, consists essentially of, or consists of an amorphous compound (1) and a pharmaceutically acceptable dispersion carrier, wherein the compound (1) is substantially in an amorphous solid form. In certain embodiments, the substantially amorphous solid form refers to a solid dispersion in which, based on 100 wt% of the total weight of the compound (1), at least 80 wt% of the compound (1) is amorphous. In certain embodiments, the substantially amorphous solid form refers to a solid dispersion in which, based on 100 wt% of the total weight of the compound (1), at least 85 wt% of the compound (1) is amorphous. In certain embodiments, the substantially amorphous solid form refers to a solid dispersion in which, based on 100 wt% of the total weight of the compound (1), at least 90 wt% of the compound (1) is amorphous. In certain embodiments, the substantially amorphous solid form refers to a solid dispersion in which, based on 100 wt% of the total weight of the compound (1), at least 95 wt% of the compound (1) is amorphous. In certain embodiments, the substantially amorphous solid form refers to a solid dispersion in which, based on 100 wt% of the total weight of the compound (1), at least 96, 97, 98, or 99 wt% of the compound (1) is amorphous. Thus, the solid dispersion can provide the compound (1) in an amorphous or substantially amorphous state. This solid dispersion can thus be referred to as an amorphous solid dispersion. In certain embodiments, the solid dispersion is thus an amorphous solid dispersion.

[0072] In one embodiment, the solid dispersion comprises a predetermined amount of the compound (1) or a pharmaceutically acceptable salt thereof. In this context, the predetermined amount refers to the initial amount of the compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion.

[0073] In another embodiment, the solid dispersion comprises a therapeutically effective amount of the compound (1) or a pharmaceutically acceptable salt thereof.

[0074] In an embodiment, based on the total weight of 100 wt% of the solid dispersion, the compound (1) is present in an amount in the range of 5 wt% to 95 wt%. In an embodiment, based on the total weight of 100 wt% of the solid dispersion, the compound (1) is present in an amount in the range of 25 wt% to 75 wt%. In an embodiment, based on the total weight of 100 wt% of the solid dispersion, the pharmaceutically acceptable dispersion carrier is present in an amount in the range of 5 wt% to 95 wt%. In an embodiment, based on the total weight of 100 wt% of the solid dispersion, the pharmaceutically acceptable dispersion carrier is present in an amount in the range of 25 wt% to 75 wt%.

[0075] In an embodiment, based on the total weight of the solid dispersion of 100 wt%, compound (1) is present in an amount in the range of 20 wt% to 50 wt%. In an embodiment, based on the total weight of the solid dispersion of 100 wt%, compound (1) is present in an amount in the range of 25 wt% to 50 wt%. In an embodiment, based on the total weight of the solid dispersion of 100 wt%, a pharmaceutically acceptable dispersion carrier is present in an amount in the range of 50 wt% to 80 wt%. In an embodiment, based on the total weight of the solid dispersion of 100 wt%, a pharmaceutically acceptable dispersion carrier is present in an amount in the range of 50 wt% to 75 wt%.

[0076] The solid dispersion may comprise approximately equal weight amounts of compound (1) and a pharmaceutically acceptable dispersion carrier. In an embodiment, based on the total weight of 100 wt%, the solid dispersion comprises approximately 50 wt% of compound (1) and approximately 50 wt% of a pharmaceutically acceptable dispersion carrier, consists of or consists essentially of the same.

[0077] In an embodiment, based on the total weight of 100 wt%, the solid dispersion comprises approximately 25 wt% or 50 wt% of compound (1) and approximately 75 wt% or 50 wt% of a pharmaceutically acceptable dispersion carrier, consists of or consists essentially of the same.

[0078] In an embodiment, the weight ratio of compound (1):pharmaceutically acceptable dispersion carrier in the solid dispersion is from about 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:1 to 1:3. In an embodiment, the weight ratio of compound (1):pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 to 1:3. In an embodiment, the weight ratio of compound (1):pharmaceutically acceptable dispersion carrier in the solid dispersion is about 1:1.

[0079] As used herein, the terms “about” and “approximate” refer to within a statistically significant range of values. This range can be within an order of magnitude, typically within 10% of the indicated value or range, more typically 5% within, even more typically 1% within and or most typically 0.1% within. Sometimes, this range can be within the typical experimental error of the standard method used to measure and / or determine a given value or range.

[0080] In an embodiment, the solid dispersion comprises compound (1) and a pharmaceutically acceptable dispersion carrier in a weight ratio of from about 1:4 to 4:1, preferably 1:3 to 3:1 (such as 1:1 to 1:3). In an embodiment, the solid dispersion comprises compound (1) and a pharmaceutically acceptable dispersion carrier in a weight ratio of 1:1 to 1:3. In an embodiment, the solid dispersion comprises compound (1) and a pharmaceutically acceptable dispersion carrier in a weight ratio of about 1:1.

[0081] In one embodiment, the solid dispersion is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or , its X-ray powder diffraction pattern (XRPD) does not include diffraction peaks at 2θ angles equal to or lower than 40.0°. The "Cu-Kα radiation" used in the present invention includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, where the Cu-Kα1 radiation has as the wavelength and the Cu-Kα1,2 radiation has as the wavelength.

[0082] In another embodiment, the solid dispersion is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or , its X-ray powder diffraction pattern (XRPD) does not include diffraction peaks in the range of 2.0 to 40.0°.

[0083] In yet another embodiment, the solid dispersion is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or , its X-ray powder diffraction pattern (XRPD) is substantially the same as that shown below Figure 5 or Figure 6 .

[0084] In still another embodiment, the solid dispersion is characterized in that when measured by modulated differential scanning calorimetry (mDSC) with a modulation amplitude of 1 °C / min and a heating rate of 3.0 °C / min, its differential scanning calorimetry curve includes a single glass transition temperature (Tg) signal. Preferably, the single glass transition temperature (Tg) signal is in the range of 90 to 190 °C, preferably 110 to 120 °C.

[0085] In still other embodiments, the solid dispersion includes particles characterized by a particle size distribution determined by laser diffraction, and the particles have the following characteristics:

[0086] (i) The D90 value does not exceed 100 μm, preferably does not exceed 90 μm, and most preferably does not exceed 85 μm; and / or

[0087] (ii) The D50 value does not exceed 50 μm, preferably does not exceed 45 μm, and most preferably does not exceed 40 μm; and / or

[0088] (iii) The D10 value does not exceed 20 μm, preferably does not exceed 15 μm, and most preferably does not exceed 13 μm.

[0089] In still other embodiments, the solid dispersion comprises particles characterized by a particle size distribution determined by laser diffraction, the particles having the following characteristics:

[0090] (i) The D90 value ranges from 50 to 100 μm, preferably from 55 to 90 μm, most preferably from 60 to 85 μm; and / or

[0091] (ii) The D50 value ranges from 25 to 50 μm, preferably from 30 to 45 μm, most preferably from 30 to 40 μm; and / or

[0092] (iii) The D10 value ranges from 1 to 20 μm, preferably from 5 to 15 μm, most preferably from 10 to 13 μm.

[0093] As used herein, the term "particle size distribution" refers to a series of values or mathematical functions that define the relative amounts (usually by mass or volume) of particles present in a sample. The particle size distribution can be characterized by one or more values, such as D90, D50 or D10. The particle size distribution can be determined by methods familiar to those skilled in the art (such as laser diffraction).

[0094] As used herein, "D90" describes the value of the particle size such that 90% of the total volume of the particles comprises particles not larger than the specified size.

[0095] As used herein, "D50" describes the value of the particle size such that 50% of the total volume of the particles comprises particles not larger than the specified size.

[0096] As used herein, "D10" describes the value of the particle size such that 10% of the total volume of the particles comprises particles not larger than the specified size.

[0097] Other aspects relate to the use of the solid dispersion as described herein for the preparation of a pharmaceutical composition, wherein the pharmaceutical composition is preferably defined as follows.

[0098] Pharmaceutical composition

[0099] On the other hand, there is provided a pharmaceutical composition comprising the solid dispersion as described herein and one or more pharmaceutically acceptable excipients. Another embodiment of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion as described herein and one or more pharmaceutically acceptable excipients.

[0100] Another embodiment of the invention is a pharmaceutical composition comprising a predetermined amount of the solid dispersion as described herein and one or more pharmaceutically acceptable excipients. In this context, the predetermined amount refers to the initial amount of the solid dispersion used to prepare the pharmaceutical composition.

[0101] The term "pharmaceutically acceptable excipient" refers to a non-toxic component that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable excipients that can be used in the compositions of the present invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions may include other pharmaceutically acceptable excipients selected from buffers, binders, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, colorants, sweeteners, flavorants, flavor correctors, diluents, and other known additives for manufacturing pharmaceutical products.

[0102] The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. In an embodiment, one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents. In an embodiment, the pharmaceutical composition includes a filler, a disintegrant, a glidant, and a lubricant. In an embodiment, the pharmaceutical composition includes a filler, a disintegrant, a glidant, a lubricant, and a coating agent. It should be understood that the pharmaceutical composition may include one or more excipients for each function, such as one or more fillers, one or more disintegrants, one or more glidants, one or more lubricants, one or more coating agents.

[0103] In an embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof. In an embodiment, the disintegrant is selected from the group consisting of sodium carboxymethylcellulose cross-linked (also denoted as cross-linked sodium carboxymethylcellulose), sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In certain embodiments, the disintegrant is sodium carboxymethylcellulose cross-linked. In an embodiment, the glidant is colloidal silicon dioxide. In an embodiment, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0104] In an embodiment, one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, colloidal silicon dioxide, and sodium stearyl fumarate.

[0105] In an embodiment, the pharmaceutical composition comprises, consists of, or consists essentially of: a solid dispersion comprising a compound (1) as defined herein or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, colloidal silicon dioxide, and sodium stearyl fumarate.

[0106] In certain embodiments, the pharmaceutical composition comprises a coating agent, such as when formulated as a film-coated tablet. In an embodiment, the coating agent comprises a film-forming agent (such as partially hydrolyzed polyvinyl alcohol), an anti-adhesive agent (such as talc), a pigment (such as titanium dioxide, glyceryl monocaprylate / dicaprylate (GMDCC) and iron oxide (such as yellow iron oxide)), and a lubricant (such as sodium lauryl sulfate). The coating agent may be commercially available, for example, under the trade name (such as yellow AMBII). In a preferred embodiment, the coating agent does not contain titanium dioxide, such as without titanium dioxide.

[0107] In an embodiment, the pharmaceutical composition comprises:

[0108] (i) a tablet core comprising a solid dispersion, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate as described herein; and

[0109] (ii) a film coating.

[0110] In an embodiment, the pharmaceutical composition consists of or consists essentially of:

[0111] (i) a tablet core comprising a solid dispersion, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate, consisting of or consisting essentially of the same; and

[0112] (ii) a film coating.

[0113] In certain embodiments, the film coating is a non-functional film coating. In one embodiment, the film coating does not contain titanium dioxide.

[0114] In an embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises a solid dispersion as described herein in the range of 25 wt% to 65 wt%, preferably 35 wt% to 60 wt% or 25 wt% to 35 wt% or 27 wt% to 31 wt%, still preferably about 30 wt%.

[0115] In an embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises:

[0116] - a solid dispersion as described herein in the range of 25 wt% to 65 wt%; and / or

[0117] - one or more fillers in the range of 25 wt% to 65 wt%; and / or

[0118] - a disintegrant in the range of 4 wt% to 10 wt%; and / or

[0119] - Glidants in the range of -1 wt% to 2 wt%; and / or

[0120] - Lubricants in the range of -1 wt% to 2 wt%; and / or

[0121] - Optionally, coating agents in the range of 2 wt% to 5 wt%.

[0122] In any of the following embodiments of the present invention and those related to the wt% of the components of the pharmaceutical composition, it should be understood that the sum of the ranges or amounts of all components does not exceed 100 wt%.

[0123] In other embodiments, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises:

[0124] - Solid dispersions as described herein in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%; and / or

[0125] - One or more fillers in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%; and / or

[0126] - Disintegrants in the range of 4 wt% to 7 wt%; and / or

[0127] - Glidants in the range of 1 wt% to 1.5 wt%; and / or

[0128] - Lubricants in the range of 1 wt% to 1.5 wt%; and / or

[0129] - Optionally, coating agents in the range of 3 wt% to 5 wt%.

[0130] In still other embodiments, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises:

[0131] - Solid dispersions as described herein in the range of 25 wt% to 35 wt%; and / or

[0132] - One or more fillers in the range of 55 wt% to 65 wt%; and / or

[0133] - Disintegrants in the range of 4 wt% to 7 wt%; and / or

[0134] - Glidants in the range of 1 wt% to 2 wt%; and / or

[0135] - Lubricants in the range of 1 wt% to 2 wt%; and / or

[0136] - Optionally, coating agents in the range of 3 wt% to 5 wt%.

[0137] In one embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises:

[0138] - a solid dispersion as described herein in the range of 28 wt% to 30 wt%; and / or

[0139] - one or more fillers in the range of 57 wt% to 62 wt%; and / or

[0140] - a disintegrant in the range of 4 wt% to 5 wt%; and / or

[0141] - a glidant in the range of 1.4 wt% to 1.5 wt%; and / or

[0142] - a lubricant in the range of 1.4 wt% to 1.5 wt%; and / or

[0143] - optionally about 4 wt% of a coating agent.

[0144] In this embodiment, preferably, the lower limit of the ranges of the solid dispersion, filler, disintegrant, glidant and lubricant refers to the pharmaceutical composition with a coating agent, while the upper limit of the same ranges refers to the pharmaceutical composition without a coating agent.

[0145] In an embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition consists essentially of or consists of:

[0146] - a solid dispersion as described herein in the range of 25 wt% to 65 wt%;

[0147] - one or more fillers in the range of 25 wt% to 65 wt%;

[0148] - a disintegrant in the range of 4 wt% to 10 wt%;

[0149] - a glidant in the range of 1 wt% to 2 wt%; and

[0150] - a lubricant in the range of 1 wt% to 2 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0151] In other embodiments, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition consists essentially of or consists of:

[0152] - a solid dispersion as described herein in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%;

[0153] - one or more fillers in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%;

[0154] - A disintegrant in the range of -4 wt% to 7 wt%;

[0155] - A glidant in the range of 1 wt% to 1.5 wt%; and

[0156] - A lubricant in the range of 1 wt% to 1.5 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0157] In still other embodiments, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition consists essentially of or consists of the following:

[0158] - A solid dispersion as described herein in the range of 25 wt% to 35 wt%;

[0159] - One or more fillers in the range of 55 wt% to 65 wt%;

[0160] - A disintegrant in the range of 4 wt% to 7 wt%;

[0161] - A glidant in the range of 1 wt% to 2 wt%; and

[0162] - A lubricant in the range of 1 wt% to 2 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0163] In an embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises a compound (1) in the range of 10 to 20 wt%. In an embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises an amount of compound (1) of approximately 15 wt%.

[0164] In a particular embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises, consists essentially of, or consists of: approximately 15 wt% of compound (1), approximately 15 wt% of hypromellose acetate succinate, approximately 36 wt% of microcrystalline cellulose, approximately 24 wt% of mannitol, approximately 7 wt% of croscarmellose sodium, approximately 1.5 wt% of colloidal silicon dioxide, and approximately 1.5 wt% of sodium stearyl fumarate.

[0165] In a particular embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises, consists essentially of, or consists of: approximately 15 wt% of compound (1), approximately 15 wt% of hypromellose acetate succinate, approximately 20 wt% of microcrystalline cellulose, approximately 42 wt% of mannitol, approximately 5 wt% of croscarmellose sodium, approximately 1.5 wt% of colloidal silicon dioxide, and approximately 1.5 wt% of sodium stearyl fumarate.

[0166] In a particular embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises, consists essentially of, or consists of the following: approximately 14 wt% of compound (1), approximately 43 wt% of hypromellose acetate succinate, approximately 19 wt% of microcrystalline cellulose, approximately 24 wt% of mannitol, approximately 7 wt% of croscarmellose sodium, approximately 1.5 wt% of colloidal silicon dioxide, and approximately 1.5 wt% of sodium stearyl fumarate.

[0167] In a particular embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises, consists essentially of, or consists of the following: approximately 17.5 wt% of compound (1), approximately 17.5 wt% of hypromellose acetate succinate, approximately 30 wt% of microcrystalline cellulose, approximately 25 wt% of mannitol, approximately 7 wt% of croscarmellose sodium, approximately 1.5 wt% of colloidal silicon dioxide, and approximately 1.5 wt% of sodium stearyl fumarate.

[0168] In a particular embodiment, based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises, consists essentially of, or consists of the following: approximately 15 wt% of compound (1), approximately 47 wt% of hypromellose acetate succinate, approximately 15 wt% of microcrystalline cellulose, approximately 15 wt% of mannitol, approximately 5 wt% of croscarmellose sodium, approximately 1 wt% of colloidal silicon dioxide, and approximately 1 wt% of sodium stearyl fumarate.

[0169] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of the following: approximately 15 mg of compound (1), approximately 15 mg of hypromellose acetate succinate, approximately 36 mg of microcrystalline cellulose, approximately 24 mg of mannitol, approximately 7 mg of croscarmellose sodium, approximately 1.5 mg of colloidal silicon dioxide, and approximately 1.5 mg of sodium stearyl fumarate.

[0170] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of the following: approximately 15 mg of compound (1), approximately 15 mg of hypromellose acetate succinate, approximately 20 mg of microcrystalline cellulose, approximately 42 mg of mannitol, approximately 5 mg of croscarmellose sodium, approximately 1.5 mg of colloidal silicon dioxide, and approximately 1.5 mg of sodium stearyl fumarate.

[0171] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of: about 60 mg of compound (1), about 60 mg of hypromellose acetate succinate, about 80 mg of microcrystalline cellulose, about 168 mg of mannitol, about 20 mg of croscarmellose sodium, about 6 mg of colloidal silicon dioxide, and about 6 mg of sodium stearyl fumarate.

[0172] In one embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle equal to or lower than 10.0°.

[0173] In another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle equal to or lower than 9.0°.

[0174] In yet another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle equal to or lower than 6.5°.

[0175] In another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak in the range of 2.0 to 10.0°.

[0176] In yet another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak in the range of 2.0 to 9.0°.

[0177] In one embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak in the range of 2.0 to 6.5°.

[0178] In another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and using Cu-Kα radiation with a wavelength of or , its X-ray powder diffraction pattern (XRPD) does not include diffraction peaks in the range of 2.0 to 10.0°.

[0179] In yet another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and using Cu-Kα radiation with a wavelength of or , its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle of (5.9 ± 0.2)°.

[0180] In another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and using Cu-Kα radiation with a wavelength of or , its X-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle of (6.2 ± 0.2)°.

[0181] In another embodiment, the pharmaceutical composition is characterized in that when measured at a temperature in the range of 20 to 30 °C and using Cu-Kα radiation with a wavelength of or , its X-ray powder diffraction pattern (XRPD) is substantially the same as that shown below Figure 15 or Figure 16 .

[0182] For therapeutic use, the solid dispersion or pharmaceutical composition may be formulated or dispensed into suitable dosage units for ease of administration. Thus, the solid dispersion or pharmaceutical composition may be formulated into suitable dosage unit formulations for each route of administration. Typical pharmaceutical unit formulations include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (especially solutions for infusion), elixirs, syrups, cachets, emulsions, or dispersible powders. The dosage forms and formulations of the active ingredient are known in the art, and the dosage units can generally be prepared in any conventional manner.

[0183] The solid dispersion or pharmaceutical composition is preferably administrable by the oral route of administration and may be formulated into suitable dosage unit formulations. The pharmaceutical composition may be administered in the form of tablets, hard or soft gelatin capsules, pills, granules or suspensions. In an embodiment, the pharmaceutical composition is in the form of tablets, granules or capsules. In a preferred embodiment, the pharmaceutical composition is in the form of coated tablets. Suitable tablets may be obtained, for example, by mixing the solid dispersion with known excipients such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets may be compressed from the solid dispersion or a mixture of the solid dispersion and excipients or from its pellets. In other embodiments, the solid dispersion, the mixture of the solid dispersion and excipients or its pellets may be encapsulated.

[0184] Although oral administration may be preferred in view of compliance, the route of administration is not limited to oral administration, and the solid dispersion or pharmaceutical composition may be administered parenterally (e.g., by intramuscular, intraperitoneal, intravenous, percutaneous or subcutaneous injection or by implant) or enterally, nasally, vaginally, rectally or topically.

[0185] The solid dispersion or pharmaceutical composition may be administered in a therapeutically effective amount or incorporated in a dosage form of a therapeutically effective amount. A therapeutically effective amount means an amount that is effective at the dosage and for the period of time required to achieve the desired therapeutic result, and is the minimum amount required to prevent, ameliorate or treat a disease or disorder, or the amount whose therapeutic beneficial effects exceed any toxic or detrimental effects. As used herein, the terms “active ingredient”, “active pharmaceutical ingredient”, “active substance” and “API” refer to the component (e.g., compound (1)) intended to provide a pharmacological activity or other direct effect.

[0186] The pharmaceutical composition preferably contains a therapeutically effective amount of compound (1). In an embodiment, a therapeutically effective amount of compound (1) may be distributed in one or more individual dosage unit formulations, and thus several individual dosage unit formulations may contain a portion of the therapeutically effective amount of compound (1). In an embodiment, a tablet, a portion of granules or a capsule may contain between 5 mg and 100 mg of compound (1). In an embodiment, a tablet, a portion of granules or a capsule may contain between 15 mg and 80 mg of compound (1). In an embodiment, a tablet, a portion of granules or a capsule may contain between 15 mg and 30 mg of compound (1). In an embodiment, a tablet, a portion of granules or a capsule may contain approximately 15, 30 or 60 mg of compound (1).

[0187] For storage, the solid dispersion or pharmaceutical composition may be packaged into a suitable container (i.e., a member containing the solid dispersion or pharmaceutical composition). These containers may be selected from bags, blisters, bottles, ampoules and vials. The containers may be made of suitable packaging materials.

[0188] Typical packaging materials are selected from glass, polyethylene, polypropylene, polystyrene, polymethyl methacrylate, low density polyethylene (LDPE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin copolymer (COC), cycloolefin polymer (COP), polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate (PETg), aluminum, polyamide, and any combination thereof. In a particular embodiment, the solid dispersion is packaged into a double low density polyethylene (LDPE) bag. In yet another embodiment, the pharmaceutical composition is packaged into a high density polyethylene (HDPE) bottle. Preferably, the HDPE bottle further contains a desiccant. Typical desiccants are selected from activated alumina, aerogel, benzophenone (as an anion), bentonite, calcium chloride, calcium oxide, calcium sulfate, cobalt(II) chloride, copper(II) sulfate, lithium chloride, lithium bromide, magnesium chloride hexahydrate, magnesium sulfate, magnesium perchlorate, molecular sieve, phosphorus pentoxide, potassium carbonate, potassium hydroxide, rice, silica gel, sodium chlorate, sodium chloride, sodium hydroxide, sodium sulfate, sucrose, and sulfuric acid. In a preferred embodiment, the desiccant is silica gel.

[0189] Other embodiments of the present invention refer to kits, which include:

[0190] - a solid dispersion or pharmaceutical composition as described herein; and

[0191] - a component containing the solid dispersion or pharmaceutical composition, preferably a high density polyethylene bottle; and

[0192] - an optional desiccant, preferably silica gel.

[0193] Use for the treatment and / or prevention of tumors and / or hyperproliferative diseases

[0194] The solid dispersions and pharmaceutical compositions as described herein can be used as medicaments. Specifically, the solid dispersions and pharmaceutical compositions as described herein can be used for the treatment and / or prevention of tumors and / or hyperproliferative disorders, particularly for anti-cancer treatment.

[0195] According to one aspect, there is provided a solid dispersion as described herein for use as a medicament. According to another aspect, there is provided a pharmaceutical composition as described herein for use as a medicament. Another embodiment of the present invention is a solid dispersion or pharmaceutical composition for the treatment or prevention of a disease.

[0196] According to one aspect, there is provided a solid dispersion as described herein for use as an anti-cancer medicament. According to another aspect, there is provided a pharmaceutical composition as described herein for use as an anti-cancer medicament.

[0197] In one embodiment, there is provided a solid dispersion as described herein for the treatment and / or prevention of a HER2-mediated disease or disorder, particularly a tumor and / or a hyperproliferative disease. In other embodiments, there is provided a pharmaceutical composition as described herein for the treatment and / or prevention of a HER2-mediated disease or disorder, particularly a tumor and / or a hyperproliferative disease. Another aspect refers to the solid dispersion as described herein or the pharmaceutical composition as described herein for use in a method for the treatment and / or prevention of a HER2-mediated disease or disorder, particularly a tumor and / or a hyperproliferative disease.

[0198] Other aspects relate to a method for the treatment and / or prevention of a HER2-mediated disease or disorder, particularly a tumor and / or a hyperproliferative disease, the method comprising the step of administering to a patient the solid dispersion as described herein or the pharmaceutical composition as described herein. In one embodiment, the method comprises administering to a human in need of treatment a therapeutically effective amount of the solid dispersion or pharmaceutical composition as described herein.

[0199] Related aspects relate to the use of the solid dispersion as described herein or the pharmaceutical composition as described herein in the manufacture of a medicament. One embodiment relates to the use of the solid dispersion as described herein or the pharmaceutical composition as described herein for the manufacture of a medicament for the treatment and / or prevention of a HER2-mediated disease or disorder, particularly a tumor and / or a hyperproliferative disease.

[0200] In one aspect, there is provided a solid dispersion or pharmaceutical composition as described herein for the treatment and / or prevention of a disease and / or condition for which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly for the treatment and / or prevention of a disease and / or condition for which inhibition of the HER2 exon 20 mutant protein is therapeutically beneficial. Examples of such diseases and / or conditions include (but are not limited to) tumors and / or hyperproliferative diseases (such as cancer).

[0201] One aspect relates to the solid dispersion as described herein for the treatment and / or prevention of tumors and / or hyperproliferative diseases. Another aspect relates to the pharmaceutical composition as described herein for the treatment and / or prevention of tumors and / or hyperproliferative diseases.

[0202] As used herein, the term "hyperproliferative disease" refers to a condition in which cell growth has increased to an extent greater than normal. Hyperproliferative diseases include malignant diseases (such as cancer) and non-malignant diseases. In a preferred embodiment, the hyperproliferative disorder is cancer. As used herein, the term "tumor disease" refers to a disease or medical condition associated with cancer or a cancer indication. Cancers can be classified according to the type of tissue from which the cancer originated (histological type) and the primary site or location in the body where the cancer initially developed.

[0203] In one embodiment, the tumor and / or hyperproliferative disease is cancer.

[0204] In one embodiment, there is provided a solid dispersion as described herein for treating and / or preventing cancer. Other embodiments provide a pharmaceutical composition as described herein for treating and / or preventing cancer. Another aspect refers to the solid dispersion or the pharmaceutical composition as described herein for a method of treating and / or preventing cancer.

[0205] Other aspects relate to methods of treating and / or preventing cancer, wherein the method comprises the step of administering to a patient the solid dispersion or the pharmaceutical composition as described herein. In one embodiment, the method comprises administering to a human in need of treatment a therapeutically effective amount of the solid dispersion or pharmaceutical composition as described herein.

[0206] One embodiment relates to the use of the solid dispersion or the pharmaceutical composition as described herein in the manufacture of a medicament for treating and / or preventing cancer.

[0207] In embodiments, the cancer is HER2-overexpressing, HER2-amplified, and / or HER2-mutated cancer. In embodiments, the cancer is HER2 exon 20-mutated cancer. In embodiments, the tumor and / or hyperproliferative disease is HER2-overexpressing, HER2-amplified, and / or HER2-mutated cancer.

[0208] As used herein, "HER2 overexpression" refers to a cancer in which the cells of the cancer or tumor express HER2 at a level detectable by methods such as immunohistochemistry (e.g., IHC 2+ or IHC 3+) and / or analysis of ERBB2 messenger RNA.

[0209] As used herein, "HER2 amplification" refers to a cancer in which the cancer or tumor cells exhibit more than 2, particularly more than 3, 4, 5, 6, 7, 8, 9, or 10, preferably more than 6, copies of the HER2 gene ERBB2.

[0210] HER2 expression, gene copy number, and amplification can be measured, for example, by determining nucleic acid sequences (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISA, and RNA quantification using techniques such as RT-PCR, microarray analysis, and next-generation sequencing (NGS). HER2 expression in or on cancer specimen cells can be compared to reference cells. The reference cells can be non-cancer cells obtained from the same individual as the specimen cells. The reference cells can be non-cancer cells obtained from different individuals or a population of individuals.

[0211] A cancer may be termed "HER2-positive" when HER2 is overexpressed and / or amplified in or on the cancer cells.

[0212] As used herein, "HER2 mutant" refers to a cancer having at least one mutation (i.e., a change in the nucleic acid sequence of the HER2 gene and / or a change in the amino acid sequence of the HER2 protein, including (but not limited to) those listed below). The mutations can be detected by any method known to those skilled in the art (e.g., molecular diagnostic methods, including (but not limited to) polymerase chain reaction (PCR), single-strand conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism analysis (RFLP), next-generation sequencing (NGS), and whole exome sequencing).

[0213] As used herein, "cancer having a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer" refers to a cancer or tumor cell having at least one HER2 exon 20 mutation (including but not limited to the mutations listed below).

[0214] ERBB2 (HER2) exon 20 encodes a part of the kinase domain and encompasses amino acids 769 to 835. Each mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation, including the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup(YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insYVMS; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsLC; p.A776_delinsVV; p.A776_delinsAVGC; p.A776_delinsIC; p.A776_V777delinsCVC; p.V777_insE; p.G778_P780dup(GSP); p.G776_delinsVC ("p." refers to the HER2 protein).

[0215] In addition, oncogenic HER2 mutations exist outside of exon 20 and include the following mutations: p.S310F; p.R678Q; p.L755S; p.L755A; p.L755P; p.S310Y; p.S310A; p.V842I; p.D769Y; p.D769H; p.R103Q; p.G1056S; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L; p.V777L; p.V777M; p.R929W; p.D277H; p.D277Y; p.G660D ("p." refers to HER2 protein).

[0216] In embodiments, the tumor and / or hyperproliferative disease or cancer is one of the following cancers, tumors or other proliferative diseases (but not limited thereto):

[0217] Cancer / tumors / carcinomas of the head and neck: such as tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridges, retromolar area, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including tongue base, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including epiglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[0218] Lung cancer / tumor / carcinoma: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0219] Neoplasms of the mediastinum: for example, neurogenic tumors (including neurofibroma, schwannoma, neurosarcoma, ganglioneuroma, ganglioneuroma, neurocytoma, pheocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);

[0220] Cancers / tumors / neoplasms of the gastrointestinal (GI) tract: such as esophagus, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC) (e.g., pediatric HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC), hepatoblastoma, cholangiocarcinoma, cholangiocellular carcinoma, cystadenocarcinoma of the liver, angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus, colorectal cancer, gastrointestinal stromal tumor (GIST)), urogenital system (including kidney (e.g., renal pelvis), renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenomatoid tumor, Grawitz tumor, ureter, bladder (e.g., urachal carcinoma, urothelial carcinoma), urethra (e.g., terminal, bulbomembranous, prostatic), prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis, tumors / cancers / neoplasms of the appendix;

[0221] Cancers / tumors / neoplasms of the testis: such as seminoma, non-seminoma;

[0222] Gynecological cancers / tumors / neoplasms: such as tumors / cancers / neoplasms of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[0223] Cancers / tumors / neoplasms of the breast: such as breast cancer (invasive ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, duct carcinoma, cystadenocarcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast;

[0224] Cancers / tumors / neoplasms of the endocrine system: such as endocrine glands, thyroid (thyroid carcinoma / tumor: papillary, follicular, undifferentiated, medullary), parathyroid (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, tumors / cancers / neoplasms of the carotid body, islet cell tumors, paraganglioma tumors, pancreatic endocrine tumors (PET; non-fluorodopamine PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

[0225] Sarcomas of soft tissue: such as fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexiform sarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor;

[0226] Sarcomas of bone: such as myeloma, reticulum cell sarcoma, chondrosarcoma (including central type, peripheral type, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including extraperiosteal, periosteal, high grade surface, small cell, radiation induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, ameloblastoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0227] Mesothelioma: such as pleural mesothelioma, peritoneal mesothelioma;

[0228] Cancers of the skin: such as basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, uveal melanoma), actinic keratosis, eyelid carcinoma;

[0229] Neoplasms of the central nervous system and brain: such as astrocytoma (cerebral, cerebellar, diffuse, fibrillary, undifferentiated, pilocytic, protoplasmic, gemistocytic), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioma, neuroblastoma, retinoblastoma, schwannoma (such as acoustic), spinal tumor;

[0230] Cancers of the peripheral nervous system;

[0231] Lymphomas and leukemias: such as B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastic sarcoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myelogenous leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphogenous leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myelogenous leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0232] Cancers of unknown primary site (CUP).

[0233] All cancers / tumors / neoplasms mentioned above (characterized by their specific location / origin in the body) are intended to include both primary tumors and metastatic tumors derived therefrom. Preferably, cancers as defined herein (including those referred to as (e.g.) cancer types in any embodiment) are metastatic, advanced and / or unresectable.

[0234] All cancers / tumors / neoplasms mentioned above can be further differentiated by their histopathological classification:

[0235] Epithelial carcinomas (such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, undifferentiated, transitional cell, lymphoepithelial)), adenocarcinomas (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic carcinoma;

[0236] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphomas, melanomas, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0237] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancer, and skin cancer.

[0238] Preferably, the brain cancer is glioblastoma or glioma.

[0239] Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic.

[0240] Preferably, the endocrine cancer is a schwannoma, more preferably a HER2-mutated schwannoma.

[0241] Preferably, the gastrointestinal cancer is selected from the group consisting of: anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small intestine cancer. Additionally or alternatively, the gastrointestinal cancer can be a gastrointestinal neuroendocrine tumor, preferably a HER2-mutated cancer. More preferably, the gastrointestinal cancer is selected from the group consisting of: gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, specifically metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0242] Preferably, the gynecological cancer is selected from the group consisting of: cervical cancer, uterine cancer, endometrial cancer, and ovarian cancer.

[0243] Preferably, the head and neck tumor is a salivary gland cancer or tumor.

[0244] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0245] Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer.

[0246] Preferably, the skin cancer is not melanoma (non - melanoma skin cancer).

[0247] In some embodiments, the cancer is selected from the group consisting of: glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non - small cell lung cancer (NSCLC), peripheral nervous system cancer, and non - melanoma skin cancer.

[0248] In some embodiments, the cancer is a HER2 overexpressing, HER2 amplified, and / or HER2 mutated (specifically HER2 exon 20 mutation) cancer, and is selected from the group consisting of: glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non - small cell lung cancer (NSCLC), peripheral nervous system cancer, and non - melanoma skin cancer.

[0249] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0250] In some embodiments, the cancer is a HER2 overexpressing, HER2 amplified, and / or HER2 mutated (especially HER2 exon 20 mutation) cancer, and is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0251] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0252] In an embodiment, the cancer is a HER2 overexpressing, HER2 amplified, and / or HER2 mutated (particularly HER2 exon 20 mutated) cancer, which is selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0253] In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In other embodiments, the cancer is selected from cancers / tumors / carcinomas of the lung: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma). In still other embodiments, the cancer is NSCLC. In still other embodiments, the cancer is HER2 exon 20 mutated NSCLC.

[0254] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC having a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second or further line of treatment.

[0255] In an embodiment, the cancer is HER2 positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second or further line of treatment.

[0256] In an embodiment, the cancer is HER2 positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second or further line of treatment.

[0257] Other aspects relate to a compound (1), a solid dispersion, or a pharmaceutical composition for use as a medicament, particularly for the treatment and / or prevention of tumors and / or hyperproliferative disorders (such as cancer), wherein the compound (1), the solid dispersion, or the pharmaceutical composition is administered to:

[0258] - fasting individuals, and / or

[0259] - in combination with an agent that increases gastric pH (preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine), and / or

[0260] - an individual with a gastric pH in the range of about 1 to 7, preferably an individual with a gastric pH in the range of about 1 to 5.

[0261] In an embodiment, the solid dispersion as described herein or the pharmaceutical composition as described herein is administered to:

[0262] - a fasting individual, and / or

[0263] - in combination with an agent that increases gastric pH (preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine).

[0264] On the other hand, it relates to compound (1) as defined above for the treatment and / or prevention of tumors and / or hyperproliferative diseases, wherein compound (1) is administered to:

[0265] - a fasting individual, and / or

[0266] - in combination with an agent that increases gastric pH.

[0267] In an embodiment, compound (1), the solid dispersion, or the pharmaceutical composition is administered to a fasting individual.

[0268] As used herein, the term "individual" refers to a human being, such as a human being suffering from, susceptible to, or likely to suffer from cancer.

[0269] In an embodiment, compound (1), the solid dispersion, or the pharmaceutical composition is administered in combination with an agent that increases gastric pH (preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine).

[0270] In an embodiment, compound (1), the solid dispersion, or the pharmaceutical composition is administered to a fasting individual and in combination with an agent that increases gastric pH (preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine).

[0271] In an embodiment, compound (1), the solid dispersion, or the pharmaceutical composition

[0272] is administered to an individual with a gastric pH in the range of about 1 to 7.

[0273] In an embodiment, compound (1), the solid dispersion, or the pharmaceutical composition

[0274] is administered to an individual with a gastric pH in the range of about 1 to 5.

[0275] As used herein, a "fasting individual" refers to an individual who has not eaten for at least 8 hours (preferably at least 10 hours, typically overnight) prior to administration of the solid dispersion, pharmaceutical composition, or dosage form thereof. The fasting individual conveniently receives the compound (1), solid dispersion, pharmaceutical composition, or dosage form thereof with water after fasting for at least 8 or 10 hours. Thereafter, food intake is not permitted for a period of time (e.g., 4 hours), but a small amount of water may be ingested after receiving the medicament (e.g., 2 hours).

[0276] In an embodiment, a fasting individual refers to an individual who has not eaten for at least two hours prior to and / or at least one hour after administration of the solid dispersion or pharmaceutical composition described herein.

[0277] In an embodiment, a fasting individual refers to an individual who has not eaten for approximately two hours prior to and approximately one hour after administration of the solid dispersion or pharmaceutical composition described herein. In this embodiment, the fasting individual may be referred to as a "modified fasting individual".

[0278] "Agents that increase gastric pH" refer to a class of agents that neutralize gastric acidity. Agents that neutralize gastric acid can reduce the activity of pepsin. In an embodiment, the agent that increases gastric pH is a proton pump inhibitor. The term "proton pump inhibitor" (PPI) refers to a class of agents that cause a severe and long-term reduction in gastric acid production. In an embodiment, it is an inhibitor of gastric acid secretion. In an embodiment, the PPI that can be administered in combination with the compound (1), solid dispersion, or pharmaceutical composition includes (but is not limited to) rabeprazole, omeprazol, pantoprazole, esomeprazole, lansoprazole, dexlansoprazole, and ilaprazole. Rabeprazole is a proton pump inhibitor suitable for diseases with increased gastric pH (such as reflux esophagitis).

[0279] In an embodiment, the agent that increases gastric pH is an antacid. The term "antacid" refers to a class of agents that neutralize gastric acidity. In an embodiment, the antacids that can be administered in combination with the compound (1), solid dispersion, or pharmaceutical composition include (but are not limited to) salts of aluminum, calcium, magnesium, or sodium (such as aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and sodium bicarbonate).

[0280] In an embodiment, the agent for increasing gastric pH is an antihistamine, particularly an H2 receptor antagonist. The term "H2 receptor antagonist" refers to a class of agents that block the action of histamine in the stomach. In an embodiment, the antihistamines that can be administered in combination with compound (1), the solid dispersion, or the pharmaceutical composition include (but are not limited to) cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine, and niperotidine.

[0281] Compound (1), the solid dispersion, the pharmaceutical composition or its dosage form, and the agent for increasing gastric pH can be administered simultaneously, synchronously, sequentially, or continuously. The term "simultaneously" means administering two compounds / compositions at substantially the same time. The term "synchronously" means administering the active ingredients within the same conventional time period (e.g., on the same day but not necessarily at the same time). The term "sequentially" administration includes administering the active ingredients using one or more doses within a first time period (e.g., over several hours, days, or a week), and then administering other active ingredients using one or more doses within a second time period (e.g., over several hours, days, or a week). An overlapping schedule can also be employed, which includes administering the active ingredients on different dates during the treatment period, not necessarily in a regular order. Additionally, the term "continuous" administration means that the second administration step is carried out immediately after the end of the first compound administration. Variations of the said conventional administration forms can also be employed.

[0282] In an embodiment, compound (1), the solid dispersion, the pharmaceutical composition or its dosage form is administered after the agent for increasing gastric pH (preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine).

[0283] In another aspect, the present invention relates to the solid dispersion or the pharmaceutical composition as described herein for treating and / or preventing tumors and / or hyperproliferative diseases as defined herein, wherein the solid dispersion or the pharmaceutical composition is administered in combination with a cytostatic and / or cytotoxic active substance and / or with radiotherapy and / or immunotherapy.

[0284] In another aspect, the present invention relates to the combination of the solid dispersion or the pharmaceutical composition as described herein for treating and / or preventing cancer with a cytostatic and / or cytotoxic active substance and / or with radiotherapy and / or immunotherapy.

[0285] The solid dispersions or pharmaceutical compositions as described herein can be used alone or in combination with one or more other pharmacologically active substances (e.g., compounds of the current art or standard of care (such as cell proliferation inhibitors, anti-angiogenic substances, steroids, or immunomodulators / checkpoint inhibitors, etc.)).

[0286] Pharmacologically active substances that can be administered in combination with a solid dispersion or a pharmaceutical composition as described herein include, but are not limited to, hormones, hormone analogs, and antihormones (such as tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (such as anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (such as goserelin acetate, luprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER (such as, HER2, HER3, HER4)) and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors being, for example, (anti)growth factor antibodies, (anti)growth factor receptor antibodies, and tyrosine kinase inhibitors (such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab, and trastuzumab));Antimetabolites (such as antifolates (such as methotrexate, raltitrexed), pyrimidine analogs (such as 5-fluorouracil (5-FU)), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs (such as mercaptopurine, thioguanine), cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (such as anthracyclins (such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin), mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (such as cisplatin, oxaliplatin, carboplatin); alkylating agents (such as estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (such as carmustin and lomustine), thiotepa); antimitotic agents (such as Vinca alkaloids (such as vinblastine, vindesin, vinorelbin and vincristine) and taxanes (such as paclitaxel, docetaxel));Angiogenesis inhibitors (such as tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (such as epipodophyllotoxins (such as etoposide and etopophos), teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (such as PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, aurora kinase inhibitors), tyrosine kinase inhibitors (such as PTK2 / FAK inhibitors), protein-protein interaction inhibitors (such as IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (such as KRAS G12C inhibitors), signal transduction pathway inhibitors (such as SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (such as everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents (such as immune checkpoint inhibitors (such as CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins (such as ipilimumab, nivolumab, pembrolizumab))), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (such as anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T-cell engagers (such as bispecific T-cell engagers; such as, for example, CD3×BCMA, CD3×CD33, CD3×CD19), PSMA×CD3), tumor vaccines, and various chemotherapeutic agents (such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon α, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer).

[0287] Method for preparing a solid dispersion

[0288] The solid dispersions of the present invention can be prepared by any method known in the art, for example, as disclosed in S.V. Bhujbal et al., Acta Pharmaceutica Sinica B 2021; 11(8):2505e2536, which is incorporated herein by reference. According to the present invention, the solid dispersions are generally prepared by dissolving the active substance and a pharmaceutically acceptable dispersion carrier in a solvent or a solvent mixture to form a feed solution, and then removing the solvent from the feed solution, for example, by spray drying, to form the solid dispersion.

[0289] In one embodiment, there is provided a method for preparing a solid dispersion as described herein, the method comprising the steps of:

[0290] a) providing a mixture of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or a suspension; and

[0291] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein.

[0292] This method may further comprise the step of drying the solid dispersion obtained from step b).

[0293] In one embodiment, there is provided a method for preparing a solid dispersion as described herein, the method comprising the steps of:

[0294] a) providing a solution or suspension comprising compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and

[0295] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; and

[0296] c) optionally, drying the solid dispersion obtained from b).

[0297] The solution or suspension according to step a) of any of the methods described above may be referred to as the feed solution.

[0298] In an embodiment, the removal of the solvent in step b) of the method defined above is carried out by spray drying, freeze drying, rotary evaporation, distillation, drum drying and / or vacuum drying. In a preferred embodiment, the removal of the solvent in step b) is carried out by spray drying.

[0299] As used herein, the term "spray drying" is conventional and widely used and generally refers to any method involving atomizing a solution, suspension, slurry or emulsion of one or more components of a desired product into droplets by spraying and then rapidly evaporating the sprayed droplets into a solid powder by hot air at a certain temperature and pressure. Spray drying is a method known to those skilled in the art.

[0300] Spray drying is generally carried out by dissolving compound (1) and a pharmaceutically acceptable dispersion carrier in a solvent to prepare a feed solution. The feed solution can be aspirated into the drying chamber via an atomizer. The feed solution can be atomized by conventional methods known in the art (such as two-fluid ultrasonic nozzles, pressure nozzles, rotary nozzles and two-fluid non-ultrasonic nozzles). Then, the solvent is removed in the drying chamber to form a solid dispersion. Typically, the drying chamber uses a hot gas (such as forced air, nitrogen, nitrogen-rich air or argon) to dry the particles. The size of the drying chamber can be adjusted to achieve particle properties or throughput.

[0301] Although the solid dispersion is preferably prepared by conventional spray drying techniques, other techniques known in the art can be used (such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, dispersion technology (KSD), fluidized bed technology, drum drying, vacuum drying or other solvent removal methods).

[0302] The method for preparing the solid dispersion as described herein as set forth above may include an additional step of spraying the solution or suspension obtained in step a) onto an inert excipient core between steps a) and b). This method belongs to fluidized bed technology, especially fluidized bed granulation technology.

[0303] In one embodiment, there is provided a method for preparing a solid dispersion as described herein, the method comprising the following steps:

[0304] (a) providing a solution or suspension comprising compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier and at least one solvent; and

[0305] (a’) spraying the solution or suspension provided in (a) onto an excipient core; and

[0306] (b’) Removing the solvent from the inert excipient core; and

[0307] (c’) Optionally, drying the excipient core comprising the solid dispersion obtained in (c’).

[0308] The spraying in step (a’) can be carried out in a fluidized bed coater, such as top spraying, bottom spraying, Wurster, tangential or side turning spraying.

[0309] Any solvent or solvent mixture in which compound (1) is at least partially soluble can be used. Examples of suitable solvents that can be used alone or as a mixture include water, alcohols (such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol and butanols (such as n-butanol, 2-butanol, isobutanol and tert-butanol)), ketones (such as acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (such as methyl acetate, ethyl acetate and propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate), and various other solvents (such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene and 1,1,1-trichloroethane). In one embodiment, any of the methods described above and the solvents involved in their embodiments are selected from the group consisting of water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane and mixtures thereof. In one embodiment, any of the methods described above and the solvents involved in their embodiments are selected from the group consisting of: alcohols (especially methanol, ethanol, n-propanol, isopropanol and butanols (such as n-butanol, 2-butanol, isobutyl alcohol and tert-butanol)), ketones (especially acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (especially methyl acetate, ethyl acetate and propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate), dichloromethane (DCM), tetrahydrofuran, acetonitrile, toluene and 1,1,1-trichloroethane. Mixtures of solvents and water can also be used.

[0310] In an embodiment, the solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture can vary. Preferably, based on the total weight of 100 wt% of the mixture, the mixture comprises at least 25 wt% of MeOH. In an embodiment, the mixture comprises an excess of DCM. More preferably, the weight:weight ratio of DCM:MeOH ranges from 25:75 to 95:5 (w / w). Preferably, the weight:weight ratio of DCM and MeOH is about 25:75, 50:50, 70:30, 75:25, 80:20, 85:15 or 90:10. Advantageously, it has been found that a solvent mixture with a ratio of DCM:MeOH of about 90:10 (w / w) can achieve a higher spray drying throughput.

[0311] In an embodiment, based on the total weight of 100 wt% of the feed solution, the solid concentration in the feed solution (in particular, the suspension or solution as defined in step a above) is in the range of about 1 to 20 wt%. Preferably, based on the total weight of 100 wt% of the feed solution, the solid concentration in the feed solution is in the range of about 5 to 15 wt%, more preferably about 8 to 12 wt%. For example, based on the total weight of 100 wt% of the feed solution, the solid concentration in the feed solution is about 8 wt% or 10 wt%.

[0312] After removing the solvent by spray drying, the obtained solid dispersion is optionally subjected to a drying method to reduce the residual solvent content. In an embodiment, the drying is carried out at a temperature in the range of about room temperature to 100 °C, preferably about 30 to 60 °C, more preferably about 35 to 45 °C. For example, the drying is carried out at a temperature of about 40 °C. In other embodiments, the drying is carried out under ambient pressure and / or reduced pressure. For example, the drying is carried out under ambient pressure or at a pressure of about 900 mbar or less, more preferably about 100 mbar or less and most preferably about 50 mbar or less (such as about 20 mbar or less). In still other embodiments, the drying is carried out for a period in the range of about 6 to 72 hours, preferably about 12 to 48 hours.

[0313] On the other hand, it relates to a solid dispersion obtained by a method comprising the following steps:

[0314] a) Providing a mixture of compound (1) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and

[0315] b) Removing the solvent from the solution or suspension to form a solid dispersion, preferably wherein the removal of the solvent in step b) is carried out by spray drying.

[0316] On the other hand, it relates to a solid dispersion obtained by a method comprising the following steps:

[0317] a) Providing a solution or suspension comprising compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier and at least one solvent; and

[0318] b) Removing the solvent from the solution or suspension to form a solid dispersion as described herein; and

[0319] c) Optionally, drying the solid dispersion obtained from b).

[0320] On the other hand, it relates to a solid dispersion obtained by a method comprising the following steps:

[0321] (a) Provide a solution or suspension comprising the compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and

[0322] (a’) Spray the solution or suspension provided in (a) onto an excipient core; and

[0323] (b’) Remove the solvent from the inert excipient core; and

[0324] (c’) Optionally, dry the excipient core comprising the solid dispersion obtained in (c’).

[0325] In the aspects regarding the solid dispersion obtained by the method, the method steps can be carried out as described above with reference to the method for preparing the solid dispersion.

[0326] The pharmaceutical composition (such as tablets, preferably coated tablets) can be manufactured according to conventional methods known to those skilled in the art. In an embodiment, the manufacturing method may include the following steps: 1) manufacture a solid dispersion by spray drying as described herein, 2) dry-granulate the solid dispersion with one or more suitable excipients, 3) blend the granules with a suitable disintegrant and / or lubricant and / or glidant, 4) compress the blend into a tablet core, and 5) optionally coat the tablet core.

[0327] In the present invention, any aspect or embodiment involving a feature (such as the compound (1) being amorphous in the solid dispersion) can be combined with any one or more aspects or embodiments involving other features (such as the weight ratio of the compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion being 1:1 and / or the pharmaceutically acceptable dispersion carrier being HPMCAS) to provide other aspects or embodiments of the present invention, such as

[0328] 1) The solid dispersion comprises the compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein the compound (1) is amorphous and the weight ratio of the compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1;

[0329] 2) The solid dispersion comprises the compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein the compound (1) is amorphous and the pharmaceutically acceptable dispersion carrier is HPMCAS;

[0330] 3) The solid dispersion comprises the compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein the compound (1) is amorphous, the weight ratio of the compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 and the pharmaceutically acceptable dispersion carrier is HPMCAS.

[0331] The terms "as defined herein", "as disclosed herein", "as set forth herein", "as used herein" and variations thereof include all aspects, embodiments, sub-aspects, sub-embodiments, etc. to which they refer in each case in which they appear.

[0332] In some embodiments, a numerical value is sometimes referred to as part of a range. The numerical value should be considered approximate, even when the term "about" or "approximate" is not explicitly recited.

[0333] Unless otherwise noted, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0334] The following examples are used to illustrate the invention in more detail but do not limit it.

[0335] Example 1 - Preparation of Solid Dispersions Comprising Compound (1) and Different Dispersing Polymers

[0336] In this example, solid dispersions were prepared containing 25 wt% or 50 wt% of Compound (1) and 75 wt% or 50 wt% of the dispersing carrier HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, L100 or HPMC HME 15LV, respectively.

[0337] The solid dispersions of this example can be prepared according to the following protocol: spray drying a solid dispersion from a spray solution composition comprising Compound (1), a dispersing carrier, and a DCM:MeOH (1:1 (w / w)) solvent system having a solids content of 8 wt% total solids. The solid dispersions were manufactured using a Procept 4M8TRX spray dryer having a 2-fluid nozzle type and a 1.0 mm / 1.0 mm nozzle cap / tip size, an inlet temperature of 85 - 90 °C, an outlet temperature of 45 - 50 °C, an atomization of 3.0 bar, a drying gas air flow rate of 0.50 m 3 / min and a solution feed rate of approximately 15 g / min. Secondary drying of the dispersion was carried out in a vacuum dryer of the tray dryer type in the collection vessel at 40 °C for 22.5 hours.

[0338] The spray drying yield results obtained following the protocol of the preceding paragraph are summarized in Table 1, where gA represents grams of API (active pharmaceutical ingredient, i.e., Compound (1)).

[0339] Table 1: Batches and Yields of Solid Dispersions of Compound (1) with Dispersing Carriers HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV

[0340]

[0341] Example 2 - Characterization of the solid dispersion by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC)

[0342] 2.1 X-ray powder diffraction (XRPD)

[0343] XRPD was obtained according to the following protocol: XRPD analysis was performed using a Rigaku Miniflexx 600 diffractometer. A sample of the solid dispersion of approximately 10 mg of compound (1) with a dispersion carrier (e.g., HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV as in Example 1) was placed on a zero-background sample disk and placed in the autosampler of the Rigaku Miniflex 600. The sample was analyzed using the instrument parameters set forth in Table 2 below.

[0344] Table 2: Summary of XRPD collection parameters

[0345]

[0346]

[0347] XRPD obtained using the various solid dispersions prepared under Example 1 following the protocol of the preceding paragraph is shown in Figures 1 - 4 and compared with the XRPD of crystalline compound (1) in the same figure to indicate the absence of crystalline material in the sample. Specifically, the XRPD of the solid dispersions of 25 wt% or 50 wt% of compound (1) and the dispersion carriers HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV showed a lack of sharp peaks and the presence of an amorphous halo. The lack of sharp diffraction peaks indicates that the solid dispersion is consistent with the amorphous form of compound (1).

[0348] 2.2 Modulated differential scanning calorimetry (mDSC)

[0349] The solid dispersions of compound (1) of Example 1 with the dispersion carriers HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV were characterized by mDSC to determine the glass transition temperature (Tg).

[0350] mDSC can be implemented according to the following protocol: mDSC analysis is performed on a thermal analyzer DSC 2500 with a thermal analysis refrigeration cooling system 90. A 2 - 5 mg amount of the sample is placed in a non - hermetic pan. A Tzero non - hermetic lid is adhered to the pan, and the sample is analyzed in modulation mode within a scan range of 20 to 250 °C (unless otherwise stated), where the modulation amplitude is 1 °C / min and the heating rate is 3.0 °C / min.

[0351] The glass transition temperatures (Tg) obtained following the protocol of the previous paragraph are presented in Table 3.

[0352] Table 3: Summary of glass transition temperatures (Tg) measured for solid dispersions of compound (1) of Example 1 with HPMCAS - M, PVP - VA, L100 and HPMC HME15LV

[0353]

[0354] It can be seen from Table 3 that all solid dispersions exhibit a single glass transition temperature, indicating no sign of phase separation in the homogeneous dispersion. The glass transition temperature values show the trend expected for the loadings of the polymer and compound (1). For L100, whose glass transition temperature is higher than that of amorphous compound (1), the glass transition temperature decreases with an increase in drug loading. For polymers HPMCAS - M, PVP - VA, and HPMC HME 15LV, whose glass transition temperatures are lower than that of compound (1), the glass transition temperature increases with an increase in drug loading. All solid dispersions provide a glass transition temperature that is high enough. For all solid dispersions, a single glass transition temperature is exhibited, indicating no sign of phase separation in the homogeneous dispersion. The glass transition temperature values show the trend expected for the loadings of the polymer and compound (1). For L100, whose glass transition temperature is higher than that of amorphous compound (1), the glass transition temperature decreases with an increase in drug loading. For polymers HPMCAS - M, PVP - VA, and HPMC HME 15LV, whose glass transition temperatures are lower than that of compound (1), the glass transition temperature increases with an increase in drug loading. All solid dispersions provide a glass transition temperature that is high enough.

[0355] Example 3 - Preparation of solid dispersions using different method parameters

[0356] Solid dispersions of compound (1) are tested under different spray - drying conditions (such as solvents, inlet temperature, and spray - drying parameters).

[0357] 3.1 Solvent selection

[0358] The solubility of compound (1) in a solvent mixture of dichloromethane (DCM): methanol is measured.

[0359] For this purpose, the following protocol can be followed: Prepare a solution of compound (1) at a high concentration and then dilute it with the solvent until compound (1) dissolves or until the concentration drops below 1 wt%. The solubility is determined by visual observation.

[0360] The solubility data of compound (1) obtained following this protocol are presented in Table 4 below.

[0361] Table 4: Results of Organic Solubility Screening for Compound (1)

[0362]

[0363]

[0364] Therefore, the 90:10 DCM:methanol solvent blend provides high solubility of Compound (1) and the highest potential flux, because the methanol concentration in the solvent system is lower compared to DCM:methanol solvent blends with higher methanol ratios.

[0365] 3.2 Inlet Temperature

[0366] Solid dispersions comprising 50 wt% Compound (1) and 50 wt% HPMCAS-M or 25 wt% Compound (1) and 75 wt% HPMC HME 15LV were manufactured on a larger scale using an inlet temperature lower than that of Example 1.

[0367] To this end, the following protocol can be followed: Using a DCM:MeOH (1:1 (w / w)) solvent system with a solids content of 8 wt% total solids, spray dry the solid dispersion from a spray solution composition comprising Compound (1) and HPMCAS-M or HPMC HME 15LV. Manufacture the solid dispersion using a Procept 4M8TRX spray dryer, which has a two-fluid nozzle type and a nozzle cap / tip size of 1.0 mm / 1.0 mm, an inlet temperature of 55 - 70 °C, an outlet temperature of 45 - 50 °C, atomization at 3.0 bar, an air flow rate of 0.50 m 3 / min, and a solution feed rate of approximately 10 - 15 g / min. Secondary drying of the dispersion is carried out in a vacuum dryer of the tray dryer type in the collection container at 40 °C for approximately 24 hours.

[0368] The spray drying yield results obtained following this protocol are summarized in Table 5, where gA represents grams of API (Active Pharmaceutical Ingredient, i.e., Compound (1)). The mDSC results (non-hermetic pan, heated at 3 °C / min, modulated at 1 °C / min) are summarized in Table 6.

[0369] Table 5: Batch and Yield of Solid Dispersions in Larger Batches and at Lower Inlet Temperatures

[0370]

[0371] Table 6: mDSC Results

[0372] Formulation Tg Amorphous compound (1) 156℃ 50wt%:50wt% compound (1):HPMCAS-M 115℃ 25wt%:75wt% compound (1):HPMC HME 15LV 92℃

[0373] 3.3 Spray Drying Parameters

[0374] Test the effects of the flow rate ( = liquid feed rate), the dryer outlet temperature, and the drying environment on the spray-dried solid dispersion. For the test, a composition containing 50 wt% of compound (1) and 50 wt% of the dispersion carrier HPMCAS-M was used. Using a 90:10 (w / w) DCM:MeOH solvent ratio with a solids content of 10 wt% of the total solids, the composition was spray-dried from a spray solution composition comprising compound (1) and HPMCAS-M. The solid dispersion was manufactured using an open-loop custom-developed spray dryer SD-90 with an SK 79-16 spray system nozzle. Test liquid feed rates between 291 and 317 g / min and outlet temperatures between 35 and 45 °C. The method parameters are summarized in Table 7 below.

[0375] Table 7: Spray drying method parameters

[0376]

[0377] acfm: actual cubic feet per minute

[0378] The yield increased from the first batch of spraying (3.3-A) until the last batch of spraying (3.3-C). The yield of batch A was lower due to fixed losses (which reduced the yield percentage of the smaller batch relative to the larger batch), and the yield increased due to carryover from previous batches and the diminishing effect of fixed losses on subsequent batches.

[0379] Characterize the solid dispersions of samples 3.3-A, 3.3-B, and 3.3-C using X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), and particle size distribution (PSD). The PSD was determined by laser diffraction.

[0380] XRPD was obtained according to the following protocol: XRPD analysis was performed using a Rigaku Miniflex 600 diffractometer. Approximately 10 mg quantities of samples 3.3-A, 3.3-B, and 3.3-C were placed in a zero-background sample holder and loaded into the automatic sampler of the Rigaku Miniflex 600. The samples were analyzed using the instrument parameters set forth in Table 8 below.

[0381] Table 8: Summary of XRPD collection parameters

[0382]

[0383] The XRPDs of the solid dispersions of samples 3.3-A, 3.3-B, and 3.3-C obtained following the protocol of the preceding paragraph are shown in Figure 5 which exhibit a lack of sharp peaks and the presence of an amorphous halo, indicating that all samples contain amorphous compound (1).

[0384] For mDSC measurements, the following protocol can be followed: Place 2 - 5 mg amounts of Samples 3.3 - A, 3.3 - B, and 3.3 - C in a Tzero pan. Attach a Tzero non - airtight lid to the pan and analyze the samples in modulation mode in the scan range from 0 to 250 °C with a modulation amplitude of 1 °C / min, a modulation period of 60 s, and a heating rate of 3.0 °C / min. The summary of the glass transition temperatures is given in Table 9.

[0385] Table 9: Summary of the glass transition temperatures (Tg) of Samples 3.3 - A, 3.3 - B, and 3.3 - C

[0386] Formulation Average midpoint Tg 3.3-A 116℃ 3.3-B 117℃ 3.3-C 116℃

[0387] The thermograms of the solid dispersions of Samples 3.3 - A, 3.3 - B, and 3.3 - C obtained following the previous paragraphs all show a single glass transition temperature of approximately 116 °C and no distinct melting or recrystallization events. This indicates that the solid dispersion is a single - phase including the amorphous compound (1).

[0388] The particle size distribution (PSD) of the solid dispersions of Samples 3.3 - A, 3.3 - B, and 3.3 - C can be measured by laser diffraction of the dried, dispersed powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder feed system. The system can operate at a dispersion pressure of 3 bar with an R4 lens. The results according to this method are summarized in Table 10.

[0389] Table 10: Particle size distribution (PSD) of Samples 3.3 - A, 3.3 - B, and 3.3 - C

[0390]

[0391] 3.4 Spray - drying parameters

[0392] Further tests were conducted on the spray - drying parameters for a larger batch. For the tests, a mixture containing 50 wt% of Compound (1) and 50 wt% of the dispersion carrier HPMCAS - M was used. Using a solvent ratio of DCM:MeOH of 90:10 (w / w) with a solid content of a solid loading of 10 wt%, the mixture was spray - dried from the spray solution composition. A solid dispersion was produced using a custom - developed open - loop spray dryer SD - 90 with an SK 79 - 16 spray system nozzle. Feed rates of 300 and 325 g / min and outlet temperatures of 44 °C and 40 °C were tested. The method parameters are summarized in Table 11 below.

[0393] Table 11: Spray - drying method parameters

[0394]

[0395] acfm: actual cubic feet per minute

[0396] It is assumed that the yield of Sample 3.4-A is low due to fixed losses in small batches. Fixed losses are independent of batch size but represent a higher proportion in smaller batches. Therefore, a larger batch size for Sample 3.4-B will result in a higher yield. Two samples were characterized using XRPD, mDSC, and PSD. PSD was determined by laser diffraction.

[0397] XRPD scans of Samples 3.4-A and 3.4-B were performed as described in Example 3.3 above. Diffraction patterns of the solid dispersions of Samples 3.4-A and 3.4-B are shown in Figure 6 and show an amorphous halo without sharp peaks, indicating that Compound (1) is in an amorphous state in both samples.

[0398] For mDSC measurements, 2 - 5 mg amounts of Samples 3.4-A and 3.4-B were placed in Tzero pans and measurements were performed as described in Example 3.3 above, except that the scan range used for Sample 3.4-B was from 0 to 200 °C. A summary of the glass transition temperatures is given in Table 12 below.

[0399] Table 12: Summary of glass transition temperatures (Tg) for Samples 3.4-A and 3.4-B

[0400] Formulation Average midpoint Tg 3.4-A 114℃ 3.4-B 111℃

[0401] Thermograms of the solid dispersions of Samples 3.4-A and 3.4-B exhibit a single glass transition temperature, indicating a single-phase, amorphous material with no distinct peaks in the mDSC thermogram indicative of crystalline material. The difference in glass transition temperature compared to Sample 3.3 can be attributed to different batches of Compound (1) used in the SDD manufacture and / or noise in the instrument measurements.

[0402] The mDSC results are consistent with the XRPD results, indicating by two orthogonal methods that the solid dispersion contains Compound (1) in an amorphous form.

[0403] The particle size distribution (PSD) of the solid dispersions of Samples 3.4-A and 3.4-B was measured by laser diffraction of dry, dispersed powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder feed system. The system can operate at a dispersion pressure of 3 bar with an R4 lens. A summary of the results according to this method is given in Table 13.

[0404] Table 13: Particle size distribution (PSD) for Samples 3.4-A and 3.4-B

[0405]

[0406] Example 4 - Physical Stability of Amorphous Solid Dispersions

[0407] 4.1 Stress Stability Study under Accelerated Stress Conditions

[0408] The physical stability of amorphous solid dispersion formulations of Compound (1) equivalent to Samples 3.3 - A, 3.3 - B, and 3.3 - C obtained in Example 3.3 was evaluated in an accelerated stability study. Each sample was incubated in open vials under the following conditions: (i) ambient temperature / ambient humidity, (ii) ambient temperature / 60% relative humidity, (iii) 40 °C / ambient humidity, and (iv) 40 °C / 75% relative humidity. Relative humidity (RH) was achieved by using saturated salt solutions (sodium bromide for approximately 60% RH at ambient temperature and sodium chloride for 75% RH at 40 °C). After two and four weeks, the samples were removed for analysis and characterized by XRPD to evaluate potential recrystallization.

[0409] No changes in physical properties were observed. The diffraction patterns of all amorphous solid dispersions remained consistent with the amorphous form of Compound (1) after four weeks under all storage conditions.

[0410] 4.2 Stress Stability Study under Harsh Stress Conditions

[0411] The amorphous solid dispersion (50 wt%:50 wt% Compound (1):HPMCAS - M, prepared, for example, according to the procedure of Example 1) was exposed in open containers to 75 °C / 79% relative humidity and 80 °C / 76% relative humidity for three weeks. The individual XRPDs are shown in Figure 7 . After three weeks of exposure to the extreme stress conditions, no form changes were observed.

[0412] Example 5 - pH - Dependent Solubility and In Vitro Dissolution

[0413] 5.1 Comparative Solubility Study in Biorelevant Media and Aqueous Media under Different pH Conditions

[0414] The solubility of the amorphous solid dispersion of Compound (1) and HPMCAS - M (50 wt%:50 wt%) and crystalline Compound (1) (prepared, for example, according to Reference Examples 1 and 2 herein) was measured in different aqueous media at room temperature and in biorelevant media at 37 °C. The media used for solubility analysis are listed in Table 14 below.

[0415] Table 14: Media for Solubility Analysis

[0416]

[0417] *SIF: Simulated Intestinal Fluid (3.402 g of KH2PO4 + 448 mg of NaOH + 49 ml of ultrapure water). Adjust the pH to 6.8 with 1N NaOH and then make up to 50 ml with ultrapure water.

[0418] The following protocol was used to prepare samples for solubility measurement:

[0419] · Weigh an appropriate amount of the crystalline compound (1) or the amorphous solid dispersion of compound (1) to achieve the desired target concentration.

[0420] · Add the selected medium at room temperature to achieve the selected target concentration.

[0421] · Stir on an orbital shaker for 24 h at room temperature or vortex under dark at 37 °C.

[0422] · Separate the soluble portion from the insoluble portion by centrifugation (15 min at 18000 rpm) and then filtration through a PTFE 0.45 μm membrane. Discard the first ~3.5 mL and then collect 3 aliquots ( ~0.5 mL) for analysis.

[0423] · Quantify the 3 aliquots by UPLC - UV - MS with an appropriate calibration curve.

[0424] UPLC - UV - MS method:

[0425]

[0426]

[0427]

[0428] For each solid form and solid dispersion, establish two standard calibration curves (chromatographic UV peak area vs. concentration) in DMSO at 254 nm or 410 nm, one between 0.025 or 0.050 μg / mL and 1 μg / mL (injection volume = 9 μL) and the other between 1 μg / mL and 500 μg / mL (injection volume = 0.4 μL). The calibration curves are linear over the entire study concentration range.

[0429] The solubility analysis results obtained following the previous paragraph are summarized in Table 15 and presented in Figure 8 in.

[0430] Table 15: Equilibrium solubility of compound (1) and the amorphous solid dispersion of compound (1) with HPMCAS - M (50 wt%:50 wt%) and the crystalline form of compound (1) in various media

[0431]

[0432] Both crystalline forms of compound (1) have been found to be soluble in strongly acidic media, but the solubility decreases at pH ≥ 5. In addition, the solubility of the crystalline forms of compound (1) is poor in biologically relevant simulated fasting and fed intestinal fluids (FaSSIF and FeSSIF). It has been found that when compound (1) is formulated with HPMCAS-M as an amorphous solid dispersion, its solubility is significantly increased at pH ≥ 5 and in biologically relevant media.

[0433] 5.2 In vitro dissolution of amorphous solid dispersion of compound (1) with respect to crystalline compound (1)

[0434] During the pH-variable non-sink dissolution test in biologically relevant media, the kinetic solubility of crystalline compound (1) and various amorphous solid dispersion formulations (25 wt%:75 wt% and 50 wt%:50 wt% compound (1):polymer) prepared according to the procedure disclosed in Example 1 using polymers selected from HPMCAS-M, HPMC HME 15LV, PVP-VA, L100 was measured.

[0435] For this purpose, the following protocol can be used: First, the sample is delivered to simulated gastric fluid (SGF), and then transferred to simulated intestinal fluid (SIF) via a dilution step. The test is carried out at 3 mg / mL in 0.01N HCl as SGF (first stage), and then after 30 minutes, it is diluted 3-fold to a target concentration of 1 mg / mL in FaSSIF at pH 6.5 (+33 mM sodium phosphate for additional buffering capacity). The "total drug" and "dissolved drug" are evaluated. The total drug is determined by sampling the supernatant of the non-sink (saturated) sample after bench-top centrifugation (~19000 rcf, 3 - 5 min). The total drug includes free drug, bile salt micelles (in SIF), and colloidal substances formed by drug-polymer interactions. The dissolved drug is determined by filtering the total drug supernatant through a 0.22 μm filter to remove large colloidal substances. The dissolved drug includes free drug and bile salt micelles.

[0436] Following this protocol, it was observed that although all formulations were completely dissolved in simulated gastric fluid at 3 mg / mL (data not shown), the amorphous solid dispersion formulations showed significantly more dissolved drug relative to the crystalline API in simulated intestinal fluid (see Figure 9 and Figure 10 ). It should be noted that generally it is expected that for a given polymer, as the drug loading in the amorphous solid dispersion formulation increases, the performance evaluated by an increase in dissolved drug and / or colloidal substance formation will either not be affected or will decrease. However, in the case of the compound (1):HPMCAS-M SDD formulation, an increase in drug loading led to a continuous increase in dissolved drug.

[0437] Example 6 - Pharmaceutical Composition

[0438] 6.1 Method for Preparing Tablets of Spray - Dried Solid Dispersions Comprising Compound (1)

[0439] Unless otherwise stated, film - coated tablets of solid dispersions comprising Compound (1) are generally prepared according to the following protocol.

[0440] Step 1: Preparation of Solid Dispersions by Spray - Drying

[0441] Compound (1) and HPMCAS - MG (hydroxypropyl methylcellulose acetate succinate - MG) are dissolved in a solvent mixture of dichloromethane (DCM) and methanol (MeOH) to produce a spray - drying solution. As an alternative to HPMCAS - MG or in addition to HPMCAS - MG, alternative dispersion carriers can be used. The solution is spray - dried using a suitable spray dryer to produce a spray - dried solid dispersion. This spray - drying step can be carried out as detailed in Examples 1 and 3. Then, the spray - dried solid dispersion is further dried in a suitable dryer as detailed in Examples 1 and 3 to remove residual solvents.

[0442] Step 2: Dry Granulation of Solid Dispersions Containing Excipients

[0443] The dried solid dispersion is mixed with part of microcrystalline cellulose, mannitol, croscarmellose sodium, and colloidal silicon dioxide, and then the mixture of the solid dispersion and fillers, disintegrants, and glidants is pre - blended and sieved / comminuted. Sodium stearyl fumarate is added as a lubricant to the pre - blend. Then, the intra - granular blend is granulated using a roller compactor equipped with a 1.0 mm sieve. The sieved dry granules are collected for subsequent final blending.

[0444] Step 3: Blending

[0445] The granules are blended together with a pre - sieved extra - granular mixture of croscarmellose sodium and colloidal silicon dioxide in a blender. Sodium stearyl fumarate is added and blended to produce the final blend.

[0446] Step 4: Compression

[0447] Then, the final blend is compressed into tablet cores.

[0448] Steps 1 to 4 are carried out using the ingredients given in Table 16 below.

[0449] Table 16: Summary of the Ingredients of Tablet Cores

[0450]

[0451]

[0452] 6.2 Manufacture of coated tablets comprising 15 mg or 60 mg of compound (1)

[0453] After steps 1 to 4, an optional coating step may be carried out, which may be implemented as outlined below.

[0454] Step 5: Coating

[0455] Disperse coating mixture yellow AMB II in water for injection using a stirrer and a container. Coat the tablet cores with the coating suspension in a suitable pan coater to obtain coated tablets comprising a solid dispersion of compound (1) and a dispersion carrier. Step 5 is optional. A coating mixture may be used to replace yellow AMB II.

[0456] Prepare coated tablets comprising a spray-dried solid dispersion of compound (1) and HPMCAS MG (hydroxypropyl methylcellulose acetate succinate, where MG refers to the grade soluble at pH ≥ 6.0 and which is a granular free-flowing powder) as described in Example 6.1, followed by step 5 as described above. Table 17 below gives a summary of the components.

[0457] Table 17: Summary of the components of the coated tablets

[0458]

[0459]

[0460] The coated tablets comprise 15 mg or 60 mg of compound (1). Dichloromethane and methanol are used as solvents and nitrogen is used as the drying gas for the solid dispersion, but is removed during the process and thus does not appear in the final product. Additionally, water for injection is used as the solvent for the coating mixture, but is also removed during drying and is thus not analyzed.

[0461] The coating mixture used is yellow AMB II 88A120087. It comprises partially hydrolyzed polyvinyl alcohol as a film-forming agent, talc as an anti-adhesive, sodium lauryl sulfate as a lubricant, and titanium dioxide, mono- and di-octanoyl glycerol (GMDCC) and iron oxide yellow as pigments.

[0462] 6.3 Manufacture of tablets comprising 400 mg or 200 mg of compound (1)

[0463] Prepare an uncoated tablet formulation of a spray-dried solid dispersion comprising compound (1) and HPMCAS-M (in a ratio of 25:75 wt% or 50:50 wt%) as described in Example 6.1 above. Summaries of the ingredients are given in Tables 18 and 19 below.

[0464] Table 18: Summary of the ingredients of a tablet of a spray-dried solid dispersion comprising 25 wt% compound (1) and 75 wt% HPMCAS-M

[0465]

[0466]

[0467] Table 19: Summary of the ingredients of a tablet of a spray-dried solid dispersion comprising 50 wt% compound (1) and 50 wt% HPMCAS-M

[0468]

[0469]

[0470] 6.4 Manufacture of tablets of solid dispersions comprising compound (1) and HPMC

[0471] Solid dispersion formulations with non-enteric polymers such as HPMC are known to gel upon tableting and thus have slow disintegration. With this potential challenge in mind, a preliminary feasibility assessment of a spray-dried solid dispersion comprising 25 wt% compound (1) and 75 wt% HPMC HME 15LV was completed. A summary of the starting ingredients is given in Table 20 below.

[0472] Table 20: Summary of the ingredients of a tablet of a spray-dried solid dispersion comprising 25 wt% compound (1) and 75 wt% HPMC HME 15LV

[0473]

[0474] The formulation described in Table 2 did not disintegrate (as expected). The formulation method to improve disintegration was an intragranular blend containing increased amounts of microcrystalline cellulose and mannitol (each 24 wt%) and only 2 wt% sodium croscarmellose and a 50% dilution of the tablet structure containing granulated and extragranular components. The final formulation contained 50 mg of compound (1) in a 700 mg tablet.

[0475] 6.5 Characterization of tablet cores and coated tablets by X-ray powder diffraction (XRPD)

[0476] The tablet cores (Example 6.1-C) and film-coated tablets (Example 6.2-C) were studied by XRPD to confirm the absence of crystalline compounds (1) (such as Form III and Form IV). For this purpose, the following protocol can be followed: Samples were prepared by gently grinding the tablet cores or film-coated tablets in a mortar with a pestle and then uniformly mixing the obtained powder with a spatula. Then the obtained powder was measured by XRPD using an X’pert PRO diffractometer, and the following settings and measurement parameters were applied:

[0477] Table 21: Experimental parameters for XRPD measurement

[0478]

[0479] XRPD profiles of the tablet cores of Example 6.1-C and the film-coated tablets of Example 6.2-C obtained following the previous procedure are shown in Figure 15 and 16 . Both formulations contain crystalline excipients in combination with an amorphous solid dispersion containing compound (1). The diffraction peaks present in the XRPD are attributed to those excipients. For example, the absence of a peak at (5.8 ± 0.2)° indicates the absence of Form IV, and the absence of a peak at (6.2 ± 0.2)° indicates the absence of Form III.

[0480] Example 7 - Determination of the properties of tablets of spray-dried solid dispersions containing compound (1) 7.1 In vitro dissolution characteristics in pH 2.0 phosphate buffer

[0481] Dissolution tests were carried out to compare a conventional film-coated tablet containing a total of 15 mg of crystalline compound (1) with the film-coated tablet of Example 6.2-B containing 15 mg of compound (1) in the form of a spray-dried solid dispersion and HPMCAS MG.

[0482] The comparative film-coated tablet with crystalline compound (1) contains 5 mg of compound (1), 64.5 mg of silicified microcrystalline cellulose including colloidal silica and microcrystalline cellulose (as a filler), 21 mg of anhydrous lactose (as a filler), 3 mg of sodium starch glycolate type A (as a disintegrant), 5 mg of hydroxypropyl cellulose (as a binder), 0.5 mg of colloidal silica (as a glidant), 1 mg of magnesium stearate of vegetable origin (as a lubricant), 4.5 mg of a film-coating mixture (such as yellow 03B120053). In the test, three 5 mg tablets were used.

[0483] For dissolution test comparison, the following protocol can be used: Conduct the dissolution test at 37 °C in 20 mM phosphate buffer (NaH2PO4) at pH 2.0 using an Agilent 708-DS Apparatus and an 850-DS Sampling Station. Suspend a 15 mg tablet containing the compound (1) in the form of a solid dispersion equivalent to Specimen 6.2-B and three 5 mg tablets with up to a total of 15 mg of the compound (1) added in crystalline form in the buffer solution. Evaluate the dissolution profile under the following conditions: Axial rotation speed: 50 rpm, medium volume: 900 mL, specimen volume: 3 mL. Measure the amount of compound (1) in the buffer at regular intervals over 60 minutes by HPLC. Calculate the dissolution % by the following operation (A):

[0484] Dissolution % = ((A smp × C S1 × DF smp ) / (A S1 × LC)) × 100 (A)

[0485] Where:

[0486] A smp Is the specimen peak area

[0487] C S1 Is the standard 1 concentration, 0.017 mg / mL of compound (1)

[0488] DF smp Is the specimen dilution factor, 900 mL

[0489] A S1 Is the average peak area response of the first five standard 1 injections

[0490] LC is the tablet label amount; 15 mg.

[0491] The results of the in vitro dissolution comparison between conventional tablets and solid dispersion tablets (in pH 2.0 buffer) obtained according to the protocol described in the previous paragraph are shown in Figure 11 . It can be seen that the tablets containing the solid dispersion show a faster initial drug release than the tablets containing the crystalline compound (1).

[0492] 7.2 In vitro dissolution characteristics in pH 6.8 phosphate buffer with 0.1% SDS

[0493] Dissolution tests were carried out for comparison purposes between a conventional coated tablet containing a total of 60 mg (3 x 20 mg) of crystalline compound (1), a coated tablet of Example 6.2 - A containing a total of 60 mg (4 x 15 mg) of compound (1) in the form of a spray - dried solid dispersion with HPMCAS MG, and a coated tablet of Example 6.2 - C containing 60 mg of compound (1) in the form of a spray - dried solid dispersion with HPMCAS MG.

[0494] The conventional coated tablet with crystalline compound (1) contains 20 mg of compound (1), 49.5 mg of silicified microcrystalline cellulose including colloidal silicon dioxide and microcrystalline cellulose (as filler), 21 mg of anhydrous lactose (as filler), 3 mg of sodium starch glycolate type A (as disintegrant), 5 mg of hydroxypropyl cellulose (as binder), 0.5 mg of colloidal silicon dioxide (as glidant), 1 mg of magnesium stearate of vegetable origin (as lubricant), 4.5 mg of coating mixture (e.g., yellow 03B120053). In the test, three 20 - mg tablets were used.

[0495] The dissolution test was carried out under the conditions outlined in Table 22.

[0496] Table 22: In vitro dissolution conditions

[0497]

[0498] The dissolution % (identical to dissolution %) was calculated as described in Example 7.1 above. The results of the comparison of the in vitro dissolution of the conventional tablets and the solid - dispersion tablets in pH 6.8 buffer are shown in Figure 12 . It can be seen that the tablets containing the solid dispersion have similar dissolution profiles and exhibit a faster initial drug release than the tablets containing crystalline compound (1). Additionally, the tablets containing the solid dispersion dissolve completely as compared to the tablets containing crystalline compound (1).

[0499] 7.3 In vitro determination of bioaccessibility

[0500] A dynamic in vitro gastrointestinal model that simulates the physiological processes occurring in the human stomach and small intestine, TIM - Microsystem, was used to evaluate bioavailability in humans.

[0501] The conventional tablets of crystalline compound (1) (conventional formulation) and the tablets containing the solid dispersion of compound (1) (SDD formulation) were tested in the TIM - Microsystem model.

[0502] The conventional formulation contains 100 mg of compound (1), 247.5 mg of siliconized microcrystalline cellulose and 105 mg of anhydrous lactose (as fillers), 25 mg of hydroxypropyl cellulose (as binder), 15 mg of sodium starch glycolate (as disintegrant), 2.5 mg of colloidal silicon dioxide (as glidant) and 5 mg of magnesium stearate (as lubricant).

[0503] The SDD formulation tested in the mini-TIM model corresponds to Example 6.2-A, as shown in Table 17.

[0504] Mini-TIM study protocol:

[0505] Dietary matrix in the mini-TIM setup

[0506] To simulate fasting state conditions, a glass of water (240 mL) was given to the mini-TIM system.

[0507] Mini-TIM test system:

[0508] This study was conducted in the TNO dynamic, multi-compartment in vitro system of the stomach and small intestine (mini-TIM).

[0509] The mini-TIM system consists of a gastric compartment and a small intestine compartment ( Figure 13 ). This compartment consists of two glass units using a flexible polysiloxane inner wall surrounding the luminal material. The space between the inner wall and the outer wall is filled with water. The peristaltic mixing of the chyme is the result of the alternating compression and relaxation of the flexible inner wall. The compartments are connected by peristaltic valves that pump successively open and closed, allowing the chyme to be transported through the compartments over time. Thus, the oral dosage form / API is exposed to local changes and physiologically relevant conditions in the stomach and small intestine for mini-TIM.

[0510] The mini-TIM system simulates the in-lumen pH, enzyme activity, bile salt concentration, peristaltic movement, and gastrointestinal transport of the contents. The set points for gastrointestinal simulation are controlled and monitored by a specific computer process. The released and dissolved drug molecules are removed from the intestinal lumen through a semi-permeable membrane unit connected to the small intestine compartment. This allows the evaluation of the so-called bioaccessible fraction, i.e., the fraction of the drug available for absorption in the small intestine.

[0511] Simulated gastrointestinal conditions:

[0512] The experiments in mini-TIM were conducted under average physiological conditions simulating the human gastrointestinal tract in the fasting state as described. These conditions include in particular the dynamics of gastric emptying and pH drop, intestinal transit time, sweeping waves, gastric and intestinal pH values (Tables 23 and 24), and the composition and activity of secretory products. The digested and soluble (low molecular weight) compounds are continuously removed from the intestinal compartment through a special membrane system.

[0513] Before each experiment, fresh secretions (e.g., enzyme-containing gastric juice, electrolytes, bile, and pancreatic juice) were prepared, the pH electrode was calibrated, and the semipermeable membrane (hollow fiber) unit was installed.

[0514] Table 23: Parameters Simulating the Average Gastrointestinal Physiology Conditions in the Fasting State of Healthy Young Adults in Mini-TIM

[0515]

[0516]

[0517] Table 24: Parameters Simulating the Average Gastrointestinal Physiology Conditions in the Fasting State + PPI of Healthy Young Adults in Mini-TIM

[0518] Micro TIM Fasting state + PPI 1 Gastric compartment micro TIM Intake (total) 270g Diet (HFM) - Water and artificial saliva 240g Gastric starting fluid 30g Gastric emptying T1 / 2 20 min Scavenging wave 60 min Gastric pH 5.0 continuously Small intestine compartment micro TIM pH intestinal compartment 6.5 Experiment duration 5 hours

[0519] Scavenging wave

[0520] The scavenging wave (HKW) was simulated by automatically transferring the residual material from the gastric compartment to the intestinal compartment after 60 minutes.

[0521] Experiment

[0522] The experiment was conducted as a replicate experiment. All runs were carried out under yellow light to prevent the degradation of compound (1).

[0523] Sampling

[0524] Filtrate

[0525] Drug molecules released and dissolved / dissolved out by filtration from the intestinal lumen via the semipermeable membrane unit (Fresenius P1dry) allowed the evaluation of the so-called bioaccessible fraction (i.e., the fraction of the drug available for absorption in the small intestine). Filtrates were collected at the following time intervals: 0 - 30, 30 - 60, 60 - 90, 90 - 120, 120 - 180, 180 - 240, and 240 - 300 minutes after the start of the experiment ( Figure 13 , sampling point H). Analysis of the samples yielded data on the bioaccessibility and utilization of compound (1). The volume collected for each time period was measured and subsamples were taken, immediately diluted in an organic solvent and stored protected from light at 2 - 10 °C until analysis.

[0526] Residue

[0527] At the end of each experiment, the residues in the gastric compartment and the small intestine compartment plus the filtration unit were collected, measured, and analyzed. The residue samples represented the non-bioaccessible fraction. This rinse was pooled with the residue samples from the same compartment, the volume was measured and stored protected from light at 2 - 10 °C until analysis.

[0528] Storage of Spare Samples

[0529] After the research report is finalized, store the backup samples in the dark at ≤ -18 °C for 1 month, and then destroy the samples.

[0530] Analysis of Samples

[0531] Analyze the concentration of compound (1) in the collected samples.

[0532] Calculation of Results

[0533] Calculate the absolute amount of API in the sample by multiplying the analyzed concentration in the sample by the collected volume (Equation 1).

[0534] A (mg) = C 试样 (μg / mL) · 10 -3 · V 试样 [mL] (1)

[0535] Determine the recovery rate of API by summing the filtered portion through the intestinal compartment, the residues and rinsed portions of the gastric and intestinal compartments, and all amounts recovered from the drug product. The overall recovery rate is expressed as a percentage of the added amount (Equation 2).

[0536]

[0537] Calculate the bioaccessibility (percentage of intake) by expressing the amount of API recovered from the filtrate as a percentage of the intake (Equation 3).

[0538]

[0539] The results of repeated runs are expressed as mean ± SD. For SD, use the STDEVP function in (Equation 4).

[0540]

[0541] Statistics

[0542] Statistical analysis was not performed in this study.

[0543] Results

[0544] For the conventional (conv.) formulations and SDD formulations under two conditions (fasting state and simulated PPI condition (i.e., higher gastric pH)), the bioaccessibility curves obtained from the above-mentioned mini-TIM protocol are shown in Figure 14In the middle. Under fasting conditions with low gastric pH (from 3.0 to 1.8 within 30 min), comparable bioaccessibility was observed between the conv. and SDD tablets. Under PPI conditions (fasting with gastric pH of 5), the conventional tablets showed approximately 5-fold reduced bioaccessibility, while the SDD tablets were not affected. Therefore, compared with the conventional tablets, the performance of the SDD formulation is pH-independent. The tablets of Examples 6.2-B and 6.2-C described in Table 17 have been tested under the same mini TIM study protocol and showed comparable results.

[0545] 7.4 In Vivo Relative Bioavailability Clinical Study

[0546] A clinical study was conducted to evaluate the relative bioavailability of compound (1) in two different oral formulations, namely conventional tablets containing the crystalline form of compound (1) and tablets containing the solid dispersion of compound (1) of the present invention. Additionally, after orally administering the above solid dispersion formulation to healthy male individuals, the effects of food and the multi-dose protein pump inhibitor (PPI) rabeprazole on the pharmacokinetics of a single dose of compound (1) were studied.

[0547] 7.4.1 Protocol

[0548] The study included 16 healthy male individuals aged 18 to 45 years (inclusive) with a body mass index (BMI) of 18.5 to 29.9 kg / m 2 (inclusive). The study was designed as an open-label, randomized, four-way crossover trial. The primary endpoints were the area under the plasma concentration-time curve from time 0 (t0) corresponding to the drug administration time point to time z (tz) corresponding to the last quantifiable time point (AUC 0-tz ) and the maximum plasma concentration (C max ) of compound (1). The secondary endpoint was the area under the plasma concentration-time curve of compound (1) extrapolated from t0 to infinity (AUC 0-∞ ).

[0549] Therefore, the objectives of the trial were to study

[0550] Trial 1: The relative bioavailability of compound (1) in crystalline form and two different tablet formulations in solid dispersion form under fasting conditions,

[0551] Trial 2: The relative bioavailability of compound (1) formulated as a solid dispersion under fasting and fed conditions, and

[0552] Trial 3: The relative bioavailability of compound (1) formulated as a solid dispersion alone or in combination with rabeprazole under fasting conditions.

[0553] Test Product 1: A comparative coated tablet with crystalline compound (1) contains 5 mg or 20 mg of compound (1), 64.5 or 49.5 mg (respectively) of silicified microcrystalline cellulose including colloidal silicon dioxide and microcrystalline cellulose (as filler), 21 mg of anhydrous lactose (as filler), 3 mg of type A sodium starch glycolate (as disintegrant), 5 mg of hydroxypropyl cellulose (as binder), 0.5 mg of colloidal silicon dioxide (as glidant), 1 mg of magnesium stearate of vegetable origin (as lubricant), 4.5 mg of coating mixture (e.g., yellow 03B120053).

[0554] Test Product 2: A coated tablet containing 15 mg of compound (1) (in the form of a spray-dried solid dispersion) and HPMCAS MG as defined in Example 6.2-A.

[0555] Test Product 3: A proton pump inhibitor rabeprazole anti-gastric tablet with a strength of 20 mg

[0556] Reference treatment (R or TF1) consists of a total dose of 30 mg of crystalline compound (1) orally administered with 240 Ml of water after an overnight fast of at least 10 hours on Day 1 (in the form of Test Product 1 (1 tablet of 20 mg and 2 tablets of 5 mg)).

[0557] Test treatment 1 (T1 or NF1) consists of a total dose of 30 mg of compound (1) in the form of a solid dispersion orally administered with 240 mL of water after an overnight fast of at least 10 hours on Day 1 (as Test Product 2 (2 tablets of 15 mg)).

[0558] Test treatment 2 (T2) consists of a total dose of 30 mg of compound (1) in the form of a solid dispersion administered on Day 1 under fed conditions after a high-fat, high-calorie breakfast (as Test Product 2 (2 tablets of 15 mg)). The high-fat, high-calorie breakfast provides a total calorie content of approximately as follows: 150 kcal of protein, 250 kcal of carbohydrates, and 500 to 600 kcal of fat; ingredients: 2 eggs (total content) for scrambled eggs 192 kcal, 10 g of butter for scrambled eggs 75 kcal, 35 g of fried bacon 186 kcal, 2 slices of toasted wheat bread 130 kcal, 15 g of butter for spreading on toasted bread 113 kcal, 115 g of fried potato cakes 132 kcal, 240 mL of whole milk (3.5% fat) 156 kcal; total 984 kcal.

[0559] Test treatment 3 (T3) consisted of a total dose of 30 mg of compound (1) in solid dispersion form (2 tablets of 15 mg each) of test product 2, administered under fasting conditions. T3 subjects further received test product 3, rabeprazole, at a daily dose of 40 mg (2 tablets of 20 mg each), for a total dose of 200 mg once daily, 4 days prior to and on the day of administration of compound (1).

[0560] For all treatments, blood samples were taken up to 118 hours after administration of compound (1) to analyze the plasma concentration of compound (1). The plasma concentration-time curve was evaluated by non-compartmental analysis to calculate individual PK parameters. The relative bioavailability was estimated by the ratio of the geometric means of the primary and secondary endpoints (T1 / R, T2 / T1, and T3 / T1). In addition, its two-sided 90% confidence interval (CI) was provided. This method corresponded to two one-sided t-test procedures, each with a significance level of 5%. Since the main focus was on estimation rather than testing, no formal hypothesis testing and associated acceptance ranges were specified. The statistical model was an analysis of variance (ANOVA) based on a logarithmic scale, which included the effects of sequence, individuals included in the sequence, cycle, and treatment. The CI was calculated based on the residual error of the ANOVA. Descriptive statistics were calculated for all endpoints. Pharmacokinetic analysis was performed based on the pharmacokinetic parameter analysis set (PKS) and safety analysis was performed based on the treatment set (TS). No formal interim analysis was planned or implemented.

[0561] 7.4.2 Results

[0562] Of the 16 individuals planned to be included in the trial, 13 individuals completed the study. For the treatment comparison, 12 individuals were evaluable for the relative bioavailability comparison of T1 and R, 9 individuals were evaluable for the food effect (comparison of T2 and T1), and 11 individuals were evaluable for the drug-drug interaction between compound (1) and rabeprazole (comparison of T3 and T1). The relative bioavailability comparison showed that the variability of the tablet of compound (1) in solid dispersion (T1) was lower compared to the tablet containing crystalline compound (1) (R). Compared to R, the exposure of T1 increased on average by 3% (Cmax) and 35% (AUC0-tz). The food effect assessment showed that the exposure under fed conditions (T2) was reduced compared to fasting (T1) (Cmax decreased on average by -46% and AUC0-tz decreased on average by -26%). Pretreatment with rabeprazole did not relevantly change the exposure of the tablet of compound (1) in solid dispersion (average Cmax was -13% and average AUC0-tz was -3%), indicating no relevant DDI between compound (1) and proton pump inhibitors or other pH-increasing co-medications.

[0563] The trial results are discussed in more detail below.

[0564] Compliance of Test Subjects and Clinical Trial Protocols

[0565] A total of 13 individuals received the test drug treatment and completed the planned observation period. There were no reports of major protocol violations. Among the 13 healthy male individuals treated in the trial, 12 individuals (92.3%) were white and 1 individual (7.7%) was black or African American. The average age of the individuals was 34.8 years (standard deviation [SD]=5.8 years); the age range was from 25 to 45 years. The average BMI was 25.49 kg / m 2 (SD = 3.03 kg / m 2 ); the BMI range was from 20.7 to 29.5 kg / m 2 . The treatment groups were similar in terms of demographics and baseline characteristics.

[0566] Twelve individuals received the reference treatment (R) randomly, twelve individuals received the test treatment 1 (T1) randomly, nine individuals received the test treatment 2 (T2) randomly, and eleven individuals received the test treatment 3 (T3) randomly, and there was a washout interval of at least 14 days between the administration of compound (1) and the subsequent treatment.

[0567] Table 25 gives the relative bioavailability of the formulations NF (T1) and TF1 (R) under fasting conditions. The range of the adjusted geometric mean ratios of the primary and secondary endpoints for the individuals receiving the T1 / R treatment was from 129.1% to 139.3%, and the range of the 90% CI was from 87.7% to 221.3% (Table 25). Compared with the individuals receiving treatment T1 with C max (gCV 37.3%), AUC 0-tz (gCV 18.8%), and AUC 0-∞ (gCV 19.2%), the pharmacokinetic (PK) parameters C max (geometric coefficient of variation [gCV] 93.1%), AUC0-tz (gCV 52.7%), and AUC 0-∞ (gCV 52.7%) of the individuals receiving treatment R had higher variability. The trend of increased NF bioavailability was not continuously observed in all individuals, however, an overall trend of increased oral bioavailability has been demonstrated.

[0568] Table 25: Adjusted Geometric Means and Relative Bioavailability - Pharmacokinetic Set of Compound (1) NF Fasting (T1) vs TF1 Fasting (R) Using Individuals as Random Effects

[0569]

[0570] Table 26 provides the ANOVA results comparing the primary and secondary endpoints of one of the NF formulations after fasting (T1) or ingestion of a high-fat, high-calorie meal (T2). The range of the adjusted gMean ratios of the primary and secondary endpoints for individuals receiving treatment T2 / T1 was 53.5% to 74.9%, and the range of the 90% CI was 40.5% to 81.7% (Table 26). The C max , AUC 0-tz and AUC 0-∞ values were lower, indicating a negative food effect.

[0571] Table 26: Adjusted Geometric Mean and Relative Bioavailability of Compound (1) NF Fed (T2) vs NF Fasted (T1) Using Individuals as Random Effects – Pharmacokinetic Set

[0572]

[0573] Abbreviations: adj = adjusted, gCV = geometric coefficient of variation, gMean = geometric mean, gSE = geometric standard error, ind = individual

[0574] Table 27 presents the ANOVA results comparing the primary and secondary endpoints of one of the NF formulations when administered fasting in the absence (T1) and in the presence of co-administration with the proton pump inhibitor (PPI) rabeprazole (T3). In individuals receiving treatment T3 / T1, the range of the adjusted geometric mean (gMean) ratios of the endpoints was 87.0% to 97.1%, and the range of the 90% CI was 66.8% to 113.2% (Table 27). The PK parameters and characteristics of T1 and T3 were similar, while in the presence of rabeprazole, the time to the maximum measured concentration of the analyte in plasma (t max ) appeared to be delayed. In summary, the results indicate that rabeprazole does not interfere with the PK of compound (1).

[0575] Table 27: Adjusted Geometric Mean and Relative Bioavailability of Compound (1) NF Fasted + Rabeprazole (T3) vs NF Fasted (T1) Using Individuals as Random Effects – Pharmacokinetic Set

[0576] Abbreviations: adj = adjusted, gCV = geometric coefficient of variation, gMean = geometric mean, gSE = geometric standard error, ind = individual

[0577] Reference Example 1: Preparation of the Crystalline Form of Compound (1)

[0578] Forms III and IV of compound (1) involved in Example 5.1 can be produced according to the procedures given below. It should be noted that if complete dissolution is achieved before crystallization, the input form of compound (1) has no significant impact on the crystallization operation. In the case of complete dissolution, the starting material of compound (1) can be produced, for example, according to the synthesis described in WO 2021 / 213800.

[0579] Reference Example 1.1 - Manufacture of Form I

[0580] First example procedure for preparing Form I (crystalline): Dissolve 19 kg of compound (1) (in any solid form) in a mixture of ~54 kg of THF, ~160 kg of DCM, and ~48 kg of MeOH. Remove residual inorganic salts by washing with brine (48 kg). Remove undissolved particles by polishing filtration of the organic layer. Then distill the organic layer to ~160 L and dilute the mixture with 78 kg of THF. Repeat the sequence of distillation, THF dilution, and distillation until the water and methanol contents are ≤1.0% w / w, respectively. After distillation is complete, hold the resulting slurry at ambient temperature for no more than 12 hr and filter to obtain Form I.

[0581] Second example procedure for preparing Form I (crystalline): Dissolve 6 g of Form IV of compound (1) (prepared, for example, according to any of the examples described herein) in 75 g of a 5% w / w H2O / IPA solution at 90°C. Slowly cool the solution to 75°C and seed with 60 mg of Form I. Stir the mixture at 75°C for 2 hours and then cool it to 20°C at a rate of 0.3°C / min. After cooling is complete, filter the solid and dry it to obtain Form I.

[0582] Reference Example 1.2 - Manufacture of Form III

[0583] Example procedure for preparing Form III (slurry): Mix 17 kg of Form I of compound (1) with 271 kg of IPAc. Heat the slurry to 70°C. Add 0.2 kg of seed crystals of Form III of compound (1) (prepared, for example, according to any of the examples described herein) to the slurry and stir the mixture for ~16 hours. After the holding is complete, gradually cool the mixture to 53°C in ~40 minutes, then cool it to 33°C in ~40 min, and then to 25°C. Stir the resulting slurry for ~1 hour and filter. Wash the solid with 27 kg of IPAc and dry to obtain Form III.

[0584] This operation can also be carried out without adding seed crystals.

[0585] Reference Example 1.3 - Manufacture of Form IV

[0586] Procedure for the First Embodiment for Preparing Form IV (Crystalline): 300 mg of Form I of Compound (1) was dispersed in 3 ml of 1-BuOH. The mixture was heated to 90 °C and top-stirred. Dissolution was observed. The solution was cooled to 75 °C at a rate of 0.2 °C / min and then rapidly cooled to 20 °C. The obtained slurry was held at 20 °C for ~12 hr while stirring and filtered to yield Form IV.

[0587] Procedure for the Second Embodiment for Preparing Form IV (Crystalline): Form III of Compound (1) was dissolved in 10 volumes of a 1-BuOH / anisole (1:1) mixture at 110 °C. The solution was subjected to distillation under a slight vacuum during which most of the 1-BuOH was removed. The solution was seeded with Form III seeds, maintained at 110 °C, and a slurry was obtained. The mixture was cooled to ambient temperature while stirring and filtering to obtain the isolated Compound (1) of Form IV. This procedure can be carried out without seeding with Form III.

[0588] Procedure for the Third Embodiment for Preparing Form IV (Slurry): A slurry of Form I and Form IV of Compound (1) was slurried in IPAc in the temperature range of 25–75 °C for 72–168 hr. If applicable, the mixture was raised to ambient temperature and filtered to obtain Compound (1) of Form IV.

[0589] Reference Example 2 - XRPD of the Solid Forms of Compound (1)

[0590] The crystalline forms of Compound (1) were analyzed by XRPD. XRPD was measured using CuK radiation with a wavelength in the temperature range of 20 to 30 °C. α

[0591] The method for this analysis was as follows: Each individual solid compound (approximately 0.2 g) was representative re-sampled into a stainless-steel sample holder equipped with a zero-diffraction plate (ZDP). The sample holder was then leveled with a cover slip so that the sample surface was flush with the sample holder. The instrument used for analysis was a Bruker D2 Phaser (System EQ-SSRD-XRD-01). A corundum reference standard was run daily to evaluate the system performance. Two peaks must be within the range of ±0.02° 2θ to achieve acceptable system suitability. The instrument settings for measuring the solid compound samples are shown in Table 28. Processing (Kα2 contribution removed, peak labeling) was completed using DIFFRAC.EVA software (Version 5.0).

[0592] The experimental parameters for XRPD measurement are given below:

[0593] Table 28: Experimental Parameters for XRPD Measurement

[0594]

[0595]

[0596] Table 29 lists the peaks of each form (relative intensity higher than 5%). Table 30 lists the most preferred characteristic peaks used when attempting to identify the presence of another form of a given polymorph. Diagnostic peaks indicate the peak positions where the impurities have relatively high-intensity peaks, and the dominant form of the sample has a flat baseline.

[0597] Table 29: XRPD Peak Comparison

[0598]

[0599]

[0600] Regarding Table 29, the bold peaks were determined to be characteristic peaks, the peaks marked with "*" have a relative intensity greater than 10%, and the peaks marked with "**" have a relative intensity greater than 50%. Additionally, the peaks are listed in the order of peak position (°2θ), with similar peak positions on the same row.

[0601] Table 30: XRPD Characteristic Peaks (°2θ) for Polymorphic Impurity Identification

[0602]

Claims

1. A solid dispersion, which comprises compound (1) as defined below or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier.

2. The solid dispersion according to claim 1, wherein the pharmaceutically acceptable dispersion carrier is a polymer.

3. The solid dispersion according to claim 2, wherein the polymer is enteric-soluble or non-enteric-soluble.

4. The solid dispersion according to claim 2 or 3, wherein the polymer is enteric-soluble.

5. The solid dispersion according to any one of claims 1 to 4, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of: hydroxypropyl methylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylate and its copolymers.

6. The solid dispersion according to claim 5, wherein the hydroxypropyl methylcellulose and its esters are selected from the group consisting of: hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, and carboxymethylcellulose acetate butyrate.

7. The solid dispersion according to claim 5 or 6, wherein the hydroxypropyl methylcellulose and its esters are selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, especially hot melt extrusion grade hydroxypropyl methylcellulose.

8. The solid dispersion according to any one of claims 5 to 7, wherein the polyvinylpyrrolidone and its copolymers are selected from the group consisting of: polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone.

9. The solid dispersion according to any one of claims 5 to 8, wherein the polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymer.

10. The solid dispersion according to any one of claims 5 to 9, wherein the polymethacrylate and its copolymers are selected from the group consisting of: methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methyl methacrylate, and methacrylic acid copolymer.

11. The solid dispersion according to any one of claims 5 to 10, wherein the polymethacrylate and its copolymers are methacrylic acid-methyl methacrylate copolymer.

12. The solid dispersion according to any one of claims 1 to 11, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone-vinyl acetate copolymer, methacrylic acid-methyl methacrylate copolymer, and hot melt extrusion grade hydroxypropyl methylcellulose.

13. The solid dispersion according to any one of claims 1 to 12, wherein compound (1) is amorphous.

14. The solid dispersion according to any one of claims 1 to 13, wherein the compound (1) is present in an amount in the range of 25 wt% to 75 wt% based on the total weight of 100 wt% of the solid dispersion.

15. The solid dispersion according to any one of claims 1 to 14, wherein the pharmaceutically acceptable dispersion carrier is present in an amount in the range of 25 wt% to 75 wt% based on the total weight of 100 wt% of the solid dispersion.

16. The solid dispersion according to any one of claims 1 to 15, wherein the weight ratio of the compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is from 1:1 to 1:

3.

17. The solid dispersion according to any one of claims 1 to 16, wherein the weight ratio of the compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is about 1:

1.

18. The solid dispersion according to any one of claims 1 to 17, wherein when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or , the solid dispersion has an X-ray powder diffraction pattern that does not include a diffraction peak at a 2θ angle equal to or lower than 40.0°.

19. The solid dispersion according to any one of claims 1 to 18, wherein when measured by modulated differential scanning calorimetry with a modulation amplitude of 1 °C / min and a heating rate of 3.0 °C / min, the solid dispersion has a differential scanning calorimetry curve comprising a single glass transition temperature signal.

20. The solid dispersion according to claim 19, wherein the single glass transition temperature signal is in the range of 90 to 190 °C.

21. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 20 and one or more pharmaceutically acceptable excipients.

22. The pharmaceutical composition according to claim 21, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents.

23. The pharmaceutical composition according to claim 22, wherein the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof.

24. The pharmaceutical composition according to claim 22 or 23, wherein the disintegrant is selected from the group consisting of sodium carboxymethylcellulose cross-linked, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof.

25. The pharmaceutical composition according to any one of claims 22 to 24, wherein the glidant is colloidal silicon dioxide.

26. The pharmaceutical composition according to any one of claims 22 to 25, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, and mixtures thereof.

27. The pharmaceutical composition according to any one of claims 21 to 26, wherein the one or more pharmaceutically acceptable excipients comprise mannitol, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, colloidal silicon dioxide, and sodium stearyl fumarate.

28. The pharmaceutical composition according to any one of claims 21 to 27, wherein based on the total weight of 100 wt% of the pharmaceutical composition, the pharmaceutical composition comprises: - the solid dispersion according to any one of claims 1 to 20 in the range of 25 wt% to 65 wt%; and / or - one or more fillers in the range of 25 wt% to 65 wt%; and / or - a disintegrant in the range of 4 wt% to 10 wt%; and / or - a glidant in the range of 1 wt% to 2 wt%; and / or - a lubricant in the range of 1 wt% to 2 wt%; and / or - Optionally, a coating agent in the range of 2 wt% to 5 wt%.

29. The pharmaceutical composition according to any one of claims 21 to 28, wherein the composition is in the form of a tablet, granule or capsule.

30. The pharmaceutical composition according to any one of claims 21 to 29, comprising: (i) a tablet core comprising a solid dispersion according to any one of claims 1 to 20, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate; and (ii) a film coating.

31. A pharmaceutical composition according to any one of claims 21 to 30, wherein when measured at a temperature in the range of 20 to 30 °C and with Cu-Kα radiation having a wavelength of or , the pharmaceutical composition has an X-ray powder diffraction pattern that does not include a diffraction peak at a 2θ angle equal to or lower than 6.5°.

32. The solid dispersion according to any one of claims 1 to 20 or the pharmaceutical composition according to any one of claims 21 to 31, which is used as a medicament.

33. The solid dispersion according to any one of claims 1 to 20 or the pharmaceutical composition according to any one of claims 21 to 31, which is used for treating and / or preventing tumors and / or hyperproliferative diseases, especially cancer.

34. The solid dispersion or pharmaceutical composition for use according to claim 33, wherein the tumor and / or hyperproliferative disease is a cancer selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

35. The solid dispersion or pharmaceutical composition for use according to claim 33 or 34, wherein the tumor and / or hyperproliferative disease is a HER2 overexpressing, HER2 amplified and / or HER2 mutant cancer.

36. The solid dispersion or pharmaceutical composition for use according to any one of claims 32 to 35, wherein the solid dispersion or the pharmaceutical composition is administered to a fasting individual.

37. The solid dispersion or pharmaceutical composition for use according to any one of claims 32 to 36, wherein the solid dispersion or the pharmaceutical composition is administered in combination with an agent that increases gastric pH.

38. The solid dispersion or pharmaceutical composition for use according to claim 37, wherein the agent that increases gastric pH is selected from the group consisting of proton pump inhibitors, antacids and antihistamines.

39. A method for preparing a solid dispersion according to any one of claims 1 to 20, comprising the steps of: a) providing a mixture of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and b) removing the solvent from the solution or suspension to form a solid dispersion according to any one of claims 1 to 20.

40. The method according to claim 39, wherein the removal of the solvent in step b) is carried out by spray drying.

41. The method according to claim 39 or 40, wherein the solvent is selected from the group consisting of: water, alcohol, ketone, ester, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane and mixtures thereof.

42. The method according to any one of claims 39 to 41, wherein the solvent is a mixture of dichloromethane and methanol.

43. Use of a solid dispersion according to any one of claims 1 to 20 for the preparation of a pharmaceutical composition according to any one of claims 21 to 31.

44. A kit, comprising: - a solid dispersion according to any one of claims 1 to 20 or a pharmaceutical composition according to any one of claims 21 to 31; and - a component containing the solid dispersion or the pharmaceutical composition; and - an optional desiccant.

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