Solid dispersion of HER2 inhibitor

Abstract

Solid dispersion of HER2 inhibitor. The present invention relates to a solid dispersion of a HER2 inhibitor and a pharmaceutically acceptable dispersion carrier. Also provided herein are a pharmaceutical composition and kit containing the solid dispersion, uses thereof, particularly use in the treatment and / or prevention of cancer, and a method for producing the solid dispersion.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION 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.

[0002] background 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 2021213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2, sparing wild-type epidermal growth factor receptor (EGFR). Therefore, it is useful for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly neoplastic and / or hyperproliferative diseases, such as cancer.

[0003] The solubility of compound (1) in aqueous media is limited and has been found to be strongly pH-dependent, with the solubility increasing under acidic conditions. Specifically, the solubility increases by approximately 10% between pH 1.2 and pH 6.8. 5 A 2-fold decrease in absorption of Compound (1) was observed. As a result, the in vivo absorption of Compound (1) is affected by gastric pH. In particular, lower gastric pH is associated with increased absorption of Compound (1), while higher gastric pH is associated with decreased blood serum levels of Compound (1). This pH dependence is undesirable because it may reduce the bioavailability and / or bioaccessibility of Compound (1). Such a decrease may occur to different degrees in different patients due to variations in gastric pH among patients.

[0004] Furthermore, gastric pH in cancer patients can be altered by therapeutic agents in their treatment regimens, such as protein pump inhibitors (PPIs), antacids, and antihistamines. These therapeutic agents are acid-reducing agents known to increase gastric pH. These therapeutic agents are frequently administered to cancer patients, for example, to alleviate gastrointestinal side effects caused by medications, particularly those that lower gastric pH, and also to manage the effects of tumors in the gastric region. Therefore, coadministration of acid-reducing agents with Compound (1) can reduce the absorption and systemic exposure of Compound (1).

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

[0006] Additionally, there is a need to find methods of administering Compound (1) that are therapeutically effective in the context of existing treatments, and as such are safe and tolerable. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) and 75 wt. % HPMCAS-M (top curve) and a spray-dried amorphous solid dispersion of Compound (1) and 50 wt. % HPMCAS-M (bottom curve) from Example 1 herein, compared with the XRPD of crystalline Compound (1). [Figure 2] FIG. 2 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % PVP-VA (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % PVP-VA (bottom curve) from Example 1 herein, compared with the XRPD of crystalline Compound (1). [Figure 3]FIG. 3 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % Eudragit® L100 (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % Eudragit® L100 (bottom curve) from Example 1 herein, compared with the XRPD of crystalline Compound (1). [Figure 4] FIG. 4 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % HPMC HME 15LV (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % HPMC HME 15LV (bottom curve) from Example 1 herein, compared to the XRPD of crystalline Compound (1). [Figure 5] 5 shows the powder X-ray diffraction diagrams (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 3.3 herein. From top to bottom curve: Sample 3.3-A (top curve), Sample 3.3-B (middle curve), and Sample 3.3-C (bottom curve). [Figure 6] 6 shows the powder X-ray diffraction diagrams (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 3.4 herein. From top to bottom curve: Sample 3.4-A (top curve) and Sample 3.4-B (bottom curve). [Figure 7] 7 shows powder X-ray diffraction patterns (XRPD) of an amorphous solid dispersion of Compound (1) and HPMCAS-M (50 wt%:50 wt%) after exposure to 75°C / 79% relative humidity and 80°C / 76% relative humidity for 3 weeks. From top to bottom curve: unstressed sample (top), sample stressed at 75°C / 79% relative humidity (middle), and sample stressed at 80°C / 76% relative humidity (bottom). [Figure 8] FIG. 8 shows a comparison of the Log solubility values ​​measured in aqueous media at various pH values ​​for an amorphous solid dispersion of Compound (1) and HPMCAS-M (50 wt %:50 wt %) (circles), crystalline Form III of Compound (1) (squares), and crystalline Form IV of Compound (1) (triangles). [Figure 9] Figure 9 shows the in vitro dissolution profiles of various amorphous solid dispersions with various polymers (25 wt%:75 wt% Compound (1):polymer) in simulated intestinal fluid after transit from simulated gastric fluid, compared to the dissolution profile of crystalline Compound (1) in the two-stage gastric transit study of Example 5.2. From top to bottom curve (relative to the first measurement point): HPMC HME 15LV, PVP-VA, HPMCAS-M, Eudragit® L100, and crystalline Compound (1). [Figure 10] 10 shows the in vitro dissolution profiles of various amorphous solid dispersions with various polymers (50 wt%:50 wt% Compound (1):polymer) compared to the dissolution profile of crystalline Compound (1) in simulated intestinal fluid after transit from simulated gastric fluid in the two-stage gastric transit study of Example 5.2. From top to bottom curve (relative to the first measurement point): HPMCAS-M, HPMC HME 15LV, PVP-VA, Eudragit® L100, and crystalline Compound (1). [Figure 11] FIG. 11 shows the results of a comparison of in vitro dissolution at pH 2.0 between tablets containing crystalline Compound (1) (squares) and tablets containing a solid dispersion of Compound (1) (circles). [Figure 12] FIG. 12 shows the results of a comparison of in vitro dissolution at pH 6.8 between conventional tablets (circles) containing crystalline Compound (1) and tablets containing a solid dispersion of Compound (1) (squares: Example 6.2-A, triangles: Example 6.2-C). [Figure 13] Figure 13 shows a schematic diagram of a dynamic in vitro gastrointestinal model (tiny-TIM model) for simulating physiological processes occurring in the human stomach and small intestine: A: meal inlet, B: gastric body, C: proximal antrum, D: distal antrum, E: pyloric valve, F: peristaltic valve, G: small intestinal segments, H: filtration system, I: gastric secretion, J: intestinal secretion, K: pH electrode, L: level sensor. [Figure 14]Figure 14 shows the in vitro bioaccessibility over time of a solid dispersion of Compound (1) ("SDD") compared to administration of a conventional tablet of crystalline Compound (1) ("Conv."), both at a 100 mg dose, under fasting conditions (normal low gastric pH) and under simulated high gastric pH conditions following proton pump inhibitor (PPI) administration. [Figure 15] FIG. 15 shows the X-ray powder diffraction diagram (XRPD) of the formulation disclosed in Example 6.1-C. [Figure 16] FIG. 16 shows the X-ray powder diffraction diagram (XRPD) of the formulation disclosed in Example 6.2-C.

[0008] overview According to a first aspect, there is provided a compound of formula (1) defined below: [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0009] Another aspect relates to a pharmaceutical composition comprising a solid dispersion described herein and one or more pharmaceutically acceptable excipients.

[0010] Another aspect relates to a solid dispersion as described herein or a pharmaceutical composition as described herein for use as a medicament.

[0011] Another aspect relates to a solid dispersion as described herein or a pharmaceutical composition as described herein for use in treating and / or preventing a neoplastic disease and / or a hyperproliferative disease.

[0012] In an embodiment of all aspects disclosed herein, the neoplastic and / or hyperproliferative disease is cancer.

[0013] Another aspect is 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; b) removing the solvent from the solution or suspension to form the described solid dispersion; and a method for producing the solid dispersion described herein, comprising:

[0014] Another aspect relates to the use of a solid dispersion as described herein for the manufacture of a pharmaceutical composition as described herein.

[0015] Another aspect is a solid dispersion or a pharmaceutical composition as described herein; - a means for containing said solid dispersion or pharmaceutical composition; - optionally with a desiccant The present invention relates to a kit comprising:

[0016] Detailed Description The object of the present invention is to reduce the pH dependency of compound (1) and improve its bioavailability and / or bioaccessibility.

[0017] It has surprisingly been discovered that formulation of Compound (1) as a solid dispersion has the potential to achieve consistent bioavailability and / or bioaccessibility and overcome patient-to-patient variations in gastric pH compared to administration of a formulation containing Compound (1) in crystalline form.

[0018] Specifically, administration of solid dispersions of Compound (1) provides high uptake not only when administered to subjects with normal low gastric pH, but also when administered in combination with pharmaceutical agents that elevate gastric pH, such as proton pump inhibitors, antacids, or antihistamines. The surprising results presented in the examples herein, particularly the superior in vitro and in vivo performance of the solid dispersions of the present invention compared to formulations containing crystalline Compound (1), demonstrate that formulations of Compound (1) as solid dispersions provide consistently high uptake that is unaffected by pH fluctuations initiated by co-pharmaceuticals that elevate gastric pH levels, as demonstrated in Examples 5.1, 5.2, and 7.1-7.4 herein, thereby enabling the inclusion of patient populations receiving co-pharmaceuticals, such as proton pump inhibitors, antacids, or antihistamines, in treatment with Compound (1).

[0019] It has also been surprisingly found that Compound (1) can maintain an amorphous state, e.g., a solid dispersion, even when exposed to temperature and humidity stress for extended periods of time, as demonstrated in Example 4 herein.

[0020] Compound (1) As used herein, the term “compound (1)” refers to the compound defined below: [ka] or a pharmaceutically acceptable salt thereof.

[0021] 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 a conflict between the IUPAC name and the formula shown, the formula shall prevail. Compound (1) is also known as zongertinib. Compound (1) is disclosed in WO 2021 / 213800 as Example Compound I-01. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines such as compound (1) as HER2 inhibitors and provides a method for synthesizing compound (1). The properties of compound (1) and evidence of its efficacy in inhibiting HER2 wild-type and YVMA kinase activity while sparing EGFR are also disclosed in WO 2021213800, which is incorporated herein by reference.

[0022] As used herein, the term "compound (1)" also encompasses any tautomers and pharmaceutically acceptable salts, as well as all solid forms of the compound and solvates, including hydrates and solvates, of its pharmaceutically acceptable salts.

[0023] In embodiments, Compound (1) is the free base. Thus, in any aspect or embodiment, the phrase "Compound (1) or a pharmaceutically acceptable salt thereof" can be substituted for "Compound (1)" without reference to a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutically acceptable salt of Compound (1) is used. As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0024] As used herein, a "pharmaceutically acceptable salt" of Compound (1) refers to Compound (1) that has been modified by making an acid or base salt thereof. As used herein, the term "pharmaceutically acceptable salt" generally includes both acid and base addition salts. Pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. 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; alkali or organic acid salts of acidic residues, such as carboxylic acids; and the like. For example, such salts include salts from 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 salts and fumarate salts.

[0025] Pharmaceutically acceptable salts can be synthesized from Compound 1 by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of Compound 1 with a sufficient amount of the 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.

[0026] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with 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 where the solvent molecule is water.

[0027] solid dispersion agent Provided herein is a solid dispersion comprising Compound (1) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0028] 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 "consists essentially of" and "consisting essentially of" have their art-defined meanings. In particular, they indicate that additional components may be present, particularly those that do not significantly affect the properties of the dispersion, composition, or formulation, respectively. Such additional components may be, for example, residual solvent.

[0029] Also provided herein is a solid dispersion comprising Compound (1) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0030] As used herein, the term "solid dispersion" refers to a solid-state system comprising at least two components, wherein one component, e.g., Compound (1), preferably in an amorphous state, or generally, an active pharmaceutical ingredient (API), is dispersed throughout another component, e.g., a pharmaceutically acceptable solid dispersion carrier, particularly a dispersion polymer.

[0031] As used herein, the term "dispersion carrier" refers to a carrier component through which an API, e.g., Compound (1), can be dispersed so as to form a solid dispersion. In an embodiment, Compound (1) is dispersed at a molecular level in the pharmaceutically acceptable dispersion carrier.

[0032] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Thus, the present invention provides a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer. Polymeric dispersion carriers are also referred to as "dispersion polymers." Polymers are widely used in solid dispersion formulations. Different polymeric carriers result in solid dispersions with different properties in terms of physical stability, phase behavior, and the rate and extent of drug release. Due to the complex nature of solid dispersion formulations, it is necessary to test the optimal carrier for a given API. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer.

[0033] In other embodiments, the pharmaceutically acceptable dispersion carrier is an enteric or non-enteric polymer, preferably an enteric polymer. In other embodiments, the polymer is enteric or non-enteric, preferably an enteric polymer. 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 at most less than pH 3) but becomes soluble at higher pH (e.g., pH 5 or higher). In certain embodiments, the pH-dependent polymer may be soluble in a pH range of about pH 5 or higher, 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 are generally less acidic than the stomach environment and roughly correspond to pH values ​​in the small intestine. Examples of enteric polymers include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer (Eudragit® L100), shellac, cellulose acetate trimellitate, sodium alginate, and zein. The term "non-enteric polymer" refers to a neutral polymer that does not exhibit pH-dependent solubility properties. 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, starch derivatives such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), poly(ethylene glycol) PEG, cyclodextrins, polyethylene glycol, Soluplus®, an amphiphilic copolymer consisting of polyvinylcaprolactam and polyvinyl acetate.

[0034] 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.

[0035] In an embodiment, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and carboxymethyl cellulose acetate butyrate (CMCAB). In an embodiment, 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.

[0036] In an 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).

[0037] In embodiments, 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. Polymethacrylate and its copolymers are available, for example, under the trade name Eudragit® from Evonik Industries AG. Methacrylic acid-methyl methacrylate copolymer is available, for example, under the trade name Eudragit® L100. In certain embodiments, the polymethacrylate and its copolymer are methacrylic acid-methyl methacrylate copolymer.

[0038] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group of hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), methylacrylic acid-methyl methacrylate copolymer (e.g., Eudragit® L100), and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0039] In a specific embodiment, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hypromellose acetate succinate. Hypromellose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinoyl groups into the hydroxyl groups of the backbone of hydroxypropyl methylcellulose (HPMC), also known as hypromellose. This method 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 be reacted with hydroxypropyl methylcellulose (HPMC) under particularly controlled conditions to produce HPMCAS with different degrees of acetyl and succinoyl substitution.

[0040] HPMCAS is available in several grades (L, M, and H) that differ in the degree of acetyl and succinoyl group substitution based on the content (wt%) of acetyl and succinoyl groups in the HPMCAS molecule. Any grade of HPMCAS can be used in the solid dispersion of the present invention. Preferably, HPMCAS grades L, M, or H are 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 contain an acetyl content of 7-11 wt%, a succinoyl content of 10-14 wt%, a methoxyl 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, granular HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used with any grade of HPMCAS, especially grade G, as can HPMCAS-MG.

[0041] In a particular embodiment, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), a linear random copolymer obtainable by free radical polymerization of monomers in which the ratio of vinyl acetate to vinylpyrrolidone varies from 70 / 30 to 30 / 70.

[0042] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methyl acrylic acid-methyl methacrylate copolymer, such as Eudragit® L100. As used herein, "methyl acrylic acid-methyl methacrylate copolymer" is used interchangeably with "methyl methacrylate copolymer."

[0043] In a particular embodiment, 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 by hot-melt extrusion. HPMC HME is a water-soluble amorphous polymer, typically provided as a white to off-white powder, and is available in three grades that differ in terms of their molecular weight: HPMC HME 15LV, HPMC HME 100LV, and HPMC HME 4M. Preferably, the molecular weight (M) is 100 kDa or less. W More preferably, HPMC HME 15LV having a molecular weight (M) of 200 kDa or less is used. W ) is used.

[0044] By dispersing Compound (1), preferably at the molecular level, in a pharmaceutically acceptable dispersion carrier, e.g., a polymeric one, the solid dispersion can maintain an amorphous state even when exposed to high temperature and / or high humidity conditions, and the solid dispersion can reliably provide Compound (1) in amorphous form. In an embodiment, Compound (1) is amorphous. The preferred feature of Compound (1) being amorphous can be applied to any of the embodiments disclosed herein to provide further embodiments of the present invention, particularly to any of the solid dispersions (including those relating to the identity of the pharmaceutically acceptable dispersion carrier, the amounts of the components of the solid dispersion, etc.), pharmaceutical compositions, kits, uses, and methods described herein. As used herein, the term "amorphous" refers to a condensed phase characterized by random molecular orientation, the absence of diffraction peaks by XRPD, and the absence of any microscopic order. Amorphous solid systems may be composed of a single chemical entity or may be multi-component systems that do not have a stoichiometric composition, e.g., containing an API, a polymer, and other excipients. Amorphous solids generally have crystal-like short-range molecular ordering, but lack the long-range molecular packing order found in crystalline solids. The solid form of a solid can be determined, for example, by powder X-ray diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0045] In embodiments, the solid dispersion comprises, consists essentially of, or consists of amorphous Compound (1) and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is in a substantially amorphous solid-state form. In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 80 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 85 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 90 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, a substantially amorphous solid-state form refers to a solid dispersion comprising at least 95 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, a substantially amorphous solid-state form refers to a solid dispersion comprising at least 96, 97, 98, or 99 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In this manner, the solid dispersion can provide Compound (1) in an amorphous or essentially amorphous state. For this reason, such solid dispersions may be referred to as amorphous solid dispersions. For this reason, in embodiments, the solid dispersion is an amorphous solid dispersion.

[0046] In one embodiment, the solid dispersion comprises a predetermined amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the predetermined amount refers to the initial amount of Compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion.

[0047] In another embodiment, the solid dispersion comprises a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.

[0048] In an embodiment, Compound (1) is present in an amount ranging from 5 wt% to 95 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, Compound (1) is present in an amount ranging from 25 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 5 wt% to 95 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 25 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion.

[0049] In an embodiment, Compound (1) is present in an amount ranging from 20 wt% to 50 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, Compound (1) is present in an amount ranging from 25 wt% to 50 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 50 wt% to 80 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 50 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion.

[0050] The solid dispersion may comprise Compound (1) and a pharmaceutically acceptable dispersion carrier in approximately equal amounts by weight. In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 50 wt% of Compound (1) and about 50 wt% of a pharmaceutically acceptable dispersion carrier, based on a total weight of 100 wt%.

[0051] In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 25 wt% or 50 wt% of Compound (1) and about 75 wt% or 50 wt% of a pharmaceutically acceptable dispersing carrier, based on a total weight of 100 wt%. In an embodiment, the weight ratio of Compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is about 1:4 to 4:1, preferably 1:3 to 3:1, for example, 1:1 to 1:3. In an embodiment, the weight ratio of Compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1 to 1:3. In an embodiment, the weight ratio of Compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is about 1:1.

[0052] As used herein, the terms "approximately" and "about" mean within a statistically meaningful range of values. Such a range may be within one order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the indicated value or range. In some cases, such a range may be within the range of experimental error typical of the standard method used to measure and / or determine the given value or range.

[0053] In an embodiment, the solid dispersion comprises a weight ratio of Compound (1) to a pharmaceutically acceptable dispersing carrier of about 1:4 to 4:1, preferably 1:3 to 3:1, for example, 1:1 to 1:3. In an embodiment, the solid dispersion comprises a weight ratio of Compound (1) to a pharmaceutically acceptable dispersing carrier of 1:1 to 1:3. In an embodiment, the solid dispersion comprises a weight ratio of Compound (1) to a pharmaceutically acceptable dispersing carrier of about 1:1.

[0054] In one embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at a 2θ angle of 40.0° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30° C. As used herein, "Cu-Kα radiation" includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, where Cu-Kα1 radiation has a wavelength of 1.54056 Å and Cu-Kα1,2 radiation has a mean wavelength of 1.54184 Å.

[0055] In another embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 40.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0056] In yet another embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) essentially the same as that shown in Figure 5 or Figure 6 below, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0057] In yet another embodiment, the solid dispersion is characterized by having a differential scanning calorimetry curve containing a single glass transition temperature (Tg) signal when measured by modulated differential scanning calorimetry (mDSC) at a modulation amplitude of 1°C / min and a heating rate of 3.0°C / min. Preferably, the single glass transition temperature (Tg) signal is in the range of 90 to 190°C, preferably in the range of 110 to 120°C.

[0058] In yet another embodiment, the solid dispersion comprises: (i) a D90 value of 100 μm or less, preferably 90 μm or less, and most preferably 85 μm or less, and / or (ii) a D50 value of 50 μm or less, preferably 45 μm or less, and most preferably 40 μm or less, and / or (iii) a D10 value of 20 μm or less, preferably 15 μm or less, and most preferably 13 μm or less The particles are characterized by a particle size distribution as measured by laser diffraction having:

[0059] In yet another embodiment, the solid dispersion comprises: (i) a D90 value in the range of 50 to 100 μm, preferably in the range of 55 to 90 μm, and most preferably in the range of 60 to 85 μm, and / or (ii) a D50 value in the range of 25 to 50 μm, preferably in the range of 30 to 45 μm, and most preferably in the range of 30 to 40 μm, and / or (iii) a D10 value in the range of 1 to 20 μm, preferably in the range of 5 to 15 μm, and most preferably in the range of 10 to 13 μm The particles are characterized by a particle size distribution as measured by laser diffraction having:

[0060] As used herein, the term "particle size distribution" refers to a list of values ​​or a mathematical function that defines the relative amount, typically mass or volume, of particles present in a sample according to size. Particle size distribution can be characterized by one or more values, for example, D90, D50, or D10. Particle size distribution can be measured by means well known to those skilled in the art, for example, laser diffraction.

[0061] As used herein, "D90" refers to the particle size value where 90% of the total volume of the particles is made up of particles no larger than the stated size.

[0062] As used herein, "D50" refers to the particle size value where 50% of the total volume of the particles is made up of particles no larger than the stated size.

[0063] As used herein, "D10" refers to the particle size value where 10% of the total volume of the particles is made up of particles no larger than the indicated size.

[0064] A further aspect relates to the use of a solid dispersion as described herein for preparing a pharmaceutical composition, wherein the pharmaceutical composition is preferably as defined below.

[0065] Pharmaceutical Composition Another aspect provides a pharmaceutical composition comprising a 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 a solid dispersion as described herein and one or more pharmaceutically acceptable excipients.

[0066] Another embodiment of the present invention is a pharmaceutical composition comprising a predetermined amount of the solid dispersion 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 in preparing the pharmaceutical composition.

[0067] The term "pharmaceutically acceptable excipient" refers to a non-toxic ingredient that does not destroy the pharmacological activity of the compound with which it is formulated. 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 further include pharmaceutically acceptable excipients selected from buffers, binders, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, colorants, sweeteners, flavors, fragrances, diluents, and other known additives that can be used in the manufacture of pharmaceuticals.

[0068] 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 comprises fillers, disintegrants, glidants and lubricants.In an embodiment, the pharmaceutical composition comprises fillers, disintegrants, glidants, lubricants and coating agents.It should be understood that the pharmaceutical composition may comprise one or more excipients for each function, for example, one or more fillers, one or more disintegrants, one or more glidants, one or more lubricants, one or more coating agents.

[0069] 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 cross-linked sodium carboxymethylcellulose, also known as croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In a particular embodiment, the disintegrant is croscarmellose sodium. In an embodiment, the glidant is colloidal silicon dioxide. In an embodiment, the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof. In a particular embodiment, the lubricant is sodium stearyl fumarate.

[0070] In embodiments, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0071] In an embodiment, the pharmaceutical composition comprises, consists of, or consists essentially of Compound (1), as defined herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, a solid dispersion comprising mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0072] In certain embodiments, the pharmaceutical composition comprises a coating agent, for example, when formulated as a film-coated tablet.In an embodiment, the coating agent comprises a film-forming agent, for example, polyvinyl alcohol, which may be partially hydrolyzed, an anti-tacking agent, for example, talc, a pigment, for example, titanium dioxide, glyceryl mono- and dicaprylocaprate (GMDCC), and iron oxide, for example, iron oxide yellow, and a lubricant, for example, sodium lauryl sulfate.Coating agents are commercially available, for example, under the trade name Opadry®, for example, Opadry® AMB II yellow.In a preferred embodiment, the coating agent does not contain titanium dioxide, for example, is titanium dioxide-free.

[0073] In an embodiment, the pharmaceutical composition comprises: (i) a tablet core comprising a solid dispersion as described herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; (ii) film coating and Includes.

[0074] In an embodiment, the pharmaceutical composition comprises: (i) a tablet core comprising, consisting of, or consisting essentially of a solid dispersion as described herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; (ii) film coating and consisting of, or consisting essentially of, these.

[0075] In certain embodiments, the film coating is a non-functional film coating. In one embodiment, the film coating does not contain titanium dioxide.

[0076] In an embodiment, the pharmaceutical composition comprises 25 wt% to 65 wt%, preferably 35 wt% to 60 wt%, or 25 wt% to 35 wt%, or 27 wt% to 31 wt%, more preferably about 30 wt%, of a solid dispersion described herein, based on 100 wt% total weight of the pharmaceutical composition.

[0077] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein, and / or - one or more fillers in the range of 25wt% to 65wt%, and / or - disintegrants in the range of 4 wt% to 10 wt%, and / or - Glidants in the range of 1 wt% to 2 wt%, and / or - lubricant in the range of 1 wt% to 2 wt%, and / or - Optionally, coating agent in the range of 2wt% to 5wt% include.

[0078] In any of the present and following embodiments referring to wt % of ingredients of the pharmaceutical composition, it is to be understood that the sum of the ranges or amounts of all ingredients does not exceed 100 wt %.

[0079] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, and / or one or more fillers in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, and / or - disintegrants in the range of 4 wt% to 7 wt%, and / or - Glidants in the range of 1 wt% to 1.5 wt%, and / or - lubricants in the range of 1 wt% to 1.5 wt%, and / or - Optionally, coating agent in the range of 3wt% to 5wt% include.

[0080] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 25 wt% to 35 wt%, and / or - one or more fillers in the range of 55wt% to 65wt%, and / or - disintegrants in the range of 4 wt% to 7 wt%, and / or - Glidants in the range of 1 wt% to 2 wt%, and / or - lubricant in the range of 1 wt% to 2 wt%, and / or - Optionally, coating agent in the range of 3wt% to 5wt% include.

[0081] In one embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 28 wt% to 30 wt%, and / or - one or more fillers in the range of 57wt% to 62wt%, and / or - disintegrants in the range of 4 wt% to 5 wt%, and / or - Glidants in the range of 1.4wt% to 1.5wt%, and / or - lubricant in the range of 1.4wt% to 1.5wt%, and / or - optionally about 4 wt% coating agent Includes.

[0082] In this embodiment, preferably, the lower limits of the ranges for solid dispersion agent, filler, disintegrant, glidant, and lubricant refer to pharmaceutical compositions that include a coating, while the upper limits of the same ranges refer to pharmaceutical compositions that do not include a coating.

[0083] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein, - one or more fillers in the range of 25 wt% to 65 wt%; - a disintegrant in the range of 4 wt% to 10 wt%; - Glidants in the range of 1wt% to 2wt% and - Lubricant in the range of 1wt% to 2wt% The total of the range of all components does not exceed 100 wt%.

[0084] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, of a solid dispersion as described herein, - one or more fillers in the range of 30wt% to 60wt%, preferably 35wt% to 60wt%, - a disintegrant in the range of 4 wt% to 7 wt%; - Glidants in the range of 1wt% to 1.5wt% and - Lubricant in the range of 1wt% to 1.5wt% The total of the range of all components does not exceed 100 wt%.

[0085] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 35 wt% of a solid dispersion as described herein, - 55wt% to 65wt% of one or more fillers, - a disintegrant in the range of 4 wt% to 7 wt%; - Glidants in the range of 1wt% to 2wt% and - Lubricant in the range of 1wt% to 2wt% The total of the range of all components does not exceed 100 wt%.

[0086] In one embodiment, the pharmaceutical composition contains Compound (1) in an amount ranging from 10 to 20 wt%, based on 100 wt% of the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition contains Compound (1) in an amount of about 15 wt%, based on 100 wt% of the total weight of the pharmaceutical composition.

[0087] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 15 wt% hypromellose acetate succinate, about 36 wt% microcrystalline cellulose, about 24 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0088] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 15 wt% hypromellose acetate succinate, about 20 wt% microcrystalline cellulose, about 42 wt% mannitol, about 5 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0089] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 14 wt% Compound (1), about 43 wt% hypromellose acetate succinate, about 19 wt% microcrystalline cellulose, about 24 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0090] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 17.5 wt% Compound (1), about 17.5 wt% hypromellose acetate succinate, about 30 wt% microcrystalline cellulose, about 25 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0091] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 47 wt% hypromellose acetate succinate, about 15 wt% microcrystalline cellulose, about 15 wt% mannitol, about 5 wt% croscarmellose sodium, about 1 wt% colloidal silicon dioxide, and about 1 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0092] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg of Compound (1), about 15 mg of hypromellose acetate succinate, about 36 mg of microcrystalline cellulose, about 24 mg of mannitol, about 7 mg of croscarmellose sodium, about 1.5 mg of colloidal silicon dioxide, and about 1.5 mg of sodium stearyl fumarate.

[0093] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg of Compound (1), about 15 mg of hypromellose acetate succinate, about 20 mg of microcrystalline cellulose, about 42 mg of mannitol, about 5 mg of croscarmellose sodium, about 1.5 mg of colloidal silicon dioxide, and about 1.5 mg of sodium stearyl fumarate.

[0094] 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.

[0095] In one embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at 2θ angles below 10.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0096] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at 2θ angles below 9.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0097] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at 2θ angles below 6.5° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0098] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 10.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0099] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 9.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0100] In one embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 6.5° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0101] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 10.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0102] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not include a diffraction peak at a 2θ angle of (5.9±0.2) degrees when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0103] In a further embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not include a diffraction peak at a 2θ angle of (6.2±0.2) degrees when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0104] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) essentially the same as that shown in Figure 15 or Figure 16 below, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0105] For use in treatment, the solid dispersion or the pharmaceutical composition may be contained or formulated into a suitable dosage unit for easy administration. Thus, the solid dispersion or the pharmaceutical composition can be formulated into a dosage unit suitable for each administration route. Typical pharmaceutical dosage units include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, particularly infusion solutions, elixirs, syrups, sachets, emulsions or dispersible powders. Dosage forms and formulations of active ingredients are known in the art, and dosage forms can generally be prepared by any conventional method.

[0106] The solid dispersion or the pharmaceutical composition can be preferably administered orally and can be formulated into a suitable dosage unit formulation. The pharmaceutical composition can be administered as a tablet, hard or soft gelatin capsule, pill, granule, or suspension. In an embodiment, the pharmaceutical composition is in the form of a tablet, granule, or capsule. In a preferred embodiment, the pharmaceutical composition is in the form of a film-coated tablet. Suitable tablets can 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 can be compressed from the solid dispersion, a mixture of the solid dispersion and excipients, or pellets thereof. In another embodiment, the solid dispersion, a mixture of the solid dispersion and excipients, or pellets thereof can be filled into capsules.

[0107] From the viewpoint of compliance, oral administration may be preferred, but the route of administration is not limited to oral administration, and the solid dispersion or the pharmaceutical composition may be administered parenterally, for example, by intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implant, or by enteral, nasal, vaginal, rectal or topical administration.

[0108] The solid dispersion or pharmaceutical composition can be administered or included in a dosage form in a therapeutically effective amount. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as the minimum amount necessary to prevent, ameliorate, or treat a disease or disorder, or an amount in which any toxic or adverse effects of the compound are outweighed by the therapeutically beneficial effects. As used herein, the terms "active ingredient," "active pharmaceutical ingredient," "active substance," and "API" refer to the component intended to provide pharmacological activity or other direct effect, e.g., Compound (1).

[0109] The pharmaceutical composition preferably contains a therapeutically effective amount of Compound (1). In embodiments, a therapeutically effective amount of Compound (1) can be divided into one or more individual dosage unit formulations, such that multiple individual dosage unit formulations may contain portions of a therapeutically effective amount of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 5 mg to 100 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 15 mg to 80 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 15 mg to 30 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain about 15, 30, or 60 mg of Compound (1).

[0110] For storage, the solid dispersion or the pharmaceutical composition can be packaged in a suitable container (i.e., a means for containing the solid dispersion or pharmaceutical composition). Such a container can be selected from a bag, a blister, a bottle, an ampule, and a vial. The container can be made from a suitable packaging material.

[0111] Typical packaging materials are selected from glass, polyethylene, polypropylene, polystyrene, polymethyl methacrylate, low-density polyethylene (LDPE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate (PETg), aluminum, polyamide, and any combination thereof. In certain embodiments, the solid dispersion is packaged in a double low-density polyethylene (LDPE) bag. In yet another embodiment, the pharmaceutical composition is packaged in a high-density polyethylene (HDPE) bottle. Preferably, the HDPE bottle further contains a desiccant. Typical desiccants can be selected from activated alumina, aerogel, benzophenone (as anion), bentonite clay, calcium chloride, calcium oxide, calcium sulfate, cobalt(II) chloride, copper(II) sulfate, lithium chloride, lithium bromide, magnesium chloride hexahydrate, magnesium sulfate, magnesium perchlorate, molecular sieves, 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.

[0112] A further embodiment of the present invention comprises a solid dispersion or a pharmaceutical composition as described herein; - a means for containing said solid dispersion or pharmaceutical composition, preferably a high density polyethylene bottle; - optionally with a desiccant, preferably silica gel The term "kit" refers to a kit including:

[0113] Use for the treatment and / or prevention of neoplastic and / or hyperproliferative disorders The solid dispersions and pharmaceutical compositions described herein can be used as medicaments, in particular the solid dispersions and pharmaceutical compositions described herein can be used for the treatment and / or prevention of neoplastic and / or hyperproliferative disorders, in particular for anti-cancer therapy.

[0114] According to an 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 invention is a solid dispersion or pharmaceutical composition for treating or preventing a disease.

[0115] According to an 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.

[0116] In one embodiment, there is provided a solid dispersion as described herein for use in treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic and / or hyperproliferative disease. A further embodiment provides a pharmaceutical composition as described herein for use in treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic and / or hyperproliferative disease. Another aspect refers to a solid dispersion as described herein or a pharmaceutical composition as described herein for use in a method for treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic or hyperproliferative disease.

[0117] A further aspect relates to a method for treating and / or preventing a disease or disorder modulated by HER2, in particular a neoplastic disease and / or a hyperproliferative disease, comprising administering to a patient a solid dispersion as described herein or a pharmaceutical composition as described herein. In one embodiment, such a method comprises administering to a human in need of such treatment a therapeutically effective amount of a solid dispersion or a pharmaceutical composition as described herein.

[0118] A related aspect relates to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein in the manufacture of a medicament. One embodiment relates to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder modulated by HER2, in particular a neoplastic disease and / or a hyperproliferative disease.

[0119] In one aspect, there is provided a solid dispersion or pharmaceutical composition as described herein for use in treating and / or preventing diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 would be therapeutically beneficial, in particular in treating and / or preventing diseases and / or conditions in which inhibition of HER2 exon 20 mutant proteins would be therapeutically beneficial. Examples of such diseases and / or conditions include, but are not limited to, neoplastic diseases and / or hyperproliferative diseases, such as cancer.

[0120] One aspect relates to a solid dispersion as described herein for use in treating and / or preventing a neoplastic and / or hyperproliferative disorder. A further aspect relates to a pharmaceutical composition as described herein for use in treating and / or preventing a neoplastic and / or hyperproliferative disorder.

[0121] As used herein, the term "hyperproliferative disorder" refers to a condition in which cell proliferation is greater than normal. Hyperproliferative disorders include malignant disorders, e.g., cancer, and non-malignant disorders. In a preferred embodiment, the hyperproliferative disorder is cancer. As used herein, the term "neoplastic disorder" refers to a disease or condition associated with cancer or a cancer indication. Cancers can be classified by the type of tissue from which they arise (histology) and by the primary site, or location in the body where the cancer first develops.

[0122] In one embodiment, the neoplastic and / or hyperproliferative disease is cancer.

[0123] In one embodiment, there is provided a solid dispersion as described herein for use in treating and / or preventing cancer. A further embodiment provides a pharmaceutical composition as described herein for use in treating and / or preventing cancer. Another aspect refers to a solid dispersion as described herein or a pharmaceutical composition as described herein for use in a method for treating and / or preventing cancer.

[0124] A further aspect relates to a method of treating and / or preventing cancer, comprising administering to a patient a solid dispersion described herein or a pharmaceutical composition described herein, hi one embodiment, such a method comprises administering to a human in need of such treatment a therapeutically effective amount of a solid dispersion or pharmaceutical composition described herein.

[0125] One embodiment relates to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0126] In an embodiment, the cancer is HER2 overexpression, HER2 amplification, and / or HER2 mutation. In an embodiment, the cancer is a HER2 exon 20 mutation cancer. In an embodiment, the neoplastic disease and / or hyperproliferative disease is a HER2 overexpression, HER2 amplification, and / or HER2 mutation cancer.

[0127] As used herein, "HER2 overexpression" refers to a cancer in which the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g., IHC2+ or IHC3+) and / or methods that assay for ERBB2 messenger RNA.

[0128] As used herein, "HER2 amplified" refers to a cancer in which the cancer or tumor cells display two or more copies of the HER2 gene ERBB2, particularly 3, 4, 5, 6, 7, 8, 9 or 10 or more copies, preferably 6 or more copies.

[0129] HER2 expression, gene copy number, and amplification can be measured, for example, by nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH), RNA quantification using techniques such as ELISA and RT-PCR, microarray analysis, and next-generation sequencing (NGS). HER2 expression in or on cancer sample cells can be compared with reference cells. The reference cells can be non-cancerous cells obtained from the same subject as the sample cells. The reference cells can be non-cancerous cells obtained from a different subject or population of subjects.

[0130] If HER2 is overexpressed and / or amplified in or on the cells of a cancer, the cancer may be said to be "HER2 positive."

[0131] As used herein, "HER2 mutation" 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. Such mutations include, but are not limited to, those listed below. Mutations can be detected by any method known to those skilled in the art, for example, molecular diagnostic methods, including (but not limited to) polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole-exome sequencing.

[0132] As used herein, "cancer with a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer" refers to a cancer in which the cancer or tumor cells have at least one HER2 exon 20 mutation, including (but not limited to) the mutations listed below.

[0133] Exon 20 of ERBB2 (HER2) encodes part of the kinase domain, spanning amino acids 769 to 835. Any 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_G776insYV MS;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).

[0134] In addition, tumorigenic 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 the HER2 protein).

[0135] In embodiments, the neoplastic and / or hyperproliferative disease or cancer is, but is not limited to, one of the following cancers, tumors or other proliferative diseases:

[0136] Cancers / tumors / carcinomas of the head and neck: for example, tumors / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, and buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, and pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, and vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0137] Lung cancers / tumors / carcinomas: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0138] Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, nonseminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma);

[0139] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary tract (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, complex HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcomatous HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatzkin's tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum) ), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (kidney, e.g., including renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), renal epithelioma, Grawitz's tumor), ureter, bladder (e.g., urachal carcinoma, urothelial carcinoma), urethra, e.g., distal, bulbomembranous, prostate, prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis), appendix tumors / carcinomas;

[0140] Cancer / tumor / carcinoma of the testis: e.g., seminoma, nonseminoma;

[0141] Gynecological cancers / tumors / carcinomas: for example, tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and fundus);

[0142] Breast cancer / tumor / cancer type: for example, breast cancer (infiltrating ductal, colloid, lobular infiltrating, tubular, glandular cystic, papillary, medullary, mucinous), 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;

[0143] Cancers / tumors / carcinomas of the endocrine system: for example, tumors / carcinomas / cancers of the endocrine glands, thyroid gland (thyroid cancer / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid cancer / tumors), adrenal cortex (adrenocortical cancer / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functional (nonfluorine unctional) PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

[0144] Sarcomas of soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, dysplastic small cell tumor;

[0145] Sarcomas of bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcomas), osteosarcoma (including parosteal, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma;

[0146] Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma;

[0147] Cancers of the skin: e.g., basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer;

[0148] Neoplasms of the central nervous system and brain: for example, astrocytomas (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic), supinal axis tumor;

[0149] peripheral nervous system cancer;

[0150] Lymphomas and leukemias: for example, B-cell non-Hodgkin's lymphoma (NHL) (small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin's lymphoma (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), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-predominant classical HD, and lymphopenic HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), / myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0151] Carcinoma of unknown primary site (CUP).

[0152] All cancers / tumors / carcinomas referred to above that are characterized by a particular location / origin within the body are meant to include both the primary tumor and metastatic tumors derived therefrom. Preferably, cancers as defined herein (including, for example, in any embodiment that refers to a type of cancer) are metastatic, advanced, and / or unresectable.

[0153] All the above mentioned cancers / tumors / carcinomas can be further differentiated by histopathological classification.

[0154] Epithelial carcinomas, such as squamous cell carcinoma (SCC) (in situ carcinoma, superficial invasive carcinoma, verrucous carcinoma, pseudosarcoma, undifferentiated carcinoma, transitional cell carcinoma, lymphoepithelial carcinoma), adenocarcinoma (AC) (well-differentiated carcinoma, mucinous carcinoma, papillary carcinoma, pleomorphic giant cell carcinoma, tubular carcinoma, small cell carcinoma, signet ring cell carcinoma, spindle cell carcinoma, clear cell carcinoma, oat cell carcinoma, colloid carcinoma, adenosquamous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma), mucinous cystadenocarcinoma, spiculated cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid);

[0155] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed carcinomas, and undifferentiated carcinomas.

[0156] 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 cancer, lung cancer, nervous system cancer, and skin cancer.

[0157] Preferably, the brain tumor is a glioblastoma or a glioma.

[0158] Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic.

[0159] Preferably, the endocrine cancer is a nerve sheath tumor, more preferably a HER2-mutated nerve sheath tumor.

[0160] Preferably, the gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach 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 may be a gastrointestinal neuroendocrine tumor, preferably a HER2 mutant type. More preferably, the gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, in particular, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0161] Preferably, the gynecological cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer.

[0162] Preferably, the head and neck tumor is a salivary gland cancer or tumor.

[0163] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0164] Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer.

[0165] Preferably, the skin cancer is not melanoma, ie, a non-melanoma skin cancer.

[0166] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach 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.

[0167] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach 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.

[0168] 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, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach 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.

[0169] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach 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.

[0170] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0171] In an embodiment, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0172] In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colon cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In a further embodiment, the cancer is selected from lung cancers / tumors / carcinomas, such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, complex oat cell carcinoma). In a further embodiment, the cancer is NSCLC. In a further embodiment, the cancer is HER2 exon 20 mutated NSCLC.

[0173] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC with a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0174] In one embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0175] In one 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 described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0176] A further aspect relates to compound (1), a solid dispersion or a pharmaceutical composition for use as a medicament, in particular for treating and / or preventing neoplastic and / or hyperproliferative disorders, such as cancer, wherein compound (1), said solid dispersion or said pharmaceutical composition comprises: - in subjects in a fasting state, and / or in combination with medicines that increase gastric pH, preferably proton pump inhibitors (PPIs), antacids or antihistamines, and / or - subjects with a gastric pH in the range of about 1 to 7, preferably in subjects with a gastric pH in the range of about 1 to 5 It is administered.

[0177] In embodiments, the solid dispersion described herein or the pharmaceutical composition described herein comprises: - in subjects in a fasting state, and / or - in combination with medications that increase gastric pH, preferably proton pump inhibitors (PPIs), antacids or antihistamines It is administered.

[0178] Another aspect relates to compound (1) as defined above for use in treating and / or preventing neoplastic and / or hyperproliferative diseases, wherein compound (1) is - in subjects in a fasting state, and / or - In combination with medications that increase gastric pH It is administered.

[0179] In an embodiment, Compound (1), the solid dispersion or the pharmaceutical composition is administered to a subject in the fasted state.

[0180] As used herein, the term "subject" refers to a human, for example, a human who has, is at risk of having, or may have cancer.

[0181] In an embodiment, Compound (1), the solid dispersion or the pharmaceutical composition is administered in combination with a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid or an antihistamine.

[0182] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered to a subject in a fasted state in combination with a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine.

[0183] In an embodiment, Compound (1), the solid dispersion or the pharmaceutical composition is administered to a subject with a gastric pH in the range of about 1-7.

[0184] In an embodiment, Compound (1), the solid dispersion or the pharmaceutical composition is administered to a subject with a gastric pH in the range of about 1-5.

[0185] As used herein, a "fasted subject" refers to a subject who has not eaten for at least 8 hours, preferably at least 10 hours, typically overnight, before administering the solid dispersion or pharmaceutical composition or dosage form thereof. A fasted subject may conveniently be administered Compound (1), the solid dispersion, the pharmaceutical composition or dosage form thereof with water after fasting for at least 8 or 10 hours. After that, the subject cannot eat for, for example, 4 hours, but can drink a small amount of water after administration of the pharmaceutical agent, for example, 2 hours later.

[0186] In embodiments, a subject in a fasted state is a subject who has not eaten for at least 2 hours prior to administration of a solid dispersion or pharmaceutical composition described herein and / or a subject who has not eaten for at least 1 hour after administration of a solid dispersion or pharmaceutical composition described herein.

[0187] In embodiments, a fasted subject is one who has not eaten for about 2 hours before administration of a solid dispersion or pharmaceutical composition described herein and a subject who has not eaten for about 1 hour after administration of a solid dispersion or pharmaceutical composition described herein. In these embodiments, a fasted subject may be referred to as a "modified fasted subject."

[0188] "Drugs that increase gastric pH" refer to a class of drugs that neutralize stomach acidity. Drugs that neutralize gastric acid may reduce pepsin activity. In an embodiment, a drug that increases gastric pH is a proton pump inhibitor. The term "proton pump inhibitor" (PPI) refers to a class of drugs that cause a fundamental and sustained reduction in gastric acid production. In an embodiment, they are suppressors of gastric acid secretion. In an embodiment, PPIs that may be administered in combination with Compound (1), the solid dispersion, or the pharmaceutical composition include, but are not limited to, rabeprazole, omeprazole, pantoprazole, esomeprazole, lansoprazole, dexlansoprazole, and ilaprazole. Rabeprazole is a proton pump inhibitor indicated for diseases in which gastric pH is elevated, such as reflux esophagitis.

[0189] In an embodiment, the pharmaceutical agent that increases gastric pH is an antacid. The term "antacid" refers to a class of pharmaceutical agents that neutralize stomach acidity. In an embodiment, antacids that may be administered in combination with Compound (1), the solid dispersion, or the pharmaceutical composition include, but are not limited to, aluminum, calcium, magnesium, or sodium salts, such as aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and sodium bicarbonate.

[0190] In an embodiment, the pharmaceutical agent that increases gastric pH is an antihistamine, particularly an H2 receptor antagonist. The term "H2 receptor antagonist" refers to a class of pharmaceutical agents that block the action of histamine in the stomach. In an embodiment, antihistamines that may 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, lavortidine, and niperotidine.

[0191] The compound (1), the solid dispersion, the pharmaceutical composition, or dosage form thereof, and the pharmaceutical agent that increases gastric pH can be administered simultaneously, concurrently, sequentially, or consecutively. The term "simultaneous" refers to administration of both compounds / compositions at substantially the same time. The term "concurrent" refers to administration of the active ingredients within the same general period, e.g., on the same day, but not necessarily simultaneously. The term "sequential" administration includes administration of one active ingredient using one or more doses during a first period, e.g., over several hours, days, or a week, followed by administration of the other active ingredient using one or more doses during a second period, e.g., over several hours, days, or a week. Overlapping schedules can also be used, including administration of the active ingredients on different days throughout the treatment period, not necessarily in a regular order. The term "sequential" administration alternatively refers to administration in which the administration of the first compound is completed immediately followed by a second administration step. Variations on these general administration forms can also be used.

[0192] In an embodiment, Compound (1), the solid dispersion, the pharmaceutical composition, or a dosage form thereof is administered after a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine.

[0193] In another aspect, the present invention relates to a solid dispersion or a pharmaceutical composition as described herein for use in treating and / or preventing a neoplastic and / or hyperproliferative disease as defined herein, wherein said solid dispersion or said pharmaceutical composition is administered in combination with a cytostatic and / or cytotoxic active substance, and / or in combination with radiation therapy, and / or immunotherapy.

[0194] In another aspect, the present invention relates to the combination of a solid dispersion or a pharmaceutical composition as described herein with a cytostatic and / or cytotoxic agent, and / or radiation therapy, and / or immunotherapy, for use in treating and / or preventing cancer.

[0195] The solid dispersions or pharmaceutical compositions described herein can be used alone or in combination with one or more other pharmacologically active agents, such as state-of-the-art or standard of care compounds, such as cell growth inhibitors, anti-angiogenic agents, steroids or immune modulators / checkpoint inhibitors.

[0196] Pharmacologically active substances that may be administered in combination with the solid dispersions or pharmaceutical compositions described herein include hormones, hormone analogs and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, etc.), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors, e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), etc.), and the like. ), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors, etc.), such as (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, anti-metabolites (e.g., antifolates, e.g., methotrexate, raltitrexed, pyrimidine analogs, e.g., 5-fluorouracil, ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs, e.g., mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose),C), fludarabine); antitumor antibiotics (e.g., anthracyclines, e.g., doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride, Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); Alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa, etc.); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine, etc. and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.), serine / threonine kinase inhibitors (e.g., PDK1 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, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (e.g., KRASG12C inhibitors), signal transduction pathway inhibitors (e.g., 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 (e.g., everolimus, temsirolimus, ladaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents, for example, immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LA G3 and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTE®), e.g., CD3×BCMA, CD3×CD33, CD3×CD19, PSMA×CD3, etc.), tumor vaccines, and various chemotherapeutic agents such as amifostine, anagrelide, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0197] Method for producing a solid dispersion The solid dispersions of the present invention can be prepared by any method known in the art for this purpose, for example, as disclosed in SV Bhujbal et al., Acta Pharmaceutica Sinica B 2021;11(8):2505e2536, which is incorporated herein by reference. In accordance with the present invention, solid dispersions are generally prepared by dissolving the active agent and a pharmaceutically acceptable dispersion carrier in a solvent or mixture of solvents to form a feed solution, and then removing the solvent from the feed solution, such as by spray drying, to form the solid dispersion.

[0198] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: 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; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; Includes.

[0199] The method may further comprise the step of drying the solid dispersion obtained in step b).

[0200] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: 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; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; c) optionally drying the solid dispersion obtained in b); Includes.

[0201] The solution or suspension of step a) according to any of the methods described above may be referred to as a feed solution.

[0202] In an embodiment, the removal of the solvent in step b) of the above defined process 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.

[0203] As used herein, the term "spray drying" is used conventionally and broadly to generally refer to any process involving atomizing a solution, suspension, slurry, or emulsion containing one or more components of a desired product into droplets, followed by rapid evaporation of the atomized droplets with hot air at a specific temperature and pressure to a solid powder. Spray drying is a process known to those skilled in the art.

[0204] 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 delivered to a drying chamber through an atomizer. The feed solution can be atomized by conventional means known in the art, such as a two-fluid ultrasonic nozzle, a pressure nozzle, a rotary nozzle, and a two-fluid non-ultrasonic nozzle. The solvent is then removed in the drying chamber to form the solid dispersion. In a typical drying chamber, hot gas, such as forced air, nitrogen, nitrogen-enriched air, or argon, is used to dry the particles. The size of the drying chamber can be adjusted to achieve particle characteristics or processing capacity.

[0205] The solid dispersions are preferably prepared by conventional spray drying techniques, although other techniques known in the art can be used, such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, KinetiSol® Dispersing Technology (KSD), fluidized bed techniques, drum drying, vacuum drying, or other solvent removal processes.

[0206] The above-described method for producing the solid dispersions described herein may comprise an additional step between step a) and step b) of spraying the solution or suspension obtained in step a) onto an inert excipient core. This process belongs to the fluidized bed technique, in particular the fluidized bed granulation technique.

[0207] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: (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; (a') spraying the solution or suspension provided in (a) onto an inert excipient core; (b') removing the solvent from the inert excipient cores; (c') optionally drying the excipient cores containing the solid dispersion obtained in (c'); Includes.

[0208] The spraying in step (a') can be carried out in a fluidized bed coater, for example as top spray, bottom spray, Wurster spray, tangential spray or side rotor spray.

[0209] Any solvent or mixture of solvents in which compound (1) is at least partially soluble can be used. Examples of suitable solvents that can be used individually 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, as well as various other solvents such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. In one embodiment, the solvent referred to in any of the above-described methods and embodiments thereof is 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, the solvent referred to in any of the above-described methods and embodiments thereof is selected from the group consisting of alcohols (especially methanol, ethanol, n-propanol, isopropanol, and butanol, such as n-butanol, 2-butanol, isobutanol, 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 with water can also be used.

[0210] 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 be varied. Preferably, the mixture contains at least 25 wt% MeOH, based on 100 wt% of the total weight of the mixture. In an embodiment, the mixture contains an excess of DCM. More preferably, the weight:weight ratio of DCM:MeOH ranges from 25:75 to 95:5 (w / w). Preferably, DCM and MeOH are in a weight:weight ratio of about 25:75, 50:50, 70:30, 75:25, 80:20, 85:15, or 90:10. It has been advantageously found that a solvent mixture of DCM:MeOH in a ratio of about 90:10 (w / w) allows for higher throughput for spray drying.

[0211] In an embodiment, the solids concentration in the feed solution (particularly the suspension or solution defined in step a) above) is in the range of about 1 to 20 wt %, based on 100 wt % of the total weight of the feed solution. Preferably, the solids concentration in the feed solution is in the range of about 5 to 15 wt %, more preferably in the range of about 8 to 12 wt %, based on 100 wt % of the total weight of the feed solution. For example, the solids concentration in the feed solution is about 8 wt % or 10 wt %, based on 100 wt % of the total weight of the feed solution.

[0212] After removing the solvent by spray drying, the resulting solid dispersion is optionally subjected to a drying process to reduce the residual solvent content. In an embodiment, drying is carried out at a temperature ranging from about room temperature to 100°C, preferably about 30 to 60°C, and more preferably about 35 to 45°C. For example, drying is carried out at a temperature of about 40°C. In another embodiment, drying is carried out under ambient pressure and / or reduced pressure. For example, drying is carried out at 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, e.g., about 20 mbar or less. In yet another embodiment, drying is carried out for a period ranging from about 6 to 72 hours, preferably about 12 to 48 hours.

[0213] Another aspect is the following: a) providing a mixture of the compound (1) or a pharmaceutically acceptable salt thereof as defined above with a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; b) removing the solvent from the solution or suspension to form the solid dispersion (preferably, the removal of the solvent in step b) is accomplished by spray drying); The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0214] Another aspect is the following: 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; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; c) optionally drying the solid dispersion obtained in b); The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0215] Another aspect is the following: (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; (a') spraying the solution or suspension provided in (a) onto an inert excipient core; (b') removing the solvent from the inert excipient cores; (c') optionally drying the excipient cores containing the solid dispersion obtained in (c'); The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0216] In these embodiments relating to a solid dispersion obtainable by the process, the process steps may be carried out as described above with reference to the process for producing the solid dispersion.

[0217] Pharmaceutical compositions, such as tablets, preferably film-coated tablets, can be prepared according to conventional methods known to those skilled in the art. In an embodiment, the preparation method may include the following steps: 1) preparing a solid dispersion, for example, by spray drying as described herein; 2) dry-granulating the solid dispersion with one or more suitable excipients; 3) blending the granules with suitable disintegrants and / or lubricants and / or glidants; 4) compressing the blend into tablet cores; and 5) optionally film-coating the tablet cores.

[0218] In the present invention, any aspect or embodiment that refers to a certain feature (e.g., that Compound (1) is amorphous in the solid dispersion) may be combined with any one or more aspects or embodiments that refer to other features (e.g., that the weight ratio of Compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1, and / or that the pharmaceutically acceptable dispersion carrier is HPMCAS) to form further aspects or embodiments of the present invention, such as: 1) A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersing carrier (compound (1) is amorphous, and the weight ratio of compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1); 2) a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier (compound (1) is amorphous, and the pharmaceutically acceptable dispersion carrier is HPMCAS); 3) A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersing carrier (compound (1) is amorphous, the weight ratio of compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1, and the pharmaceutically acceptable dispersing carrier is HPMCAS). can be provided.

[0219] The phrases "defined herein," "disclosed herein," "described herein," "as used herein," and variations thereof, at each instance where they occur, include all aspects, embodiments, subaspects, subembodiments, etc. of the feature or term to which they refer.

[0220] In certain embodiments, numerical values ​​may be stated as part of a range, and such numerical values ​​should be considered as approximate values ​​even if the term "about" or "approximately" is not explicitly stated.

[0221] Unless otherwise defined, all 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 belongs.

[0222] The following examples are intended to illustrate the present invention in more detail, but are not intended to limit the same.

[0223] Example 1 - Preparation of solid dispersions containing compound (1) and various dispersing polymers In this example, solid dispersions were prepared containing 25 wt % or 50 wt % Compound (1) and 75 wt % or 50 wt % of the dispersion carrier HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, Eudragit® L100, or HPMC HME 15LV, respectively.

[0224] The solid dispersion of this example can be prepared according to the following protocol. The solid dispersion is spray dried from a spray solution composition (solids content 8 wt% total solids) containing Compound (1), a dispersion carrier, and a DCM:MeOH (1:1 (w / w)) solvent system. The solid dispersion is spray dried using a two-fluid nozzle type and 1.0 mm / 1.0 mm nozzle cap / tip dimensions, an inlet temperature of 85-90°C, an outlet temperature of 45-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m / s. 3The dispersion is prepared using a Procept 4M8TRX spray dryer with a solution feed rate of approximately 15 g / min. Secondary drying of the dispersion is carried out in a collection vessel in a tray dryer type vacuum dryer at 40° C. for 22.5 hours.

[0225] The spray drying yield results obtained following the protocol in the preceding paragraph are summarized in Table 1, where gA represents grams API (active pharmaceutical ingredient, i.e., Compound (1)).

[0226] Table 1: Batch sizes and yields for solid dispersions of compound (1) with the dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV. [Table 1]

[0227] Example 2 - Characterization of solid dispersions by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC) 2.1 X-ray powder diffraction (XRPD) XRPD can be obtained according to the following protocol: XRPD analysis is performed using a Rigaku Miniflex 600 diffractometer. For example, a solid dispersion of Compound (1) and a dispersing carrier, such as HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV, in an amount of approximately 10 mg, is placed on a zero background sample disk and inserted into the autosampler of the Rigaku Miniflex 600. The sample is analyzed using the instrument parameters listed in Table 2 below.

[0228] Table 2: Summary of XRPD collection parameters [Table 2]

[0229] XRPDs obtained for various solid dispersions prepared in Example 1 according to the protocol described above are shown in Figures 1-4. In these figures, comparison with the XRPD of crystalline Compound (1) indicates the absence of crystalline material in the samples. Specifically, XRPDs for solid dispersions of 25 wt% or 50 wt% Compound (1) with the dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV showed the absence of sharp peaks and the presence of an amorphous halo. The absence of sharp diffraction peaks indicates that the solid dispersions are consistent with the amorphous form of Compound (1).

[0230] 2.2 Modulated Differential Scanning Calorimetry (mDSC) Solid dispersions of compound (1) of Example 1 with the dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV were characterized by mDSC to determine the glass transition temperature (Tg).

[0231] mDSC can be performed according to the following protocol. mDSC analysis is performed using a Thermal Analysis DSC 2500 and a Thermal Analysis Refrigerated Cooling System 90. 2-5 mg samples are placed in a non-hermetic pan. A Tzero non-hermetic lid is attached to the pan, and the sample is analyzed in modulated mode with a scan range of 20-250°C (unless otherwise specified), a modulation depth of 1°C / min, and a ramp rate (heating rate) of 3.0°C / min.

[0232] A summary of the glass transition temperatures (Tg) obtained following the protocol described above is shown in Table 3.

[0233] Table 3: Summary of the glass transition temperatures (Tg) measured for solid dispersions of compound (1) of Example 1 with HPMCAS-M, PVP-VA, Eudragit® L100, and HPMC HME 15LV. [Table 3]

[0234] As can be seen from Table 3, all solid dispersions exhibited a single glass transition temperature. This indicates a homogeneous dispersion with no evidence of phase separation. The glass transition temperature values ​​showed the expected trends with respect to the polymer and compound (1) loading. In the case of Eudragit® L100, which has a higher glass transition temperature than amorphous compound (1), the glass transition temperature decreased with increasing drug loading. In the case of polymers HPMCAS-M, PVP-VA, and HPMC HME 15LV, which have glass transition temperatures lower than that of compound (1), the glass transition temperature increased with increasing drug loading. All solid dispersions provided sufficiently high glass transition temperatures.

[0235] Example 3 - Preparation of solid dispersions using various process parameters Solid dispersions of Compound (1) were tested under various spray drying conditions, such as solvents, inlet temperatures, and spray drying parameters.

[0236] 3.1 Solvent Selection The solubility of compound (1) was measured in a solvent blend of dichloromethane (DCM):methanol.

[0237] To this end, the following protocol can be followed: A solution of compound (1) is prepared at a high concentration and then diluted with solvent until compound (1) dissolves or the concentration drops to less than 1 wt %. The solubility is determined by visual observation.

[0238] The solubility data for compound (1) obtained according to this protocol are shown in Table 4 below.

[0239] Table 4: Organic solubility screening results for compound (1) [Table 4]

[0240] Therefore, a 90:10 DCM:methanol solvent blend provides high solubility of compound (1) and potentially the highest throughput due to the lower methanol concentration in the solvent system compared to higher DCM:methanol solvent blends.

[0241] 3.2 Inlet temperature Solid dispersions containing 50 wt% Compound (1) and 50 wt% HPMCAS-M or 25 wt% Compound (1) and 75 wt% HPMC HME 15LV were prepared on a larger scale using lower inlet temperatures than in Example 1.

[0242] To this end, the following protocol can be followed: The solid dispersion is spray-dried from a spray solution composition containing Compound (1) and HPMCAS-M or HPMC HME 15LV using a DCM:MeOH (1:1 (w / w)) solvent system (solids content 8 wt% total solids). The solid dispersion is spray-dried using a two-fluid nozzle type and 1.0 mm / 1.0 mm nozzle cap / tip dimensions, an inlet temperature of 55-70°C, an outlet temperature of 45-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m / s. 3 The dispersion is prepared using a Procept 4M8TRX spray dryer with a solution feed rate of about 10-15 g / min. Secondary drying of the dispersion is carried out in a collection vessel in a tray dryer type vacuum dryer at 40°C for about 24 hours.

[0243] Spray drying yield results obtained following this protocol are summarized in Table 5, where gA represents grams API (active pharmaceutical ingredient, i.e., Compound (1)). mDSC results (unsealed pan, heating 3°C / min, modulation 1°C / min) are summarized in Table 6.

[0244] Table 5: Batch size and yield for solid dispersions with larger batch size and lower inlet temperature [Table 5]

[0245] Table 6: mDSC results [Table 6]

[0246] 3.3 Spray drying parameters The effects of flow rate (liquid feed rate), dryer outlet temperature, and drying environment on spray-dried solid dispersions were tested. A composition containing 50 wt% Compound (1) and 50 wt% dispersion carrier HPMCAS-M was used for this study. This composition was spray-dried from a spray solution composition containing Compound (1) and HPMCAS-M using a solvent ratio of 90:10 (w / w) DCM:MeOH and a solids content of 10 wt% total solids. Solid dispersions were produced using an open-loop, custom-developed spray dryer, SD-90, equipped with an SK 79-16 atomization system nozzle. Liquid feed rates of 291 to 317 g / min and outlet temperatures of 35 to 45°C were tested. The process parameters are summarized in Table 7 below.

[0247] Table 7: Spray drying process parameters [Table 7]

[0248] Yield improved from the first lot sprayed (3.3-A) to the last lot sprayed (3.3-C). Yield for lot A was low due to retention losses. Smaller batch sizes had lower yields compared to larger batches due to retention losses, and yield improved as the lots were sprayed due to reduced carryover from earlier lots and the impact of retention losses on later lots.

[0249] The solid dispersions of Samples 3.3-A, 3.3-B, and 3.3-C were characterized using X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), and particle size distribution (PSD). PSD was measured by laser diffraction.

[0250] XRPD can be obtained according to the following protocol: XRPD analysis is performed using a Rigaku Miniflex 600 diffractometer. Approximately 10 mg quantities of Samples 3.3-A, 3.3-B, and 3.3-C are loaded onto a zero background sample disk and placed in the autosampler of the Rigaku Miniflex 600. The samples are analyzed using the instrument parameters listed in Table 8 below.

[0251] Table 8: Summary of XRPD collection parameters [Table 8]

[0252] The XRPDs obtained for solid dispersions Samples 3.3-A, 3.3-B, and 3.3-C according to the protocol described above are shown in Figure 5. The lack of sharp peaks and the presence of an amorphous halo suggest that all samples contain amorphous compound (1).

[0253] This protocol can be used for mDSC measurements. Samples 3.3-A, 3.3-B, and 3.3-C (2-5 mg each) are placed in Tzero pans. A Tzero non-hermetic lid is attached to the pan, and the samples are analyzed in modulation mode over a scan range of 0-250 °C with a modulation depth of 1 °C / min, a modulation period of 60 seconds, and a ramp rate (heating rate) of 3 °C / min. The glass transition temperatures are summarized in Table 9.

[0254] Table 9: Summary of glass transition temperatures (Tg) of samples 3.3-A, 3.3-B, and 3.3-C [Table 9]

[0255] For all solid dispersions, Samples 3.3-A, 3.3-B, and 3.3-C, the thermograms obtained according to the protocol described above showed a single glass transition at around 116°C and no obvious melting or recrystallization phenomena, indicating that the solid dispersions were single-phase containing amorphous Compound (1).

[0256] The particle size distribution (PSD) for the solid dispersions of Samples 3.3-A, 3.3-B, and 3.3-C can be measured by laser diffraction of the dry dispersion powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder delivery system. The system can be operated using an R4 lens and a dispersion pressure of 3 bar. The results from this method are summarized in Table 10.

[0257] Table 10: Particle size distribution (PSD) of samples 3.3-A, 3.3-B, and 3.3-C [Table 10]

[0258] 3.4 Spray drying parameters Spray drying parameters were further tested for larger batch sizes. A mixture containing 50 wt% Compound (1) and 50 wt% dispersion carrier HPMCAS-M was used for this test. This mixture was spray dried from a spray solution composition using a solvent ratio of 90:10 (w / w) DCM:MeOH and a solids loading of 10 wt%. Solid dispersions were produced using an open-loop, custom-developed SD-90 spray dryer equipped with an SK 79-16 atomization system nozzle. Feed rates of 300 and 325 g / min and outlet temperatures of 44 and 40°C were tested. The process parameters are summarized in Table 11 below.

[0259] Table 11: Spray drying process parameters [Table 11]

[0260] The lower yield of sample 3.4-A is likely due to solids losses resulting from the small batch size. Solids losses are independent of batch size, but are higher in smaller batches. Therefore, sample 3.4-B had a higher yield due to the larger batch size. Both samples were characterized using XRPD, mDSC, and PSD. PSD was measured by laser diffraction.

[0261] XRPD scans of Samples 3.4-A and 3.4-B were performed as described in Example 3.3 above. Diffractograms for the solid dispersions of Samples 3.4-A and 3.4-B are shown in Figure 6, which shows an amorphous halo without sharp peaks, suggesting that Compound (1) was in an amorphous state in both samples.

[0262] For mDSC measurements, 2-5 mg amounts of Samples 3.4-A and 3.4-B were placed in Tzero pans and the measurements were performed as described in Example 3.3 above, except that a scan range of 0-200 °C was used for Sample 3.4-B. A summary of the glass transition temperatures is shown in Table 12 below.

[0263] Table 12: Summary of Glass Transition Temperatures (Tg) of Samples 3.4-A and 3.4-B [Table 12]

[0264] The thermograms of the solid dispersions of Samples 3.4-A and 3.4-B showed only a single glass transition, indicating a single-phase amorphous material; the mDSC thermograms showed no obvious peaks that would indicate crystalline material. The difference in glass transition temperature compared to Sample 3.3 may be due to the different lots of Compound (1) used in the preparation of the SDD and / or noise in the measurement equipment.

[0265] The mDSC results are consistent with the XRPD results, demonstrating by two orthogonal methods that the solid dispersion contains compound (1) in amorphous form.

[0266] The particle size distribution (PSD) for the solid dispersions of Samples 3.4-A and 3.4-B can be measured by laser diffraction of the dry dispersion powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder delivery system. The system can be operated using an R4 lens and a dispersion pressure of 3 bar. The results from this method are summarized in Table 13.

[0267] Table 13: Particle size distribution (PSD) of samples 3.4-A and 3.4-B [Table 13]

[0268] Example 4 - Physical Stability of Amorphous Solid Dispersants 4.1 Stress stability test under accelerated stress conditions The physical stability of amorphous solid dispersion formulations of Compound (1), corresponding to Samples 3.3-A, 3.3-B, and 3.3-C obtained in Example 3.3, was evaluated using accelerated stability testing. Each sample was incubated in an open vial at (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 using saturated salt solutions (sodium bromide for approximately 60% RH at ambient temperature and sodium chloride for 75% RH at 40°C). After 2 and 4 weeks, samples were removed for analysis and characterized by XRPD to assess the possibility of recrystallization.

[0269] No changes in physical properties were observed: the diffraction patterns of all amorphous solid dispersions were consistent with the amorphous form of Compound (1) after 4 weeks at all storage conditions.

[0270] 4.2 Stress stability test under severe stress conditions An amorphous solid dispersion (50 wt%:50 wt% Compound (1):HPMCAS-M, prepared, for example, according to the procedure in Example 1) was exposed to 75°C / 79% relative humidity and 80°C / 76% relative humidity in an open container for three weeks. The XRPDs for each are shown in Figure 7. No morphological changes were observed even after three weeks of exposure to these extreme stress conditions.

[0271] Example 5 - pH-dependent solubility and in vitro solubility 5.1 Comparative solubility tests in biologically relevant media and aqueous media at various pH levels The solubilities of an 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 below) were measured in various aqueous media at room temperature and in biorelevant media at 37° C. The media used in the solubility assays are listed in Table 14 below.

[0272] Table 14: Media used in solubility assays [Table 14]

[0273] The following protocol was used to prepare samples for solubility measurements. A suitable amount of crystalline compound (1) or amorphous solid dispersion of compound (1) is weighed out to achieve the desired target concentration. Add the selected vehicle at room temperature to reach the selected target concentration. Protect from light and orbital shake at room temperature or vortex at 37°C for 24 hours. The soluble and insoluble fractions are separated by centrifugation (18,000 rpm for 15 minutes) followed by filtration through a 0.45 μm PTFE membrane. The first 3.5 mL is discarded, and then three aliquots (approximately 0.5 mL) are collected for analysis. Quantitate 3 aliquots by UPLC-UV-MS and appropriate calibration curve.

[0274] UPLC-UV-MS method Instrument: Waters Acquity H-Class equipped with PDA and QDa detectors Column: Waters Acquity BEH C18, 17 μm, 2.1 × 50 mm Flow rate: 0.65mL / min UV detection: 254nm or 410nm Column temperature: 40°C ± 2°C Sample temperature: 23°C ± 2°C Injection volume: 0.4 μL (for concentrations of 1 to 500 μg / mL) and 9 μL (for concentrations of 0.050 to 1 μg / mL) Mobile phase: gradient with solutions A and B prepared as follows: [Table 15] Ionization mode: ESI+ / ESI- Source temperature: 600℃ Capillary voltage: 0.8 kV Cone voltage: +20V / -20V

[0275] Two calibration curves (chromatographic UV peak area vs. concentration) are established in DMSO at 254 nm or 410 nm for each solid form and solid dispersion, one from 0.025 or 0.050 μg / mL to 1 μg / mL (injection volume = 9 μL) and the other from 1 μg / mL to 500 μg / mL (injection volume = 0.4 μL). The calibration curves are linear over the entire concentration range investigated.

[0276] The results of the solubility assay obtained according to the protocol in the previous section are summarized in Table 15 and shown in Figure 8.

[0277] Table 15: Equilibrium solubility in various media of amorphous solid dispersions of Compound (1) and HPMCAS-M (50 wt%:50 wt%) and crystalline forms of Compound (1). [Table 16]

[0278] Both crystalline forms of Compound 1 were found to be soluble in strongly acidic media, but solubility decreased at pH ≥ 5. Additionally, the solubility of the crystalline forms of Compound 1 was low in biorelevant fasted and fed simulated intestinal fluids (FaSSIF and FeSSIF). When Compound 1 was formulated as an amorphous solid dispersion with HPMCAS-M, the solubility of Compound 1 was found to be significantly improved at pH ≥ 5 and in biorelevant media.

[0279] 5.2 In vitro solubility of amorphous solid dispersions of compound (1) vs. crystalline compound (1) The kinetic solubilities of 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 crystalline Compound (1) and polymers selected from HPMCAS-M, HPMC HME 15LV, PVP-VA, and Eudragit® L100 were measured in biorelevant media during pH-shift non-sinking dissolution tests.

[0280] To this end, the following protocol can be used: First, the sample is transferred to simulated gastric fluid (SGF) and then, through a series of dilution steps, to simulated intestinal fluid (SIF). The test is performed at 3 mg / mL in 0.01 N HCl SGF (step 1), followed by a 3-fold dilution after 30 minutes in FaSSIF pH 6.5 (+33 mM sodium phosphate for additional buffering capacity) to a target of 1 mg / mL. "Total drug" and "dissolved drug" are assessed. Total drug is measured by sampling the supernatant of the non-settled (saturated) sample after benchtop centrifugation (approximately 19,000 rcf, 3-5 minutes). Total drug includes free drug, bile salt micelles (in SIF), and colloidal species formed by drug-polymer interactions. Dissolved drug is measured by filtering the total drug supernatant through a 0.22 μm filter to remove larger colloidal species. Dissolved drug includes free drug and bile salt micelles.

[0281] Following this protocol, all formulations were completely dissolved at 3 mg / mL in simulated gastric fluid (data not shown), but the amorphous solid dispersion formulations demonstrated significantly more dissolved drug compared to the crystalline API in simulated intestinal fluid (see Figures 9 and 10). It should be noted that for a given polymer, increasing drug loading in an amorphous solid dispersion formulation is typically expected to either be unaffected or degrade performance as assessed by increasing dissolved drug and / or colloidal species formation. However, for the Compound (1):HPMCAS-M SDD formulation, increasing drug loading consistently increased dissolved drug.

[0282] Example 6 - Pharmaceutical Composition 6.1 Methods for Producing Tablets Containing a Spray-Dried Solid Dispersion of Compound (1) Film-coated tablets containing a solid dispersion of Compound (1) were prepared generally according to the following scheme unless otherwise noted.

[0283] Step 1: Preparation of solid dispersions by spray drying 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-dried solution. Alternative dispersion carriers can be used in place of or in addition to HPMCAS-MG. This solution is spray-dried using a suitable spray dryer to produce a spray-dried solid dispersion. This spray-drying process can be carried out as detailed in Examples 1 and 3. The spray-dried solid dispersion is then further dried in a suitable dryer to remove residual solvent, as detailed in Examples 1 and 3.

[0284] Step 2: Dry granulation of solid dispersion and excipients The dry solid dispersion is mixed with microcrystalline cellulose, mannitol, croscarmellose sodium, and a portion of colloidal silicon dioxide, and then this mixture of solid dispersion and filler, disintegrant, and glidant is pre-blended and screened / delumped. Sodium stearyl fumarate is added to this pre-blend as a lubricant. The intragranular blend is then granulated using a roller compactor equipped with a 1.0 mm screen. The screened dry granules are collected for subsequent final blending.

[0285] Step 3: Blending The granules are blended in a blender with a pre-screened extragranular mixture of croscarmellose sodium and colloidal silicon dioxide. Sodium stearyl fumarate is added and blended to produce the final blend.

[0286] Step 4: Tablet compression The final blend is then compressed into tablet cores.

[0287] Steps 1-4 were performed for the ingredients shown in Table 16 below.

[0288] Table 16: Summary of tablet core ingredients [Table 17]

[0289] 6.2 Manufacture of film-coated tablets containing 15 mg or 60 mg of Compound (1) Steps 1 to 4 can be followed by an optional film coating step, which can be carried out as outlined below.

[0290] Process 5: Film coating The film-coating mixture Opadry® AMB II yellow is dispersed in water for injection using a stirrer and a container. The tablet cores are coated with the film-coating suspension in a suitable pan coater to obtain film-coated tablets containing a solid dispersion of Compound (1) and a dispersing carrier. Step 5 is optional. An alternative film-coating mixture can be used instead of Opadry® AMB II yellow.

[0291] Film-coated tablets containing a spray-dried solid dispersion of Compound (1) and HPMCAS-MG (hypromellose acetate succinate, where MG refers to the grade soluble at pH ≥ 6.0 and is a granular, free-flowing powder) were prepared as described in Example 6.1, followed by step 5 above. The ingredients are summarized in Table 17 below.

[0292] Table 17: Summary of ingredients for film-coated tablets [Table 18]

[0293] The film-coated tablets contained 15 mg or 60 mg of Compound (1). Dichloromethane and methanol were used as solvents, and nitrogen was used as the drying gas for the solid dispersion, but was removed during the process and therefore not included in the final product. Additionally, water for injection was used as the solvent for the film-coating mixture, but was also removed during drying and therefore not analyzed.

[0294] The film coating mixture used was Opadry® AMB II yellow 88A120087, which contains partially hydrolyzed polyvinyl alcohol as a film former, talc as an anti-tack agent, sodium lauryl sulfate as a lubricant, and titanium dioxide, glyceryl mono- and dicaprylocaprate (GMDCC), and iron oxide yellow as pigments.

[0295] 6.3 Preparation of tablets containing 400 mg or 200 mg of Compound (1) Uncoated tablet formulations containing spray-dried solid dispersions of Compound (1) and HPMCAS-M at 25:75 wt% or 50:50 wt% were prepared as described in Example 6.1 above, with the ingredients summarized in Tables 18 and 19 below.

[0296] Table 18: Summary of ingredients for tablets containing a spray-dried solid dispersion of 25 wt% Compound (1) and 75 wt% HPMCAS-M [Table 19]

[0297] Table 19: Summary of ingredients for tablets containing a spray-dried solid dispersion of 50 wt% Compound (1) and 50 wt% HPMCAS-M. [Table 20]

[0298] 6.4 Preparation of tablets containing a solid dispersion of compound (1) and HPMC Solid dispersion formulations containing non-enteric polymers, such as HPMC, are known to be prone to gelation when formulated as tablets, resulting in slow disintegration. Understanding this potential challenge, an initial feasibility study was completed on a solid dispersion containing a spray-dried solid dispersion of 25 wt% Compound (1) and 75 wt% HPMC HME 15LV. The starting ingredients are summarized in Table 20 below.

[0299] Table 20: Summary of ingredients for tablets containing a spray-dried solid dispersion of 25 wt% Compound (1) and 75 wt% HPMC HME 15LV. [Table 21]

[0300] The formulations listed in Table 20 did not disintegrate as expected. A formulation approach to improve disintegration involved increasing the amount of microcrystalline cellulose and mannitol (24 wt% each), diluting the intragranular blend of Table 20 by 50%, and using only 2 wt% croscarmellose sodium, resulting in a tablet structure that utilized both granular and extragranular components. The final formulation contained 50 mg of Compound (1) per 700 mg tablet.

[0301] 6.5 Characterization of tablet cores and film-coated tablets by X-ray powder diffraction (XRPD) The tablet cores (Example 6.1-C) and film-coated tablets (Example 6.2-C) were investigated by XRPD to confirm the absence of crystalline Compound (1), e.g., Forms III and IV. To this end, the following protocol can be followed: Samples are prepared by slightly crushing the tablet cores or film-coated tablets in a mortar with a pestle, followed by homogeneous mixing of the resulting powder with a spatula. The resulting powder is then measured by XRPD using an X'pert PRO diffractometer with the following settings and measurement parameters:

[0302] Table 21: Experimental parameters for XRPD measurements [Table 22]

[0303] The XRPDs of the tablet cores of Example 6.1-C and the film-coated tablets of Example 6.2-C obtained according to the procedures in the previous section are shown in Figures 15 and 16. Both formulations contain crystalline excipients mixed with an amorphous solid dispersion containing Compound (1). The diffraction peaks present in the XRPD are attributable to these excipients. The absence of Form IV is indicated, for example, by the absence of a peak at (5.8±0.2)°, and the absence of Form III is indicated, for example, by the absence of a peak at (6.2±0.2)°.

[0304] Example 7 - Determination of the properties of tablets containing a spray-dried solid dispersion of Compound (1) 7.1 In vitro dissolution profile in phosphate buffer pH 2.0 A dissolution study comparison was conducted comparing a conventional film-coated tablet containing a total of 15 mg crystalline Compound (1) with a film-coated tablet containing 15 mg Compound (1) as a spray-dried solid dispersion with HPMCAS-MG from Example 6.2-B.

[0305] A comparative film-coated tablet containing crystalline Compound (1) contained 5 mg of Compound (1), 64.5 mg of silicified microcrystalline cellulose composed of colloidal silicon dioxide 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 silicon dioxide as a glidant, 1 mg of vegetable-derived magnesium stearate as a lubricant, and 4.5 mg of a film coating mixture (e.g., Opadry® yellow 03B120053). Three 5 mg tablets were used in this study.

[0306] The following protocol can be used to conduct dissolution comparisons. Dissolution tests are performed in 20 mM phosphate buffer (NaH2PO4) pH 2.0 at 37°C using an Agilent 708-DS instrument equipped with an 850-DS sampling station. A 15 mg tablet containing Compound (1) as a solid dispersion equivalent to Sample 6.2-B and three 5 mg tablets containing Compound (1) in crystalline form (total weight of 15 mg) are suspended in the buffer solution. The dissolution profile is evaluated under the following conditions: shaft rotation speed 50 rpm, medium volume 900 mL, sample volume 3 mL. The amount of Compound (1) in the buffer is measured by HPLC at regular intervals over a 60-minute period. The % solubility is calculated using the following equation (A): % solubility=((A smp ×C S1 ×DF smp ) / (A S1 ×LC))×100 (A) [In the formula, A smp is the peak area of ​​the sample, C S1 is the concentration of standard 1, 0.017 mg / mL compound (1), Defender smp is the sample dilution factor, 900 mL, A S1 is the average peak area response from the first five standard 1 injections, LC is as stated on the tablet label and is 15 mg]

[0307] The results of an in vitro dissolution comparison between conventional tablets and solid dispersion tablets in a buffer pH 2.0 obtained according to the protocol described in the previous section are shown in Figure 11. As can be seen, the tablets containing the solid dispersion exhibited a faster initial drug release than the tablets containing crystalline Compound (1).

[0308] 7.2 In vitro dissolution profile in phosphate buffer pH 6.8 containing 0.1% SDS Comparative dissolution studies were performed comparing a conventional film-coated tablet containing 60 mg (3 x 20 mg) total of crystalline Compound 1, a film-coated tablet containing 60 mg (4 x 15 mg) total of Compound 1 as a spray-dried solid dispersion with HPMCAS-MG according to Example 6.2-A, and a film-coated tablet containing 60 mg Compound 1 as a spray-dried solid dispersion with HPMCAS-M according to Example 6.2-C.

[0309] A conventional film-coated tablet containing crystalline Compound (1) contained 20 mg of Compound (1), 49.5 mg of silicified microcrystalline cellulose composed of colloidal silicon dioxide 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 silicon dioxide as a glidant, 1 mg of vegetable-derived magnesium stearate as a lubricant, and 4.5 mg of a film-coating mixture (e.g., Opadry® yellow 03B120053). Three 20 mg tablets were used in this study.

[0310] Dissolution testing was performed under the conditions outlined in Table 22.

[0311] Table 22: In vitro dissolution conditions [Table 23]

[0312] The % dissolution% (same as % dissolved) was calculated as described above in Example 7.1. The results of an in vitro dissolution comparison between conventional tablets and solid dispersion tablets in a buffer pH 6.8 are shown in Figure 12. As can be seen, the tablets containing the solid dispersion have similar dissolution profiles and exhibit a faster initial drug release than the tablets containing crystalline Compound (1). In addition, in contrast to the tablets containing crystalline Compound (1), the tablets containing the solid dispersion dissolve completely.

[0313] 7.3 In vitro measurement of bioaccessibility Bioavailability in humans was assessed using tiny-TIM, a dynamic in vitro gastrointestinal model designed to simulate the physiological processes occurring in the human stomach and small intestine.

[0314] A conventional tablet of crystalline Compound (1) (conventional formulation) and a tablet containing a solid dispersion of Compound (1) (SDD formulation) were tested in the tiny-TIM model.

[0315] The conventional formulation contained 100 mg Compound (1), 247.5 mg silicified microcrystalline cellulose and 105 mg anhydrous lactose as fillers, 25 mg hydroxypropyl cellulose as a binder, 15 mg sodium starch glycolate as a disintegrant, 2.5 mg colloidal silicon dioxide as a glidant, and 5 mg magnesium stearate as a lubricant.

[0316] The SDD formulation tested in the tiny-TIM model corresponds to Example 6.2-A, as shown in Table 17.

[0317] tiny-TIM Test Protocol Food matrix in the tiny-TIM setup To simulate fasting conditions, one glass of water (240 mL) is presented to the tiny-TIM system.

[0318] tiny-TIM test system This study is carried out in a TNO dynamic multicompartment in vitro system of the stomach and small intestine (tiny-TIM).

[0319] The tiny-TIM system consists of a stomach compartment and one small intestine compartment (Figure 13). The compartments are composed of two glass units with a flexible silicone inner wall surrounding a lumen material. The space between the inner and outer walls is filled with water. Peristaltic mixing of the chyme results from alternating compression and relaxation of the flexible inner wall. The compartments are connected by a peristaltic valve pump, which opens and closes continuously, allowing chyme to pass through the compartment over time. In this way, the oral dosage form / API is locally altered and exposed to physiologically relevant conditions in the stomach and small intestine for the tiny-TIM.

[0320] The tiny-TIM system mimics intraluminal pH, enzyme activity, bile salt concentrations, peristalsis, and gastrointestinal transit of contents. The set points of the gastrointestinal simulation are controlled and monitored by a specific computer program. Released and dissolved drug molecules are removed from the intestinal lumen by a semipermeable membrane unit connected to the small intestinal segment. This allows the evaluation of the so-called bioabsorption rate, i.e., the proportion of drug available for small intestinal absorption.

[0321] Simulation of gastrointestinal conditions Experiments in tiny-TIM are performed under simulation of average physiological conditions in the gastrointestinal tract, as described for fasting humans. These conditions include, in particular, the kinetics of gastric emptying and pH drop, intestinal transit time, housekeeper waves, gastric and intestinal pH values ​​(Tables 23 and 24), and the composition and activity of secretions. Digested soluble (small molecule) compounds are continuously removed from the intestinal compartment via a specialized membrane system.

[0322] Before each experiment, secretory fluids (e.g., gastric juice containing enzymes, electrolytes, bile, and pancreatic juice) are freshly prepared, pH electrodes are calibrated, and semipermeable membrane (hollow fiber) units are installed.

[0323] Table 23: Parameters representing the average gastrointestinal physiological state of a fasting healthy young adult simulated in tiny-TIM [Table 24]

[0324] Table 24: Parameters representing the average gastrointestinal physiological state of a healthy young adult in the fasted state + PPI, as simulated in tiny-TIM [Table 25]

[0325] Housekeeper Waves A housekeeper wave (HKW) is simulated after 60 minutes by automatic transfer of residue from the gastric compartment to the intestinal compartment.

[0326] experiment This experiment is performed in duplicate. All experiments are performed under yellow light to prevent decomposition of compound (1).

[0327] sampling Filtrate Filtration of released, dissolved, or solubilized drug molecules from the intestinal lumen through a semipermeable membrane unit (Fresenius plasmaFlux® P1dry) allows for the assessment of the so-called bioavailability, i.e., the proportion of drug available for small intestinal absorption. Filtrate was collected at time intervals of 0-30 min, 30-60 min, 60-90 min, 90-120 min, 120-180 min, 180-240 min, and 240-300 min (Figure 13, sampling spot H). Analysis of these samples generated data on the bioaccessibility and availability of compound (1) for absorption. The amount collected at each time point was measured, and subsamples were taken, immediately diluted with organic solvent, and stored at 2-10°C, protected from light, until analysis.

[0328] residue At the end of each experiment, the retentate in the stomach and small intestinal compartments plus filter units is collected, measured, and analyzed. These retentate samples represent the non-bioabsorption rate. The rinses are pooled with the retentate samples from the same compartments, the volume is measured, and the rinses are stored at 2-10°C, protected from light, until analysis.

[0329] Saving backup samples The backup sample will be stored protected from light at -18°C or below for one month after the research report is finalized, after which the sample will be discarded.

[0330] Sample analysis The collected samples are analyzed for the concentration of compound (1).

[0331] Calculating the results The absolute amount of API in the sample is calculated by multiplying the analytical concentration in the sample by the collected volume (Equation 1). A(mg)=C サンプル (μg / mL) 10 -3 ·V サンプル [mL] (1)

[0332] The recovery of API is determined by summing the total amount recovered in the intestinal filtrate fraction and the gastric and intestinal retentate and rinse fractions, plus the drug product. Total recovery is expressed as % added dose (Equation 2).

number

[0333] Bioaccessibility (% uptake) is calculated by expressing the amount of API recovered from the filtrate as % uptake (Equation 3).

number

[0334] Results of duplicate experiments are expressed as mean ± SD. For SD, the STDEVP function in Microsoft® Excel® was used (Equation 4).

number

[0335] statistics No statistical analysis was performed in this study.

[0336] result Bioaccessibility profiles obtained from the tiny-TIM protocol described above are shown in Figure 14 for both the conventional (conv.) and SDD formulations under two conditions: fasted and simulated PPI conditions, i.e., high gastric pH. Under low gastric pH (fasted, 3.0-1.8 for 30 minutes), comparable bioaccessibility was observed between the conv. and SDD formulations. Under PPI conditions (fasted, gastric pH 5), the conventional tablet showed an approximately five-fold decrease in bioaccessibility, while the SDD tablet was unaffected. Thus, in contrast to the conventional tablet, the performance of the SDD formulation is not pH-dependent. Tablets from Examples 6.2-B and 6.2-C, listed in Table 17, were tested using the same tiny-TIM testing protocol and showed comparable results.

[0337] 7.4 In vivo relative bioavailability clinical trials A clinical trial was conducted to evaluate the relative bioavailability of Compound 1 in two different oral formulations: a conventional tablet containing the crystalline form of Compound 1 and a tablet containing a solid dispersion of Compound 1 of the present invention. In addition, the effects of food and multiple doses of the protein pump inhibitor (PPI), rabeprazole, on the pharmacokinetics of a single dose of Compound 1 after oral administration of the above-mentioned solid dispersion formulation in healthy male subjects were investigated.

[0338] 7.4.1 Protocol 18-45 years old (inclusive) and 18.5-29.9 kg / m 2 Sixteen healthy male subjects with a body mass index (BMI) of 100 mg / kg were enrolled in this study. The study design was an open-label, randomized, four-way crossover trial. The primary endpoint was the area under the plasma concentration-time curve (AUC) from time 0 (t0), corresponding to the time of drug administration of compound (1), to time z (tz), corresponding to the last quantifiable time point. 0-tz ) and maximum plasma concentration (C max) The secondary endpoint was the area under the plasma concentration-time curve (AUC) of compound (1) extrapolated from t0 to infinity.0-∞ )

[0339] Therefore, the objectives of this trial are to investigate the following:

[0340] Study 1: Relative bioavailability under fasted conditions of two different tablet formulations of Compound (1) in crystalline form and Compound (1) as a solid dispersion.

[0341] Study 2: Relative bioavailability of Compound (1) formulated as a solid dispersion under fasted and fed conditions and

[0342] Study 3: Relative bioavailability of Compound (1) formulated as a solid dispersion when administered alone and in combination with rabeprazole under fasted conditions.

[0343] Test article 1: Comparative film-coated tablets containing crystalline Compound (1) contained 5 mg or 20 mg of Compound (1) and 64.5 mg or 49.5 mg of silicified microcrystalline cellulose, respectively, composed of colloidal silicon dioxide and microcrystalline cellulose as a filler, 21 mg 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 silicon dioxide as a glidant, 1 mg of vegetable-derived magnesium stearate as a lubricant, and 4.5 mg of a film coating mixture (e.g., Opadry® yellow 03B120053).

[0344] Test Article 2: Film-coated tablets containing 15 mg Compound (1) as a solid dispersion spray-dried with HPMCAS-MG as defined in Example 6.2-A.

[0345] Test Article 3: PARIET® 20 mg strength rabeprazole gastroresistant tablets, a proton pump inhibitor

[0346] The reference treatment (R or TF1) consisted of a total dose of 30 mg crystalline Compound (1) in the form of Test Article 1 (one 20 mg tablet and two 5 mg tablets), administered orally with 240 mL of water on Day 1 after an overnight fast of at least 10 hours.

[0347] Test Treatment 1 (T1 or NF1) consisted of a total dose of 30 mg Compound (1) (two 15 mg tablets) in the form of a solid dispersion as Test Article 2, administered orally with 240 mL of water on Day 1 after an overnight fast of at least 10 hours.

[0348] Test Treatment 2 (T2) consisted of a total dose of 30 mg Compound (1) (two 15 mg tablets) in the form of a solid dispersion as Test Article 2, administered under fed conditions on Day 1 after a high-fat, high-calorie breakfast. The total calorie content of the high-fat, high-calorie breakfast was provided approximately as follows: 150 kcal protein, 250 kcal carbohydrate, and 500-600 kcal fat; Ingredients: 2 whole eggs for scrambled eggs (192 kcal), 10 g butter for frying scrambled eggs (75 kcal), 35 g fried bacon (186 kcal), 2 slices of wheat bread toast (130 kcal), 15 g butter for toast slices (113 kcal), 115 g hash brown potatoes (132 kcal), and 240 mL whole milk (3.5% fat) (156 kcal), for a total of 984 kcal.

[0349] Test Treatment 3 (T3) consists of a total dose of 30 mg Compound (1) in the form of a solid dispersion (two 15 mg tablets) as Test Article 2, administered under fasting conditions. Subjects in T3 also receive Test Article 3, total dose of 200 mg rabeprazole, at a daily dose of 40 mg once daily (two 20 mg tablets) 4 days before and on the day of Compound (1) administration.

[0350] Blood samples were collected for all treatments up to 118 hours after administration of Compound (1) to analyze the plasma concentration of Compound (1). Plasma concentration-time profiles were evaluated by non-compartmental analysis to calculate each PK parameter. Relative bioavailability was estimated by the ratios of geometric means (T1 / R, T2 / T1, and T3 / T1) for the primary and secondary endpoints. Furthermore, their two-sided 90% confidence intervals (CI) were provided. This method is equivalent to two one-sided t-tests at a 5% significance level. Because the primary focus is on estimation, not testing, formal hypothesis testing and associated tolerance limits were not specified. The statistical model was an analysis of variance (ANOVA) on a logarithmic scale, including the effects of sequence, subject nested within the sequence, period, and treatment. CIs were calculated based on the residuals from the ANOVA. Descriptive statistics were calculated for all endpoints. Pharmacokinetic analysis was performed on the pharmacokinetic parameter analysis set (PKS), and safety analysis was performed on the treatment set (TS). Formal interim analyses were not planned or performed.

[0351] 7.4.2 Results Of the 16 subjects planned for inclusion in this clinical trial, 13 completed the study. Treatment comparisons included 12 subjects evaluable for the relative bioavailability comparison between T1 and R, 9 subjects for food effect evaluation (T2 vs. T1), and 11 subjects for drug-drug interaction evaluation between Compound (1) and rabeprazole (T3 vs. T1). Relative bioavailability comparisons demonstrated that tablets containing a solid dispersion of Compound (1) (T1) exhibited reduced variability compared with tablets containing crystalline Compound (1) (R). Exposure to T1 resulted in an average increase of 3% (Cmax) and 35% (AUC0-tz) compared with R. Food effect evaluations demonstrated an average decrease of -46% in Cmax and -26% in AUC0-tz under fed conditions (T2) compared with fasted conditions (T1). Pretreatment with rabeprazole did not significantly alter the exposure of tablets containing the solid dispersion of Compound 1 (mean Cmax -13% and AUC0-tz -3%), suggesting no relevant DDIs between Compound 1 and proton pump inhibitors or other pH-raising co-medications.

[0352] The trial results are discussed in more detail below.

[0353] Clinical trial subjects and protocol compliance A total of 13 subjects received the study drug and completed the scheduled observation period. No serious protocol violations were reported. Of the 13 healthy male subjects treated in this study, 12 subjects (92.3%) were Caucasian and 1 subject (7.7%) was Black or African American. The mean age of the subjects was 34.8 years (standard deviation [SD] = 5.8 years), with an age range of 25 to 45 years. The mean BMI was 25.49 kg / m 2 (SD=3.03 kg / m 2 ) and BMI is 20.7-29.5 kg / m 2 Treatment groups were similar with respect to demographics and baseline characteristics.

[0354] Twelve subjects were randomized to receive Reference Treatment (R), 12 subjects to receive Test Treatment 1 (T1), 9 subjects to receive Test Treatment 2 (T2), and 11 subjects to receive Test Treatment 3 (T3), with a washout period of at least 14 days between administration of Compound (1) and subsequent treatments.

[0355] The relative bioavailability of formulations NF(T1) and TF1(R) under fasting conditions is shown in Table 25. The adjusted geometric mean ratios for the primary and secondary endpoints in subjects receiving treatment T1 / R ranged from 129.1% to 139.3%, with 90% CIs ranging from 87.7% to 221.3% (Table 25). The pharmacokinetic (PK) parameter, C max (geometric coefficient of variation [gCV] 93.1%), AUC0-tz (gCV 52.7%) and AUC 0-∞ (gCV 52.7%), the variation of C max (gCV 37.3%), AUC 0-tz (gCV 18.8%) and AUC 0-∞ The gCV was higher in subjects on treatment R compared to subjects on treatment T1 (gCV 19.2%). Although the trend toward improved oral bioavailability of NF was not consistently observed in all subjects, an overall trend toward improved oral bioavailability was demonstrated.

[0356] Table 25: Adjusted Geometric Mean and Relative Bioavailability of Compound (1) NF Fasted (T1) vs TF1 Fasted (R) for Subjects as a Random Effect - Pharmacokinetic Set [Table 26]

[0357] The ANOVA results comparing the primary and secondary endpoints of the NF formulations fasted (T1) or after ingestion of a high-fat, high-calorie meal (T2) are shown in Table 26. The adjusted g mean ratios for the primary and secondary endpoints in subjects receiving treatment T2 / T1 ranged from 53.5% to 74.9%, with 90% CIs ranging from 40.5% to 81.7% (Table 26). max , AUC 0-tz and AUC 0-∞ The values ​​of β-glucan were lower in subjects treated under fed conditions, indicating a negative effect of diet.

[0358] Table 26: Adjusted Geometric Mean and Relative Bioavailability of Compound (1) NF Fed (T2) vs NF Fasted (T1) for Subjects as a Random Effect - Pharmacokinetic Set [Table 27]

[0359] ANOVA results comparing the primary and secondary endpoints of the NF formulation without (T1) and with (T3) co-administration of the proton pump inhibitor (PPI), rabeprazole, at a defined fasting state are shown in Table 27. The adjusted geometric mean (g-mean) ratios of the endpoints in subjects treated T3 / T1 ranged from 87.0% to 97.1%, with 90% CIs ranging from 66.8% to 113.2% (Table 27). PK parameters and profiles for T1 and T3 were similar, except for the time from the (last) dose to the maximum measured concentration of the analyte in plasma (t max ) appeared to be delayed in the presence of rabeprazole. Taken together, these results suggest that rabeprazole does not interfere with the PK of compound (1).

[0360] Table 27: Adjusted Geometric Mean and Relative Bioavailability of Compound (1) NF Fasted + Rabeprazole (T3) vs NF Fasted (T1) for Subjects as a Random Effect - Pharmacokinetic Set [Table 28]

[0361] Reference Example 1: Preparation of crystalline compound (1) The III and IV forms of compound (1) mentioned in Example 5.1 can be prepared according to the following procedure. It should be noted that the input form of compound (1) is not strictly important to the crystallization method, provided that complete dissolution is achieved before crystallization. When completely dissolved, the starting material of compound (1) can be prepared, for example, according to the synthesis described in WO 2021 / 213800.

[0362] Reference Example 1.1 - Preparation of Form I First exemplary procedure for preparing Form I (crystallization): 19 kg of Compound (1) (any solid state) is dissolved in a mixture of about 54 kg THF, about 160 kg DCM, and about 48 kg MeOH. Residual inorganic salts are removed by washing with brine (48 kg). Undissolved particles are removed by polish filtration of the organic layer. The organic layer is then distilled to about 160 L, and the mixture is diluted with 78 kg THF. The sequence of distillation, THF dilution, and distillation is repeated until the water and MeOH levels are each 1.0% w / w or less. After distillation is complete, the resulting slurry is held at ambient temperature for at least 12 hours and filtered to produce Form I.

[0363] Second exemplary procedure for preparing Form I (crystallization): 6 g of Form IV of Compound (1) (e.g., prepared according to one of the Examples described herein) is dissolved in 75 g of a 5% w / w HO in IPA solution at 90° C. The solution is slowly cooled to 75° C. and seeded with 60 mg of Form I. The mixture is stirred at 75° C. for 2 hours and subsequently cooled to 20° C. at a rate of 0.3° C. / min. After cooling is complete, the solid is filtered and dried to yield Form I.

[0364] Reference Example 1.2 - Preparation of Form III Exemplary procedure for preparing Form III (slurry): 17 kg Form I of Compound (1) is mixed with 271 kg IPAc. The slurry is heated to 70°C. To this slurry, 0.2 kg of Form III of Compound (1) seed (e.g., prepared according to one of the Examples described herein) is added, and the mixture is stirred for about 16 hours. At the end of the hold, the mixture is gradually cooled to 53°C in about 40 minutes, then to 33°C in about 40 minutes, and then to 25°C. The resulting slurry is stirred for about 1 hour and filtered. The solid is washed with 27 kg IPAc and dried to yield Form III.

[0365] This method can also be carried out without adding crystal seeds.

[0366] Reference Example 1.3 - Preparation of Form IV First exemplary procedure for preparing Form IV (crystallization): 300 mg of Form I of Compound (1) is dispersed in 3 ml of 1-BuOH. The mixture is heated to 90°C with overhead stirring. Dissolution is observed. The solution is cooled to 75°C at a rate of 0.2°C / min, followed by rapid cooling to 20°C. The resulting slurry is held at 20°C with stirring for approximately 12 hours and filtered to yield Form IV.

[0367] Second exemplary procedure for preparing Form IV (crystallization): Form III of compound (1) is dissolved in 10 volumes of a 1:1 mixture of 1-BuOH and anisole at 110°C. The solution is subjected to distillation under slight vacuum, during which most of the 1-BuOH is removed. Crystals are precipitated from this solution by nucleating Form III and held at 110°C to obtain a slurry. The mixture is cooled to ambient temperature with stirring and filtered to produce isolated compound (1) as Form IV, despite the fact that Form III precipitated.

[0368] Third exemplary procedure for preparing Form IV (Slurry): A slurry of Forms I and IV of compound (1) is slurried in IPAc for 72 to 168 hours at a temperature ranging from 25 to 75° C. The mixture is optionally allowed to return to ambient temperature and filtered to produce compound (1) as Form IV.

[0369] Reference Example 2 - XRPD of Compound (1) in the Solid State The crystalline form of compound (1) was analyzed by XRPD, which was measured at temperatures ranging from 20 to 30°C using Cu-Kα radiation with a wavelength of 1.54184 Å.

[0370] The analytical method was as follows: Each solid compound (approximately 0.2 g) was typically subsampled into a stainless steel sample holder fitted with a zero diffraction plate (ZDP). The sample holder was then leveled with a glass slide to form a flat sample surface level with the sample holder. The instrument used for the analysis was a Bruker D2 Phaser (system EQ-SSRD-XRD-01). To evaluate the performance of the system, a corundum standard was measured daily. For the system to be considered suitable, the two peaks must be within ±0.02° 2θ. The instrument settings for the measurement of solid compound samples are shown in Table 28. Processing (Kα2 contribution stripping, peak labeling) was completed using DIFFRAC.EVA software (version 5.0).

[0371] The experimental parameters for the XRPD measurements are given below.

[0372] Table 28: Experimental parameters for XRPD measurements [Table 29]

[0373] Table 29 lists the peaks (with a relative intensity of 5% or greater) for each form. Table 30 lists the best characteristic peaks to use when trying to identify a given polymorphic form when alternative forms are present. Diagnostic peaks indicate peak positions where impurities have relatively high intensity peaks and the predominant form in a sample has a flat baseline.

[0374] Table 29: XRPD Peak Comparison [Table 30]

[0375] For Table 29, peaks in bold were determined to be characteristic peaks, peaks marked with "*" had a relative intensity of 10% or greater, and peaks marked with "**" had a relative intensity of 50% or greater. Furthermore, these peaks are listed in order of peak position (°2θ), with similar peak positions on the same line.

[0376] Table 30: XRPD characteristic peaks (°2θ) for identification of polymorphic impurities [Table 31]

Claims

1. below: 【Transformation 3】 A compound (1) as defined in, or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable dispersion carrier and Includes, A solid dispersant in which compound (1) is amorphous.

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

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

4. The solid dispersant according to claim 2 or 3, wherein the polymer is enteric coated.

5. The solid dispersant according to any one of claims 1 to 3, 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 dispersant according to claim 5, wherein the hydroxypropyl methylcellulose and its ester are selected from the group consisting of hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, 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 dispersant according to claim 5, wherein the hydroxypropyl methylcellulose and its ester are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hot-melt extruded grade hydroxypropyl methylcellulose.

8. The solid dispersant according to claim 5, wherein polyvinylpyrrolidone and its copolymer are selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone.

9. The solid dispersant according to claim 5, wherein the polyvinylpyrrolidone and its copolymer are polyvinylpyrrolidone-vinyl acetate copolymer.

10. The solid dispersant according to claim 5, wherein the polymethacrylate and its copolymer are selected from the group consisting of methacrylate-ethyl acrylate copolymer, methacrylate-methyl methacrylate copolymer, methyl methacrylate, and methacrylate copolymer.

11. The solid dispersant according to claim 5, wherein the polymethacrylate and its copolymer are methylacrylic acid-methyl methacrylate copolymer.

12. The solid dispersant according to any one of claims 1 to 3, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone-vinyl acetate copolymer, methylacrylic acid-methyl methacrylate copolymer, and hot-melt extruded grade hydroxypropyl methylcellulose.

13. A solid dispersant according to any one of claims 1 to 3, wherein the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate.

14. The solid dispersant according to any one of claims 1 to 3, wherein the pharmaceutically acceptable dispersion carrier is grade M hydroxypropyl methylcellulose acetate succinate.

15. Compound (1) is present in an amount ranging from 25 wt% to 75 wt% based on 100 wt% of the total weight of the solid dispersant, and / or The solid dispersant according to any one of claims 1 to 3, wherein a pharmaceutically acceptable dispersion carrier is present in an amount ranging from 25 wt% to 75 wt% based on 100 wt% of the total weight of the solid dispersant.

16. The solid dispersant according to any one of claims 1 to 3, wherein the weight ratio of compound (1) to pharmaceutically acceptable dispersion carrier in the solid dispersant is 1:1 to 1:

3.

17. The solid dispersant according to any one of claims 1 to 3, wherein the weight ratio of compound (1) to pharmaceutically acceptable dispersion carrier in the solid dispersant is 1:

1.

18. below: 【Chemistry 4】 Compound (1) as defined in, Hydroxypropyl methylcellulose acetate succinate and It contains in a 1:1 weight ratio, A solid dispersant in which compound (1) is amorphous.

19. A solid dispersant according to any one of claims 1 to 3 or 18, characterized in that, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C, it has a powder X-ray diffraction pattern that does not contain diffraction peaks below a 2θ angle of 40.0°.

20. A solid dispersant according to any one of claims 1 to 3 or 18, characterized in that when measured by modulated differential scanning calorimetry with a modulation amplitude of 1°C / min and a heating rate of 3.0°C / min, it has a differential scanning calorimetry curve that includes only one glass transition point signal.

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

22. A pharmaceutical composition comprising a solid dispersant according to any one of claims 1 to 3 or 18, and one or more pharmaceutically acceptable excipients.

23. One or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, flow promoters, lubricants and coatings, and / or The filler is selected from the group consisting of microcrystalline cellulose, mannitol and mixtures thereof, and / or The disintegrant is selected from the group consisting of croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate and mixtures thereof, and / or The flow accelerator is colloidal silicon dioxide, and / or The pharmaceutical composition according to claim 22, wherein the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof.

24. The pharmaceutical composition according to claim 22, wherein one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

25. The pharmaceutical composition, based on 100 wt% of the total weight of the pharmaceutical composition, - A solid dispersant in an amount ranging from 25 wt% to 65 wt%, and / or - One or more fillers in an amount ranging from 25 wt% to 65 wt%, and / or - Disintegrant in the range of 4 wt% to 10 wt%, and / or - A flow accelerator in the range of 1 wt% to 2 wt%, and / or - A lubricant in the range of 1 wt% to 2 wt%, and / or - Selectively, the coating agent can be added in a range of 2 wt% to 5 wt%. A pharmaceutical composition according to claim 22, including the one described in claim 22.

26. The pharmaceutical composition according to claim 22, wherein the composition is in the form of a tablet, granules, or capsule.

27. (i) A tablet core comprising a solid dispersant, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate, (ii) Film coating and A pharmaceutical composition according to claim 22, comprising:

28. The pharmaceutical composition according to claim 22, comprising, based on 100 wt% of the total weight of the pharmaceutical composition, 15 wt% of compound (1), 15 wt% of hypromellose acetate succinate, 20 wt% of microcrystalline cellulose, 42 wt% of mannitol, 5 wt% of croscarmellose sodium, 1.5 wt% of colloidal silicon dioxide, and 1.5 wt% of sodium stearyl fumarat, essentially consisting of or comprising these.

29. The pharmaceutical composition according to claim 22, characterized in that, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C, it has a powder X-ray diffraction pattern that does not contain diffraction peaks at a 2θ angle of 6.5° or less.

30. A solid dispersant according to any one of claims 1 to 3 or 18, for use in treating and / or preventing cancer.

31. The solid dispersant according to claim 30, wherein the cancer is selected from the group consisting of brain tumor, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach 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.

32. The solid dispersant according to claim 30, wherein the cancer is a HER2 overexpression, HER2 amplification, and / or HER2 mutation cancer.

33. a) A step of 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, b) a step of removing the solvent from the solution or suspension to form a solid dispersant according to any one of claims 1 to 3 or 18. A method for producing a solid dispersant according to any one of claims 1 to 3 or 18, including the above.

34. The method according to claim 33, wherein the removal of the solvent in step b) is performed by spray drying.

35. The method according to claim 33, 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.

36. The method according to claim 33, wherein the solvent is a mixture of dichloromethane and methanol.

37. A use of the solid dispersant according to any one of claims 1 to 3 or 18 for the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition comprises the solid dispersant and one or more pharmaceutically acceptable excipients.

38. - A solid dispersant according to any one of claims 1 to 3 or 18, - Means for containing the solid dispersant, - Optionally, desiccant and A kit that includes this.

39. A pharmaceutical composition according to claim 22 for use in treating and / or preventing cancer.

40. The pharmaceutical composition according to claim 39, wherein the cancer is selected from the group consisting of brain tumor, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach 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.

41. The pharmaceutical composition according to claim 39, wherein the cancer is a HER2 overexpression, HER2 amplification, and / or HER2 mutation cancer.

42. - The pharmaceutical composition according to claim 22, - Means for containing the pharmaceutical composition, - Optionally, desiccant and A kit that includes this.

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