Pharmaceutical composition containing a cap-dependent endonuclease inhibitor

Abstract

The present disclosure provides a pharmaceutical composition for oral administration, containing a solid dispersion, wherein the solid dispersion contains a cap-dependent endonuclease inhibitor or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 355,742, filed on 27 June 2022 pursuant to 35 U.S. Code § 119(e), the entire contents of which are incorporated herein by reference.

[0002] This disclosure relates to pharmaceutical compositions containing heterocyclic compounds or pharmaceutically acceptable salts thereof. [Background technology]

[0003] Cap-dependent endonucleases are essential enzymes in inhibiting influenza virus mRNA synthesis. Inhibitors of cap-dependent endonucleases are known to be effective against influenza A and B viruses. Several compounds exhibit potent antiviral activity against influenza viruses by inhibiting cap-dependent endonucleases. PCT publication application WO2019 / 144089 first disclosed a novel heterocyclic compound as a potent cap-dependent endonuclease inhibitor. Effective therapeutic interventions often depend on whether pharmaceutical compounds can be delivered in a comfortable and patient-friendly manner. Oral administration is a preferred route of drug delivery due to its non-invasiveness, ease of administration, and patient compliance. The aforementioned novel anti-influenza heterocyclic compound showed considerable promise in preclinical trials. However, its oral administration presents several challenges, including low solubility and low stability. Therefore, the development of an optimal pharmaceutical formulation is crucial to ensure the therapeutic effect of the compound. The formulations described herein are intended to improve solubility, enhance patient compliance, and maximize therapeutic utility across different age groups. [Overview of the Initiative]

[0004] This disclosure provides a pharmaceutical composition comprising a solid dispersion. The solid dispersion comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer. The weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is about 1:1 to about 1:5. The amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 5 mg to about 200 mg in therapeutically effective dose. In the compound of formula (II), G is hydrogen or -C(R2R 2’ )-O-CO-O-R3, and R2 and R 2’ Each is independently either hydrogen or C 1-4 It is an alkyl group, and R3 is C 1-4 It is an alkyl group, and the asterisk symbol (*) indicates a chiral center. [ka]

[0005] The disclosure also provides a process for preparing a pharmaceutical composition comprising a solid dispersion of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0006] Furthermore, this disclosure provides a method for treating influenza, comprising administering a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof to a subject in need. This disclosure also provides a pharmaceutical composition for use in the treatment of influenza. Furthermore, this disclosure provides the use of a pharmaceutical composition for manufacturing a pharmaceutical for the treatment of influenza. [Brief explanation of the drawing]

[0007] This disclosure can be better understood by referring to the attached drawings and reading the following description of the embodiments. [Figure 1] This figure shows the dissolution profiles of the granular formulation and the ASD powder itself. [Figure 2] This figure shows the dissolution profiles of the orally disintegrating formulation and the ASD powder itself. [Modes for carrying out the invention]

[0008] To facilitate understanding of the disclosure in this specification, several terms are defined below.

[0009] Generally, the nomenclature used in this specification and the experimental procedures in organic chemistry, pharmaceutical chemistry, and pharmacology are known and commonly adopted in the relevant technical fields. Unless otherwise defined specifically, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art.

[0010] The term "about" means within an acceptable error range for a given value determined by those skilled in the art, which depends in part on the method of measurement or determination of the value (e.g., the limitations of the measurement system, etc.). In this specification, for example, when indicating measurable or calculated values such as quantities, temporal durations, concentrations, ratios, etc., variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value may be included, and such variations are appropriate for the implementation of the methods disclosed in this specification.

[0011] The term "treat" includes reducing or eliminating a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or reducing or eradicating the cause of the disorder, disease or condition.

[0012] The term "prevent" includes methods of delaying or preventing the onset of a disorder, disease or condition, and / or the symptoms associated therewith; methods of avoiding a subject suffering from a disorder, disease or condition; or methods of reducing the risk of a subject suffering from a disorder, disease or condition.

[0013] The terms "patient", "individual" or "subject" refer to a human or a non-human mammal. In one embodiment, the patient, individual or subject is a human. In another embodiment, the patient, individual or subject is a child.

[0014] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms suitable for contact with human and animal tissues within the scope of sound medical judgment, which are free of excessive toxicity, irritation, allergic reaction or other problem complications and are commensurate with a reasonable risk-to-benefit ratio.

[0015] The term "one or more" refers to any one or more numbers (e.g., 2, 3, 4, 5, 6, 7 or even more).

[0016] 「C 1-4 The term "C 1-4 alkyl group" refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 4 carbon atoms. Examples of C

[0017] 「C 1-4 The term "C 1-4 alkoxy group" refers to an -OR group, where R is a C 1-4 alkyl group. Examples of C

[0018] 「C 1-4 The term "C 1-4 alkylamino group" refers to an -NHR' group, where R' is a C 1-4 alkyl group. Examples of C

[0019] The term "carbocyclyl" refers to a C3 - C 10It refers to the cyclic hydrocarbon group.

[0020] The term "aromatic carbocyclic group" refers to a monocyclic or polycyclic cyclic aromatic hydrocarbon group having two or more rings. Examples of aromatic carbocyclic groups include, but are not limited to, phenyl, naphthyl, anthryl, and phenanthryl groups.

[0021] The term "non-aromatic carbon ring group" refers to a cyclic hydrocarbon group that is either fully saturated or contains one or more unsaturated units but does not exhibit aromaticity.

[0022] The term "heterocyclic group" includes aromatic heterocyclic groups and non-aromatic heterocyclic groups, and contains one or more heteroatoms independently selected from the group consisting of O, S, N, and any combination thereof.

[0023] The term "aromatic heterocyclic group" refers to a monocyclic or polycyclic aromatic ring group containing two or more rings, which contains one or more heteroatoms independently selected from the group consisting of O, S, N, and any combination thereof.

[0024] The term "non-aromatic heterocyclic group" refers to a monocyclic or polycyclic non-aromatic ring group containing one or more heteroatoms independently selected from the group consisting of O, S, N, and any combination thereof.

[0025] The term "pharmaceutically acceptable salt" includes non-toxic acid and base addition salts, or the compounds referred to by that term. Pharmaceutically acceptable salts include those derived from organic and inorganic acids or bases known in the art.

[0026] The term "solid dispersion" refers to a molecular dispersion of a compound, particularly a molecular dispersion of a drug substance in a pharmaceutically acceptable carrier (e.g., a polymer). Generally, the term "solid dispersion" means a system in a solid state containing at least two components, where one component is substantially uniformly dispersed throughout the other components. For example, a solid dispersion may be a dispersion of one or more active ingredients in a solid state in an inert carrier or matrix, prepared by spray drying, thermal melt extrusion, fluidized bed, or freeze-drying methods. The formation of molecular dispersions can provide a means of reducing particle size to nearly molecular levels.

[0027] In this specification, polyvinylpyrrolidone (also known as PVP) refers to polymer compounds obtained by polymerizing N-vinyl-2-pyrrolidone. Examples of polyvinylpyrrolidone include, but are not limited to, PVP-K17, PVP-K25, PVP-K30, PVP-K40, PVP-K50, PVP-K60, PVP-K70, PVP-K80, PVP-K85, PVP-K90, and PVP-K120.

[0028] In this specification, polyvinylpyrrolidone-vinyl acetate (also known as PVP-VA) refers to a copolymer of vinylpyrrolidone (VP) and vinyl acetate (VA) monomers. Examples of polyvinylpyrrolidone-vinyl acetate copolymers include, but are not limited to, PVP-VA64 and Kollidon SR.

[0029] In this specification, a methacrylic acid-methyl methacrylate copolymer refers to a copolymer derived from an ester of acrylic acid and methacrylic acid. Eudragit is a trade name for a variety of methacrylic acid-methyl methacrylate copolymers. Examples of methacrylic acid-methyl methacrylate copolymers include, but are not limited to, Eudragit EPO, Eudragit E100, Eudragit RS100, Eudragit RL100, Eudragit L100, Eudragit NE, Eudragit NM, and Eudragit FS.

[0030] In this specification, polyethylene glycol (also known as PEG) refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Examples of polyethylene glycol include, but are not limited to, PEG-1000, PEG-1500, PEG-2000, PEG-2500, PEG-3000, PEG-3350, PEG-3500, PEG-4000, PEG-5000, PEG-6000, and PEG-8000.

[0031] In this specification, a polyoxyethylene-polyoxypropylene copolymer refers to a block copolymer in which one block is polyoxyethylene and the other block is polyoxypropylene. Examples of polyoxyethylene-polyoxypropylene copolymers include the Pluronic® series of surfactants (commercially available from BASF). For example, the Pluronic® series of surfactants can be represented by the CTFA names Poloxamer 108, 124, 188, 217, 237, 238, 288, 338, 407, 101, 105, 122, 123, 181, 182, 183, 184, 212, 231, 282, 331, 401, 402, 185, 215, 234, 235, 284, 333, 334, 335, and 403, but are not limited to these.

[0032] In this specification, hydroxypropyl cellulose is also referred to as HPC. Examples of hydroxypropyl cellulose include HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H, depending on their average molecular weight.

[0033] In this specification, hydroxypropyl methylcellulose is also referred to as HPMC. Examples of hydroxypropyl methylcellulose include, but are not limited to, E3, E5, E6, E15, E50 Lv, etc., depending on their viscosity.

[0034] In this specification, hydroxypropyl methylcellulose acetate succinate (also known as HPMCAS) refers to a mixture of hydroxypropyl methylcellulose acetate and monosuccinate esters. In one embodiment, HPMCAS includes, but is not limited to, various types such as LF, LG, MF, MG, HF, and HG.

[0035] In this specification, hydroxypropyl methylcellulose phthalate is also referred to as HPMCP. Examples of HPMCP include, but are not limited to, HPMCP HP-50, HPMCP HP-55, and HPMCP HP-55S.

[0036] The term "amorphous" refers to the solid form of molecules that are not crystalline. In particular, amorphous solids do not exhibit a clear X-ray diffraction pattern.

[0037] The term "therapeutic effective dose" refers to the amount or dosage of an active compound or its salt sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated. Compound A (5 mg / kg, for oral use) of this disclosure was tested in vivo in an influenza virus (A / PR / 8 / 34) infected mouse (BALB / c) model and showed good antiviral effects on survival rate and weight change. The effect of compound A on influenza virus replication was also examined in the lungs of BALB / c mice infected with a low infection dose of A / PR / 8 / 34 (100 pfu / mouse) on post-infection day 1. The compound A-treated groups (5 mg / kg, 25 mg / kg) had significantly lower viral titers than the media-treated groups. In a 14-day repeated oral toxicity study, compound A did not cause death or toxic effects when administered at a dose of 300 mg / kg / day. Therefore, based on the results of these preliminary in vivo animal studies, it is inferred that appropriate therapeutically effective doses for humans of the compound of formula (I) or its pharmaceutically acceptable salts may be approximately 5–200 mg, 5–150 mg, 5–100 mg, 10–80 mg, 10–40 mg, 10–30 mg, 10–20 mg, 5–10 mg, 5–20 mg, 20–40 mg, or 40–80 mg. For example, the therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg, but is not limited to these.

[0038] The invention provided in this disclosure relates to a pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion is i) Compounds of formula (I) or pharmaceutically acceptable salts thereof [ka] (wherein G is hydrogen, a prodrug group or a suitable substituent, R1 is a halogen, C 1-4 It is an alkyl group or deuterium, m is an integer from 1 to 9, and the asterisk symbol (*) indicates a chiral center. ii) Pharmaceutically acceptable polymers and Includes, The weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable polymer is about 1:1 to about 1:5, and the therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 20 mg to about 40 mg, or about 40 mg to about 80 mg.

[0039] In one embodiment, R1 is a halogen and m is an integer from 1 to 3. In another embodiment, R1 is a fluoropolymer and m is an integer of 1 or 2.

[0040] A method for treating influenza in patients in need includes administering the oral pharmaceutical compositions of this disclosure. In one embodiment, the method includes administering to a patient about 1 mg / kg of the compound of formula (I) or a pharmaceutically acceptable salt thereof in a dosage form. In another embodiment, the method includes administering to a patient about 2 mg / kg of the compound of formula (I) or a pharmaceutically acceptable salt thereof in a dosage form.

[0041] In one embodiment, the cyclic group in formula (I) is represented by the following formula: [ka] It is a cyclic group represented by one of the following structural formulas. [ka]

[0042] In one embodiment, the compound of formula (I) is represented by formula (II). [ka]

[0043] In one way, G is hydrogen, -C(R2R 2’ )-O-CO-R3, -C(R2R 2’ )-O-CO-O-R3, -C(R2R 2’ )-NR4-C(=O)-CO-O-R3, -C(R2R 2’ )-O-CO-C(R2R 2’ )-NR4-CO-O-R3, -C(R2R 2’ )-C(R2R 2’ )-O-CO-R3, -C(R2R 2’ Selected from the group consisting of -R3, -C(=O)-O-R3, -C(=O)-R3, -C(=O)-O-alkylene-O-R3, -C(=O)-NR3R4, -(CH2)2-OH, -(CH2)3-OH, -(CH2)2-O-SO2R5, -(CH2)2-OP(=O)(R5R6) and -P(=O)(R5R6), where R2, R 2’ And R4 are independently hydrogen or C 1-8 It is an alkyl group, and R3 is C 1-4 Alkyl alkyl group, C 3-10 Carbocyclic group or C 3-10 It is a heterocyclic group, and R5 is OH, NH2, C 1-4 Alkyl or C 1-4 It is an alkoxy group, and R6 is OH, C 1-4 Alkoxy group or C 1-4 It is an alkylamino group. In another embodiment, G is hydrogen or -C(R2R 2’ )-O-CO-O-R3. In one embodiment, R2 and R 2’ Each is independently hydrogen or C 1-8 It is an alkyl group. In another embodiment, R2 and R 2’Each is independently either hydrogen or C 1-4 It is an alkyl group.

[0044] In one embodiment, the G group is hydrogen, [ka] It is selected from the group consisting of the following.

[0045] In one embodiment, the compound of formula (I) is [1-((11S)-7,8-difluoro(6H,11H-dibenzo[c,f]thiepin-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyridino[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methylmethoxyformate, or its metabolite, 1'-((11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compounds of this disclosure can be prepared by the methods / procedures disclosed in PCT Publication WO2019 / 144089 or WO2021 / 239126, which are incorporated herein by reference in their entirety.

[0047] In one embodiment, the present disclosure provides an amorphous solid dispersion of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which further comprises a pharmaceutically acceptable polymer.

[0048] In another embodiment, an amorphous solid dispersion is disclosed comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is molecularly dispersed in a polymer matrix formed by a pharmaceutically acceptable polymer in a solid state.

[0049] The pharmaceutically acceptable polymers used in the amorphous solid dispersions of this disclosure are water-soluble polymers. A suitable water-soluble polymer needs to act as a water-soluble carrier to improve the solubility of the active ingredient by making it hydrophilic, and it also contributes to maintaining the amorphous state of the solid dispersion.Common examples of water-soluble polymers include vinyl polymers and copolymers, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene-polyvinyl alcohol copolymer, polyvinyl caprolactam and polyvinyl acetate, polyvinyl acetate phthalate (PVAP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus), acrylate and methacrylate copolymer, methacrylate-methyl methacrylate copolymer (e.g., Eudragit), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene copolymer (also called poloxamer), hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl This includes, but is not limited to, methylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), carboxymethylcellulose acetate butyrate (CMCAB), carboxymethylcellulose calcium (CMC calcium), carboxymethylcellulose sodium (CMC sodium), β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, doxate sodium, and cellacefate.

[0050] In one embodiment, pharmaceutically acceptable polymers include polyvinylpyrrolidone-vinyl acetate copolymers (PVP-VA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (Soluplus), methacrylate-methyl methacrylate copolymers (such as Eudragit), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), or mixtures thereof.

[0051] In one embodiment, the pharmaceutically acceptable polymer is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof. In another embodiment, the pharmaceutically acceptable polymer is HPC, which includes HPC-SSL, HPC-SL, HPC-L, HPC-M, or HPC-H.

[0052] In one embodiment, the pharmaceutically acceptable polymers are Soluplus, HPC-SSL, HPMCAS, or mixtures thereof.

[0053] In one embodiment, an amorphous solid dispersion is disclosed comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is in the range of 4:1 to 1:7, 2:1 to 1:7, 3:1 to 1:6, 2.5:1 to 1:6, 2:1 to 1:5, 2:1 to 1:4, 2:1 to 1:3.5, 2:1 to 1:2, 2:1 to 1:1.5, 2:1 to 1:5, 1.5:1 to 1:5, 1.5:1 to 1:3.5, 1.5:1 to 1:2, 1.5:1 to 1:1.5, 1:1 to 1:5, 1:1 to 1:3.5, 1:1 to 1:3, 1:1 to 1:2.5, 1:1 to 1:2, or 1:1 to 1:1.5. In one embodiment, the weight ratio is approximately 1:1 to approximately 1:5. In another embodiment, the weight ratio is approximately 1:1 to approximately 1:3.5. In yet another embodiment, the weight ratio is approximately 1:1 to approximately 1:3. In yet another embodiment, the weight ratio is approximately 1:3.

[0054] In one embodiment, the amount of the compound of formula (I) or a pharmaceutically acceptable salt in a solid dispersion is typically 10-60% by weight, 10-55% by weight, 10-50% by weight, 10-45% by weight, 10-40% by weight, 15-60% by weight, 15-55% by weight, 15-50% by weight, 15-45% by weight, or 15-40% by weight. For example, the amount of the compound of formula (I) or a pharmaceutically acceptable salt in a solid dispersion (drug load) is about 15% by weight, 25% by weight, 33% by weight, 40% by weight, or 50% by weight.

[0055] In one embodiment, the solid dispersion of the present disclosure is a D in the range of about 4 μm to about 15 μm. 50 Particle size, or D in the range of approximately 15 μm to approximately 50 μm 90 It has particle size.

[0056] The solid dispersions described herein can be administered orally to subjects requiring them (e.g., humans) to treat or prevent infectious diseases such as influenza.

[0057] The amorphous solid dispersions of this disclosure can be prepared by methods known in the art, such as spray drying, thermal extrusion, fluidized bed, or freeze-drying. In one embodiment, the amorphous solid dispersion is prepared by spray drying.

[0058] In one embodiment, an amorphous solid dispersion of the disclosure is prepared by dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a sufficient amount of an organic solvent, and mixing the resulting solution with a solution containing a pharmaceutically acceptable polymer. The solvent can then be evaporated to disperse / dissolve the drug in the matrix. Any organic solvent capable of dissolving or dispersing the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable polymer can be used. Examples of organic solvents include lower alcohols (e.g., methanol, ethanol, propanol, or isopropanol), ketones (e.g., acetone, methyl ethyl ketone, or methyl isobutyl ketone), haloalkanes (e.g., dichloromethane, chloroform, or carbon tetrachloride), acetic acid, ethyl acetate, N,N-dimethylformamide, DMSO, tetrahydrofuran, and mixtures thereof.

[0059] In one embodiment, the preparation of an amorphous solid dispersion includes the steps of (i) dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable polymer in a solvent, and (ii) drying the solution obtained in step (i).

[0060] In one embodiment, step (i) includes dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a sufficient amount of organic solvent, dissolving a pharmaceutically acceptable polymer in a solvent, and mixing the two solutions.

[0061] In one embodiment, step (ii) includes spray drying. In another embodiment, step (ii) includes combining spray drying with a fluidized bed. In yet another embodiment, step (ii) includes evaporating the solvent using a rotary evaporator (rotovap).

[0062] In one embodiment, the solvent can be removed by evaporation using a spray drying method. The term "spray drying" has been conventionally used and broadly refers to the process of rapidly removing a solvent from a liquid mixture by dispersing the mixture into fine droplets (atomizing) and using a spray drying apparatus (e.g., a nozzle) with a powerful driving force to evaporate the solvent from the droplets. In a typical spray drying process, the feed liquid may be a solution, slurry, emulsion, gel, or paste, as long as it can be pumped and atomized.

[0063] In one embodiment, a pharmaceutical composition comprises a solid dispersion of the Disclosure and further comprises one or more pharmaceutically acceptable excipients selected from binders, disintegrants, fillers, diluents, lubricants, glidants, surfactants, wetting agents, release rate modifiers, sweeteners, taste masking agents, colorants, flavors, and combinations thereof.

[0064] In one embodiment, the pharmaceutical composition of the present disclosure further comprises one or more fillers and / or one or more binders and / or one or more disintegrants.

[0065] In one embodiment, the filler includes mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrolyzed starch hydrolysate (i.e., HSH). In another embodiment, the filler includes mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, and the like. In yet another embodiment, the filler includes D-mannitol, MCC101, or a combination thereof.

[0066] In one embodiment, the binder includes hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, carboxycellulose, polyvinyl alcohol, starch, sucrose, lactose, lactose monohydrate, maltitol, sorbitol, xylitol, poloxamer, gelatin, sugar, gum (xanthan gum, gum arabic, or acacia gum), calcium hydrogen phosphate, dicalcium phosphate, glycerides, tragacanth, alginate, etc. In another embodiment, the binder includes hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, or mixtures thereof. In some embodiments, the binder may include HPMC, HPC, PEG-4000, povidone K30, PVP-VA64, or a mixture thereof.

[0067] In one embodiment, the disintegrant includes, but is not limited to, croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, pregelatinized starch, sodium starch glycolate, starch, carboxymethylcellulose (sodium carboxymethylcellulose or calcium carboxymethylcellulose), carmellose sodium, potassium polaritrin, alginate, etc. In another embodiment, the disintegrant includes, but is not limited to, croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch, sodium starch glycolate, starch, carboxymethylcellulose, alginate, or mixtures thereof. In some embodiments, the disintegrant includes, but is not limited to, croscarmellose sodium, crospovidone, starch 1500, or mixtures thereof.

[0068] Suitable diluents include, but are not limited to, lactose, mannitol, maltitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium aluminometasilicate.

[0069] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, stearyl alcohol, glycerol monostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodium benzoate, and sodium lauryl sulfate.

[0070] Suitable surfactants include, but are not limited to, sodium lauryl sulfate, monooleic acid, monolauric acid, monopalmitic acid, monostearic acid, or other esters of polyoxyethylene sorbitan, sodium dioctyl succinate sulfonate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene lysine oil, polyoxyethylene fatty acid glycerides, poloxamer, or commercially available co-processed surfactants such as SEPITRAP® 80 and SEPITRAP® 4000.

[0071] Suitable sweeteners include, but are not limited to, sucralose, aspartame, neotame, and acesulfame K.

[0072] Suitable flow enhancers include, but are not limited to, silicon dioxide, stearic acid, magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, and starch.

[0073] The pharmaceutical composition comprises a solid dispersion in an amount of about 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 16% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, or 40% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 40% w / w. In another embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 30% w / w. In yet another embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 20% w / w.

[0074] In one embodiment, a pharmaceutical composition comprising a solid dispersion may further comprise one or more fillers. The pharmaceutical composition may contain fillers in amounts of about 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 88% by weight, 90% by weight, 92% by weight, or 95% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 40% w / w to about 95% w / w of fillers. In another embodiment, the pharmaceutical composition comprises about 50% w / w to about 95% w / w of fillers. In yet another embodiment, the pharmaceutical composition comprises about 50% w / w to about 92% w / w of fillers.

[0075] In one embodiment, a pharmaceutical composition comprising a solid dispersion and one or more fillers may further comprise one or more binders and / or disintegrants. The pharmaceutical composition may contain about 1% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, or 35% by weight of the binders and / or disintegrants, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 1% w / w to about 35% w / w of binders and / or disintegrants. In another embodiment, the pharmaceutical composition comprises about 1% w / w to about 10% w / w of binders and / or disintegrants. In yet another embodiment, the pharmaceutical composition comprises about 10% w / w to about 30% w / w of binders and / or disintegrants.

[0076] In one embodiment, a pharmaceutical composition comprising a solid dispersion may further comprise one or more fillers, binders, and disintegrants. The pharmaceutical composition may contain fillers, binders, and disintegrants in amounts of about 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 88% by weight, 90% by weight, 92% by weight, 95% by weight, or 98% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 50% w / w to about 98% w / w of fillers, binders, and disintegrants. In another embodiment, the pharmaceutical composition comprises about 70% w / w to about 95% w / w of fillers, binders, and disintegrants. In yet another embodiment, the pharmaceutical composition comprises about 80% w / w to about 92% w / w of fillers, binders, and disintegrants.

[0077] In one embodiment, the pharmaceutical composition comprises about 3% w / w to about 40% w / w of a solid dispersion and about 40% w / w to about 95% w / w of a filler. In another embodiment, the pharmaceutical composition comprises about 3% w / w to about 30% w / w of a solid dispersion and about 50% w / w to about 95% w / w of a filler. In yet another embodiment, the pharmaceutical composition comprises about 3% w / w to about 20% w / w of a solid dispersion and about 50% w / w to about 92% w / w of a filler.

[0078] In one embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 40% w / w, a filler of about 40% w / w to about 95% w / w, and a binder and / or disintegrant of about 1% w / w to about 35% w / w. In another embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 30% w / w, a filler of about 50% w / w to about 95% w / w, and a binder and / or disintegrant of about 1% w / w to about 30% w / w. In yet another embodiment, the pharmaceutical composition comprises a solid dispersion of about 3% w / w to about 20% w / w, a filler of about 50% w / w to about 92% w / w, and a binder and / or disintegrant of about 2% w / w to about 30% w / w.

[0079] In one embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of granules, orally disintegrating tablets (i.e., ODTs), suspensions, powders, solutions, granules or powders for reconstitution as a suspension or solution, syrups, elixirs, dispersible / effervescent tablets, chewable tablets, lozenges, oral thin strips, sachets, pellets, pills, capsules, sprinkle oral powder, and inhaler forms.

[0080] In one embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration by pediatric patients.

[0081] The pharmaceutical compositions provided herein can be further film-coated. The film coating comprises a film-forming polymer and one or more coating additives. Suitable film-forming polymers include cellulose derivatives (e.g., methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and ethylcellulose), vinyl polymers, acrylic polymers, or combinations thereof.

[0082] This disclosure may be further understood by the following non-limiting embodiments. (Example 1)

[0083] Preparation of compound A ([1-((11S)-7,8-difluoro(6H,11H-dibenzo[c,f]thiepin-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyridino[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methylmethoxyformate)

[0084] Compound A was prepared by Hsu et al. using the synthetic route and protocol reported in WO2019 / 144089. The mass spectrum (MS) and nuclear magnetic resonance (NMR) of compound A are shown below. MS:m / z 541.0(M + +1); 1 H NMR(CDCl3)δ7.31(d,1H), 7.06-7.00(m,4H),6.85-6.84(m,1H),6.73(d,1H),6.03(d,1H),5.96 (d,1H),5.80(d,1H),5.49(d,1H),5.15(s,1H),4.13(d,1H),4.05(d,1H),3.87(s,3H),2.91 (d,1H),1.95-1.90(m,1H),1.49-1.48(m,1H),0.88-0.76(m,2H) Furthermore, 1'-((11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione, a metabolite of compound A, was also prepared using a similar synthetic route and protocol. The mass spectra (MS) and nuclear magnetic resonance (NMR) of the metabolites of compound A are shown below. MS:m / z 453.1(M+H) + ; 1 H NMR(CDCl3)δ7.27(d,1H),7.08-7.00(m,4H),6.80-6.78(m,1H),6.63(d,1 H),5.83(d,1H),5.50(dd,1H),5.23(s,1H),4.15(d,1H),4.06(d,1H),2.91 (d,1H),2.43(br,1H),1.92-1.84(m,1H),1.78-1.67(m,1H),0.96-0.92(m,1H),0.86-0.81(m, 1H) (Example 2)

[0085] Preparation of amorphous solid dispersions

[0086] The amorphous solid dispersions of this disclosure were prepared by spray drying methods well known in the art. See, for example, Singh et al., Advanced Drug Delivery Reviews, 2016, 100, 27-50. Different pharmaceutically acceptable polymers, e.g., PVP-VA64, Soluplus, HPMCAS-MG, Eudragit EPO, HPC-SSL, HPMCP HP-55, Kollidon SR, and PEG3350, were used to prepare the amorphous solid dispersions. A 4M8-Trix spray dryer was used for the preparation of the amorphous solid dispersions. The spray drying concentration of compound A was set to 25 mg / mL. Compound A was mixed with different pharmaceutically acceptable polymers in various ratios and dissolved in a solvent such as acetone in a glass bottle to prepare a feed solution. The resulting feed solution was delivered as a fine spray through a nozzle into a chamber, where the solvent was rapidly evaporated to produce particles containing compound A and the corresponding polymer. The resulting spray-dried powder was further dried in a static dryer to remove any residual solvent. (Example 3)

[0087] Solubility evaluation

[0088] A predetermined amount of compound A (approximately 6 mg) and an amorphous solid dispersion (corresponding to approximately 6 mg of compound A) were weighed into an 8 mL bottle, and 6 mL of FaSSIF (fasted state simulated intestinal fluid) was added (target concentration 1.0 mg / mL). Next, the suspension was stirred with a thermomixer at 37°C and 600 rpm, and 200 μL of the suspension was aspirated after a set time (e.g., 5 minutes). Then, centrifugation was performed at 14000 rpm for 4 minutes. Subsequently, to prevent precipitation, 100 μL of the supernatant was diluted 5-fold with 500 μL of CAN and analyzed by HPLC. The water solubility of compound A was low.

[0089] FaSSIF was manufactured using the following process. 1) In a 250 mL volumetric flask, 0.1024 g of sodium hydroxide, 0.7518 g of anhydrous sodium dihydrogen phosphate, and 1.5470 g of sodium chloride were added, and approximately 225 mL of water was added. The pH was adjusted to 6.5 using 1 N sodium hydroxide or 1 N hydrochloric acid. Pure water was then added to a volume of 250 mL. 2) In a 200 mL volumetric flask, 0.4480 g of SIF Powder Original was added and dissolved in 100 mL of buffer solution (from step 1), water was added to the volumetric flask, and the mixture was thoroughly mixed.

[0090] Table 1 shows the solubility of compound A and the amorphous solid dispersion in FaSSIF, collected manually at 5 and 15 minutes.

[0091] [Table 1] (Example 4)

[0092] Stability investigation of compound A and amorphous solid dispersion

[0093] Amorphous solid dispersions were stored at 4°C (sealed) or 40°C / 75%RH (sealed and open). After 10 days or 4 weeks, samples were observed with a camera, characterized by XPRD, and analyzed by HPLC for purity and dynamic solubility. All samples stored under sealed conditions were placed in clear glass vials with gaskets and screw-on caps. All samples stored under open conditions were placed in clear glass vials with caps, and the vial openings were covered with pinhole aluminum foil to prevent cross-contamination.

[0094] Table 2 shows the total impurity levels (i.e., TRS%) of compound A and ASD after stability testing. The sample numbers in Table 2 correspond to the sample numbers in Table 1.

[0095] [Table 2] (Example 5)

[0096] Formulation and preparation

[0097] Formulations containing a solid dispersion of compound A are shown in Tables 3 and 4. An amorphous solid dispersion (i.e., ASD) containing compound A is disclosed in Example 2. A granular formulation was prepared using a roller compactor. The ASD and an equal amount of mannitol were mixed manually for 2 minutes, then the mannitol was added to the bag of ASD and shaken for 2 minutes to remove any remaining ASD. Other excipients were then added by increasing the amount in equal increments. Finally, the mixture was mixed using a Shaker Mixer TURBULA for 46 minutes. rpm / min Mix for 10 minutes.

[0098] [Table 3]

[0099] Figure 1 shows the dissolution profiles of the granular formulation and the ASD powder itself. The tested granular formulation achieved approximately 80% dissolution within 15 minutes.

[0100] [Table 4]

[0101] Figure 2 shows the dissolution profiles of the D9 formulation and the ASD powder itself. The tested formulation achieved approximately 80% dissolution within 15 minutes. (Other embodiments)

[0102] All features disclosed herein can be combined in any combination. Each feature disclosed herein can be replaced by an alternative feature that serves the same, equivalent, or similar purpose. Thus, unless otherwise specified, each disclosed feature is merely an example of a series of equivalent or similar features.

[0103] From the above description, those skilled in the art can easily grasp the essential features of this disclosure without departing from the scope of the present invention, and can adapt this disclosure to various uses and conditions by making various changes and modifications. Accordingly, other embodiments are also within the scope of the following claims. <Note> Item 1 A pharmaceutical composition comprising a solid dispersion, The solid dispersion i) Compounds of formula (II) or pharmaceutically acceptable salts thereof [ka] (In the formula, G is hydrogen or -C(R) 2 R 2 ')-O-CO-OR 3 And R 2 and R 2 ' are each independently of hydrogen or C 1-4 It is an alkyl group, R 3 C 1-4 It is an alkyl group, and the asterisk symbol (*) indicates a chiral center. ii) Pharmaceutically acceptable polymers and Includes, The weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is approximately 1:1 to approximately 1:5. A pharmaceutical composition comprising the compound of formula (II) or a pharmaceutically acceptable salt thereof in a therapeutically effective dose of approximately 5 mg to approximately 200 mg. Section 2 The compound of formula (II) is [1-((11S)-7,8-difluoro(6H,11H-dibenzo[c,f]thiepin-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyridino[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methylmethoxyformate, or 1'-((11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione, The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable polymer is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof. Section 3 The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable polymer is Soluplus, HPC-SSL, HPMCAS-MG, HPMCAS-HG, or a mixture thereof. Section 4 The pharmaceutical composition according to item 1, wherein the weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is about 1:1 to about 1:3. Section 5 The pharmaceutical composition according to item 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective dose of about 5 mg to about 100 mg. Section 6 The pharmaceutical composition according to item 1, wherein the solid dispersion is present at a concentration of approximately 3% w / w to approximately 40% w / w. Section 7 The solid dispersion has a particle size of approximately 4 μm to approximately 15 μm. 50 Particle size, or D in the range of approximately 15 μm to approximately 50 μm 90 A pharmaceutical composition according to item 1, having particle size. Section 8 The pharmaceutical composition according to item 1, further comprising one or more fillers. Section 9 The pharmaceutical composition according to item 8, further comprising one or more binders and / or disintegrants. Section 10 The filler is selected from the group consisting of mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mantitol, lactitol, xylitol, isomalt, erythritol, hydrolyzed starch, and combinations thereof. The binder is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, and combinations thereof. The pharmaceutical composition according to claim 9, wherein the disintegrant is selected from the group consisting of croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch, sodium starch glycolate, starch, carboxymethylcellulose, alginic acid, and combinations thereof. Section 11 The filler is selected from the group consisting of D-mannitol, MCC101, and combinations thereof. The binder is selected from the group consisting of HPMC, HPC, PEG-4000, povidone K30, PVP-VA64, and combinations thereof. The pharmaceutical composition according to claim 10, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, starch 1500, and combinations thereof. Section 12 The aforementioned solid dispersion is present at a concentration of approximately 3% w / w to approximately 40% w / w. The pharmaceutical composition according to item 8, wherein the filler is present at a concentration of approximately 40% w / w to approximately 95% w / w. Section 13 The aforementioned solid dispersion is present at a concentration of approximately 3% w / w to approximately 40% w / w. The aforementioned filler is present at a concentration of approximately 40% w / w to approximately 95% w / w. The pharmaceutical composition according to item 9, wherein the binder and / or disintegrant is present in a concentration of about 1% w / w to about 35% w / w. Item 14 The pharmaceutical composition according to claim 9, further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, lubricants, flow promoters, surfactants, wetting agents, release rate modifiers, sweeteners, taste masking agents, colorants, and flavors. Section 15 The pharmaceutical composition according to item 1, wherein the dosage form is selected from the group consisting of granules, orally disintegrating tablets (ODTs), suspensions, powders, solutions, granules or powders for reconstitution as a suspension or solution, syrups, elixirs, dispersible / effervescent tablets, chewable tablets, lozenges, oral flakes, sachets, pellets, pills, capsules, sprinkle oral powders, and inhalants.

Claims

1. A pharmaceutical composition comprising a solid dispersion, The solid dispersion i) Compounds of formula (II) or pharmaceutically acceptable salts thereof 【Chemistry 1】 (In the formula, G is hydrogen or -C(R) ２ R ２ ')-O-CO-O-R ３ And R ２ and R ２ ' are each independently of hydrogen or C １－４ It is an alkyl group, R ３ C １－４ It is an alkyl group, and the asterisk symbol (*) indicates a chiral center. ii) Pharmaceutically acceptable polymers and Includes, The weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is 1:1 to 1:

5. The compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective dose of 5 mg to 200 mg. A pharmaceutical composition in which the pharmaceutically acceptable polymer is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof.

2. The pharmaceutical composition according to claim 1, wherein the compound of formula (II) is [1-((11S)-7,8-difluoro(6H,11H-dibenzo[c,f]thiepin-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyridino[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methylmethoxyformate, or 1'-((11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl-1',2'-dihydro-5'-hydroxyspiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable polymer is a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer, HPC-SSL, HPMCAS-MG, HPMCAS-HG, or a mixture thereof.

4. The pharmaceutical composition according to claim 1, wherein the weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is 1:1 to 1:

3.

5. The pharmaceutical composition according to claim 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount of 5 mg to 100 mg.

6. The pharmaceutical composition according to claim 1, wherein the solid dispersion is present at a concentration of 3% w / w to 40% w / w.

7. The solid dispersion has a D in the range of 4 μm to 15 μm ５０ particle size, or a D in the range of 15 μm to 50 μm ９０ particle size, and the pharmaceutical composition according to claim 1

8. The pharmaceutical composition according to claim 1, further comprising one or more fillers.

9. The pharmaceutical composition according to claim 8, further comprising one or more binders and / or disintegrants.

10. The filler is selected from the group consisting of mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mantitol, lactitol, xylitol, isomalt, erythritol, hydrolyzed starch, and combinations thereof. The binder is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, and combinations thereof. The pharmaceutical composition according to claim 9, wherein the disintegrant is selected from the group consisting of croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch, sodium starch glycolate, starch, carboxymethylcellulose, alginic acid, and combinations thereof.

11. The filler is selected from the group consisting of D-mannitol, MCC101, and combinations thereof. The binder is selected from the group consisting of HPMC, HPC, PEG-4000, povidone K30, PVP-VA64, and combinations thereof. The pharmaceutical composition according to claim 10, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, starch 1500, and combinations thereof.

12. The solid dispersion is present at a concentration of 3% w / w to 40% w / w. The pharmaceutical composition according to claim 8, wherein the filler is present in a concentration of 40% w / w to 95% w / w.

13. The solid dispersion is present at a concentration of 3% w / w to 40% w / w. The aforementioned filler is present at a concentration of 40% w / w to 95% w / w. The pharmaceutical composition according to claim 9, wherein the binder and / or disintegrant is present in a concentration of 1% w / w to 35% w / w.

14. The pharmaceutical composition according to claim 9, further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, lubricants, flow promoters, surfactants, wetting agents, release rate modifiers, sweeteners, taste masking agents, colorants, and flavors.

15. The pharmaceutical composition according to claim 1, wherein the dosage form is selected from the group consisting of granules, orally disintegrating tablets (ODTs), suspensions, powders, solutions, granules or powders for reconstitution as a suspension or solution, syrups, elixirs, dispersible / effervescent tablets, chewable tablets, lozenges, oral flakes, sachets, pellets, pills, capsules, sprinkle oral powders, and inhalants.

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