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 to Related Applications) This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 355,742, filed on June 27, 2022, under 35 U.S.C. § 119(e), the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to a pharmaceutical composition containing a heterocyclic compound or a pharmaceutically acceptable salt thereof.

Background Art

[0003] Cap - dependent endonuclease is an enzyme essential for the inhibition of influenza virus mRNA synthesis. Inhibitors of cap - dependent endonuclease are known to be effective against influenza A virus and influenza B virus. Some compounds exhibit potent antiviral activity against influenza virus by inhibiting cap - dependent endonuclease. In PCT Published Application WO2019 / 144089, novel heterocyclic compounds were first disclosed as potent cap - dependent endonuclease inhibitors. Effective therapeutic intervention often depends on the ability to deliver pharmaceutical compounds in a comfortable and patient - friendly manner. Oral administration is a preferred route of administration in terms of its non - invasiveness, ease of administration, and patient compliance. The above - mentioned novel anti - influenza heterocyclic compounds have shown considerable promise in pre - clinical trials. However, there are several issues with their oral administration, including low solubility and low stability. Therefore, the development of an optimal pharmaceutical formulation is extremely important to ensure the therapeutic effect of the compound. The formulations of the present disclosure aim to improve solubility, enhance patient compliance, and maximize the therapeutic utility across different age groups.

Summary of the Invention

[0004] The present 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 from about 1:1 to about 1:5. The compound of formula (II) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount of about 5 mg to about 200 mg. In the compound of formula (II), G is hydrogen or -C(R2R 2’ )-O-CO-O-R3, where R2 and R 2’ are each independently hydrogen or C 1-4 alkyl, and R3 is C 1-4 alkyl, and the asterisk (*) indicates a chiral center. [Chemical Formula]

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

[0006] The present disclosure also provides a method for treating influenza, comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof. The present disclosure also provides a pharmaceutical composition for use in the treatment of influenza. Further, the present disclosure provides the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of influenza. [Brief Description of the Drawings]

[0007] The present disclosure can be better understood by reading the following description of embodiments with reference to the accompanying drawings.

Figure 1

Figure 2

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

[0009] Generally, the nomenclature used in this specification, as well as the experimental procedures in organic chemistry, pharmaceutical chemistry, and pharmacology, are known and commonly employed 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 from 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 that are suitable for contact with human and animal tissues within the scope of sound medical judgment, and that are free of excessive toxicity, irritation, allergic reaction or other problem complications, and that exhibit a reasonable risk-to-benefit ratio.

[0015] The term "one or more" refers to any number of one or more (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] alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl groups, etc. 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] alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy groups. 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 containing aromatic carbocyclic groups and / or non-aromatic carbocyclic groups. 10refers to an annular hydrocarbon group.

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

[0021] The term "non-aromatic carbocyclic group" refers to a cyclic hydrocarbon group that is completely 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 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 addition salts and base addition salts, or the compounds referred to by that term. Pharmaceutically acceptable salts include those derived from organic acids 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). The term "solid dispersion" generally means a solid-state system containing at least two components, in which one component is substantially uniformly dispersed throughout the other component. For example, a solid dispersion may be a dispersion of one or more active ingredients in an inert carrier or matrix in a solid state, prepared by spray drying, hot melt extrusion, fluid bed or freeze drying methods. The formation of a molecular dispersion can provide a means to reduce the particle size to approximately the molecular level.

[0027] As used herein, polyvinylpyrrolidone (also referred to as PVP) refers to a polymeric compound 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, PVP-K120, etc.

[0028] As used herein, polyvinylpyrrolidone-vinyl acetate (also referred to as PVP-VA) refers to a copolymer of the monomers vinylpyrrolidone (VP) and vinyl acetate (VA). Examples of copolymers of polyvinylpyrrolidone-vinyl acetate include, but are not limited to, PVP-VA64, Kollidon SR, etc.

[0029] As used herein, the copolymer of methacrylic acid-methyl methacrylate refers to a copolymer derived from esters of acrylic acid and methacrylic acid. Eudragit is the trade name for various copolymers of methacrylic acid-methyl methacrylate. Examples of the copolymer of methacrylic acid-methyl methacrylate include, but are not limited to, Eudragit EPO, Eudragit E100, Eudragit RS100, Eudragit RL100, Eudragit L100, Eudragit NE, Eudragit NM, Eudragit FS, etc.

[0030] As used herein, polyethylene glycol (also referred to 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, PEG-8000, etc.

[0031] As used herein, the copolymer of polyoxyethylene-polyoxypropylene refers to a block copolymer, wherein one block is polyoxyethylene and the other block is polyoxypropylene. Examples of the copolymer of polyoxyethylene-polyoxypropylene include the Pluronic® series of surfactants (commercially available from BASF). For example, the Pluronic® series of surfactants can be designated by their CTFA names as 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 thereto.

[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, etc., depending on its 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, E50Lv, etc., depending on its viscosity.

[0034] In this specification, hydroxypropyl methylcellulose acetate succinate (also referred to as HPMCAS) refers to a mixture of acetic acid and monosuccinic acid esters of hydroxypropyl methylcellulose. 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 distinct X-ray diffraction pattern.

[0037] The term "therapeutically effective amount" refers to the amount or dosage of an active compound or its salt that is sufficient to prevent the onset of one or more symptoms of a disorder, disease or condition to be treated, or to alleviate it to some extent. Compound A (5 mg / kg, for oral use) of the present disclosure was tested in vivo in a mouse (BALB / c) model infected with influenza virus (A / PR / 8 / 34), and showed good antiviral effects on survival rate and body weight change. Also, on the first day after infection, the effect of Compound A on the growth of influenza virus was verified in the lungs of BALB / c mice infected with a low infection dosage of A / PR / 8 / 34 at 100 pfu / mouse. The Compound A treatment groups (5 mg / kg, 25 mg / kg) had significantly lower virus titers than the vehicle treatment group. In a 14-day repeated oral administration toxicity test, when the dosage of Compound A was set at 300 mg / kg / day, Compound A did not cause death or bring about toxic effects. Therefore, based on the results of these preliminary in vivo animal tests, the appropriate therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt for humans is presumed to be about 5 - 200 mg, about 5 - 150 mg, about 5 - 100 mg, about 10 - 80 mg, about 10 - 40 mg, about 10 - 30 mg, about 10 - 20 mg, about 5 - 10 mg, about 5 - 20 mg, about 20 - 40 mg, or about 40 - 80 mg. For example, the therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt is 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 thereto.

[0038] The invention provided by the present disclosure relates to a pharmaceutical composition containing a solid dispersion, and the solid dispersion is i) a compound of formula (I) or its pharmaceutically acceptable salt [Chemical formula] (wherein G is hydrogen, a prodrug group or a suitable substituent, R1 is halogen, C 1-4 alkyl group or deuterium, m is an integer from 1 to 9, and the asterisk (*) indicates a chiral center.) and ii) a pharmaceutically acceptable polymer and comprising the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from about 1:1 to about 1:5, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount of 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 halogen and m is an integer from 1 to 3. In another embodiment, R1 is fluoro and m is an integer of 1 or 2.

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

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

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

Chemical formula

[0043] In one embodiment, G is selected from the group consisting of 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’ )-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-O-P(=O)(R5R6) and -P(=O)(R5R6), wherein R2, R 2’ and R4 are each independently hydrogen or a C 1-8 alkyl group, R3 is a C 1-4 alkyl group, a C 3-10 carbocyclic group or a C 3-10 heterocyclic group, R5 is OH, NH2, a C 1-4 alkyl group or a C 1-4 alkoxy group, and R6 is OH, a C 1-4 alkoxy group or a C 1-4 alkylamino group. In another embodiment, G is hydrogen or -C(R2R 2’ )-O-CO-O-R3. In one embodiment, R2 and R 2’ are each independently hydrogen or a C 1-8 alkyl group. In another embodiment, R2 and R 2’is independently hydrogen or a C 1-4 alkyl group.

[0044] In one embodiment, the G group is hydrogen,

Chemical formula

[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]methyl methoxyformate, or a metabolite thereof, 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 the present disclosure can be prepared by the methods / procedures disclosed in PCT Publication WO2019 / 144089 or WO2021 / 239126, which are hereby incorporated 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 comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer is disclosed, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is molecularly dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer in the solid state.

[0049] The pharmaceutically acceptable polymers used in the amorphous solid dispersions of the present disclosure are water-soluble polymers. Suitable water-soluble polymers need to act as water-soluble carriers for improving the solubility of the active ingredient by making it hydrophilic, and it also contributes to maintaining the amorphous state of the solid dispersion.General 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, polyvinylcaprolactam and polyvinyl acetate, polyvinyl acetate phthalate (PVAP), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), acrylate and methacrylate copolymers, methacrylic acid-methyl methacrylate copolymer (such as Eudragit), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene copolymer (also called poloxamer), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), carboxymethylcellulose acetate butyrate (CMCAB), carboxymethylcellulose calcium (CMC calcium), carboxymethylcellulose sodium (CMC sodium), β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, docusate sodium, cellacefate, etc., but are not limited thereto.

[0050] In one embodiment, the pharmaceutically acceptable polymer is a copolymer of polyvinylpyrrolidone-vinyl acetate (PVP-VA), a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), a copolymer of methacrylic acid-methyl methacrylate (such as Eudragit), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), or a mixture thereof.

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

[0052] In one embodiment, the pharmaceutically acceptable polymer is Soluplus, HPC-SSL, HPMCAS, or a mixture thereof.

[0053] In one embodiment, an amorphous solid dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer is disclosed, 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 from about 1:1 to about 1:5. In another embodiment, the weight ratio is from about 1:1 to about 1:3.5. In yet another embodiment, the weight ratio is from about 1:1 to about 1:3. In other embodiments, the weight ratio is about 1:3.

[0054] In one embodiment, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion is usually 10 to 60% by weight, 10 to 55% by weight, 10 to 50% by weight, 10 to 45% by weight, 10 to 40% by weight, 15 to 60% by weight, 15 to 55% by weight, 15 to 50% by weight, 15 to 45% by weight, or 15 to 40% by weight. For example, the amount (drug loading) of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion 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 has a D 50 particle size in the range of about 4 μm to about 15 μm, or a D 90 particle size in the range of about 15 μm to about 50 μm.

[0056] The solid dispersion described herein can be orally administered to a subject (e.g., a human) in need thereof to treat or prevent an infectious disease such as influenza.

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

[0058] In one embodiment, to prepare a spray solution, the amorphous solid dispersion of the present disclosure is dissolved in a sufficient amount of an organic solvent with a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the resulting solution is mixed with a solution containing a pharmaceutically acceptable polymer. Then, the solvent can 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 the amorphous solid dispersion includes step (i) of dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer in a solvent, and step (ii) of 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 an organic solvent, dissolving a pharmaceutically acceptable polymer in a solvent, and mixing these two solutions.

[0061] In one embodiment, step (ii) includes spray drying. In another embodiment, step (ii) includes combining spray drying and 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 by the spray drying method. The term "spray drying" has been conventionally used and broadly refers to a process of rapidly removing the solvent from a liquid mixture by dispersing (atomizing) the liquid mixture into fine droplets and providing a strong driving force for evaporating the solvent from the droplets in a spray drying device (e.g., a nozzle). In a typical spray drying process, the feed liquid can be transported by a pump and can be a solution, slurry, emulsion, gel, or paste as long as it can be atomized.

[0063] In one embodiment, the pharmaceutical composition includes the solid dispersion of the present disclosure and further includes 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 includes one or more fillers, and / or one or more binders, and / or one or more disintegrants.

[0065] In one embodiment, the fillers include mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysate (i.e., HSH). In another embodiment, the fillers include mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, etc. In another embodiment, the fillers include D-mannitol, MCC101, or a combination thereof.

[0066] In one embodiment, binders include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, carboxymethylcellulose, 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, glyceride, tragacanth, alginate, etc. In another embodiment, binders include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, or a mixture thereof. In some embodiments, binders include HPMC, HPC, PEG-4000, povidone K30, PVP-VA64, or a mixture thereof.

[0067] In one embodiment, disintegrants include, but are not limited to, croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl starch, pregelatinized starch, sodium starch glycolate, starch, carboxymethyl cellulose (sodium carboxymethyl cellulose or calcium carboxymethyl cellulose), sodium carmellose, potassium polyacrylate, alginate, etc. In another embodiment, disintegrants include, but are not limited to, croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethyl starch, sodium starch glycolate, starch, carboxymethyl cellulose, alginate, or mixtures thereof. In some embodiments, disintegrants include, but are not limited to, sodium croscarmellose, crospovidone, starch 1500, or mixtures thereof.

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

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

[0070] Suitable surfactants include, but are not limited to, sodium lauryl sulfate, monooleic acid, monolauric acid, monopalmitic acid, monostearic acid, or another ester of polyoxyethylene sorbitan, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene lysine oil, polyoxyethylene fatty acid glyceride, 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, acesulfame K, and the like.

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

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

[0074] In one embodiment, a pharmaceutical composition comprising a solid dispersion can further comprise one or more fillers. The pharmaceutical composition can comprise about 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 88 wt%, 90 wt%, 92 wt% or 95 wt% filler 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 filler. In another embodiment, the pharmaceutical composition comprises about 50% w / w to about 95% w / w filler. In other embodiments, the pharmaceutical composition comprises about 50% w / w to about 92% w / w filler.

[0075] In one embodiment, a pharmaceutical composition comprising a solid dispersion and one or more fillers can further comprise one or more binders and / or disintegrants. The pharmaceutical composition can comprise about 1 wt%, 2 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt% or 35 wt% binder and / or disintegrant 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 binder and / or disintegrant. In another embodiment, the pharmaceutical composition comprises about 1% w / w to about 10% w / w binder and / or disintegrant. In other embodiments, the pharmaceutical composition comprises about 10% w / w to about 30% w / w binder and / or disintegrant.

[0076] In one embodiment, a pharmaceutical composition comprising a solid dispersion can further comprise one or more fillers, binders, and disintegrants. The pharmaceutical composition can comprise about 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 88 wt%, 90 wt%, 92 wt%, 95 wt% or 98 wt% of fillers, binders, and disintegrants, 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 other embodiments, 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 the solid dispersion and about 40% w / w to about 95% w / w of the filler. In another embodiment, the pharmaceutical composition comprises about 3% w / w to about 30% w / w of the solid dispersion and about 50% w / w to about 95% w / w of the filler. In other embodiments, the pharmaceutical composition comprises about 3% w / w to about 20% w / w of the solid dispersion and about 50% w / w to about 92% w / w of the filler.

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

[0079] In one embodiment, the pharmaceutical composition is in a dosage form selected from the group consisting of granules, oral 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, troches, oral thin strips, sachets, pellets, pills, capsules, sprinkle oral powders, 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 further be film-coated. The film coating includes 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] The present disclosure can be further understood by the following non-limiting examples. (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]methyl methoxyformate)

[0084] Compound A was prepared according to the synthetic routes and protocols reported by Hsu et al. 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 1H NMR (CDCl3) δ 7.31 (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], which is a metabolite of Compound A, was also prepared according to the same synthetic routes and protocols. The mass spectrum (MS) and nuclear magnetic resonance (NMR) of the metabolite of Compound A are shown below. MS: m / z 453.1 (M + H) + ; 1 1H NMR (CDCl3) δ 7.27 (d, 1H), 7.08 - 7.00 (m, 4H), 6.80 - 6.78 (m, 1H), 6.63 (d, 1H), 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 dispersion

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

[0087] Solubility evaluation

[0088] A predetermined amount of Compound A (about 6 mg) and an amorphous solid dispersion (equivalent to about 6 mg of Compound A) were weighed into an 8 mL vial, and 6 mL of FaSSIF (fasted state simulated intestinal fluid) was added (target concentration 1.0 mg / mL). Next, the suspension was stirred at 37 °C and 600 rpm with a thermomixer, 200 μL of the suspension was aspirated at a set time (for example, 5 minutes), and then centrifuged at 14000 rpm for 4 minutes. Then, to prevent precipitation, 100 μL of the supernatant was diluted 5-fold with 500 μL of CAN and analyzed by HPLC. The aqueous solubility of Compound A was low.

[0089] FaSSIF was prepared by the following procedure. 1) In a 250 mL volumetric flask, add 0.1024 g of sodium hydroxide, 0.7518 g of sodium dihydrogen phosphate anhydrous, and 1.5470 g of sodium chloride. Add approximately 225 mL of water and adjust the pH to 6.5 using 1 N sodium hydroxide or 1 N hydrochloric acid. Add pure water to make up to 250 mL in volume. 2) In a 200 mL volumetric flask, add 0.4480 g of SIF Powder Original and dissolve it in 100 mL of buffer solution (from Step 1). Add water to make up to the volume and mix well.

[0090] The solubilities of Compound A and the amorphous solid dispersion in FaSSIF manually collected at the 5-minute and 15-minute time points are shown in Table 1.

[0091]

Table 1

[0092] Investigation of the stability of Compound A and the amorphous solid dispersion

[0093] The amorphous solid dispersion was stored at 4 °C (sealed) or 40 °C / 75% RH (sealed and open states). After 10 days or 4 weeks, the samples were observed by camera, characterized by XPRD, and analyzed by HPLC for purity and dynamic solubility. All samples under sealed storage conditions were placed in transparent glass vials with gaskets and screw caps. All samples under open storage conditions were placed in transparent glass vials with caps, and the mouths of the vials were covered with aluminum foil with pinholes to prevent cross-contamination.

[0094] The total impurity levels (i.e., TRS%, total relative substances%) of Compound A and ASD after the stability test are shown in Table 2. The sample numbers in Table 2 correspond to the sample numbers in Table 1.

[0095]

Table 2

[0096] Formulations and Preparations

[0097] The formulations containing the solid dispersion of Compound A were as shown in Tables 3 and 4. The amorphous solid dispersion (i.e., ASD) containing Compound A was disclosed in Example 2. Granular formulations were prepared using a roller compactor. The ASD and the same amount of mannitol were manually mixed for 2 minutes, and then the mannitol was added to the bag of ASD and shaken for 2 minutes to remove the residual ASD. Next, other excipients were added by the method of increasing the amount in equal portions. Finally, the mixture was mixed for 10 minutes at 46 rpm / minute with a Shaker Mixer TURBULA.

[0098] [Table 3]

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

[0100] [Table 4]

[0101] The dissolution profiles of Formulation D9 and the ASD powder itself are shown in Figure 2. The tested formulations achieved approximately 80% dissolution within 15 minutes. (Other Embodiments)

[0102] All features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification can be replaced by alternative features that serve 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 the present disclosure without departing from the scope of the present invention, and can also make various changes and modifications to the present disclosure to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the following claims.

Claims

Claim 1 A pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises i) a compound of formula (II) or a pharmaceutically acceptable salt thereof 【Chemical 1】 (wherein G is hydrogen or -C(R ２ R ２ ’) -O-CO-O-R ３ ; R ２ and R ２ ’ are each independently hydrogen or a C １－４ alkyl group; R ３ is a C １－４ alkyl group; and the asterisk symbol (*) indicates a chiral center.), and ii) a pharmaceutically acceptable polymer, and wherein the weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from about 1:1 to about 1:5, and the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount of about 5 mg to about 200 mg, a pharmaceutical composition. Claim 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]methyl methoxyformate, 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, and the pharmaceutically acceptable polymer is a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (Solupres), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof, the pharmaceutical composition according to claim 1. Claim 3 The pharmaceutically acceptable polymer is Solupres, HPC-SSL, HPMCAS-MG, HPMCAS-HG, or a mixture thereof, the pharmaceutical composition according to claim 2. Claim 4 The weight ratio of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from about 1:1 to about 1:3, the pharmaceutical composition according to claim 1. Claim 5 The compound of formula (II) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount of about 5 mg to about 100 mg, the pharmaceutical composition according to claim 1. Claim 6 The solid dispersion is present at a concentration of from about 3% w / w to about 40% w / w, the pharmaceutical composition according to claim 1. Claim 7 The solid dispersion has a D in the range of about 4 μm to about 15 μm ５０ particle size, or a D in the range of about 15 μm to about 50 μm ９０ particle size, and the pharmaceutical composition according to claim 1. Claim 8 The pharmaceutical composition according to claim 1, further comprising one or more fillers. Claim 9 The pharmaceutical composition according to claim 8, further comprising one or more binders and / or disintegrants. Claim 10 The filler is selected from the group consisting of mannitol, microcrystalline cellulose, lactose, maltitol, dicalcium phosphate, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mannitol, lactitol, xylitol, isomalt, erythritol, hydrogenated starch hydrolysate, and combinations thereof, The binder is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), a copolymer of polyvinylpyrrolidone-vinyl acetate (PVP-VA), povidone, polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC), methylcellulose, and combinations thereof, The disintegrant is selected from the group consisting of croscarmellose, crospovidone, copovidone, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethyl starch, sodium starch glycolate, starch, carboxymethyl cellulose, alginic acid, and combinations thereof, the pharmaceutical composition according to claim 9.

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 disintegrant is selected from the group consisting of sodium croscarmellose, crospovidone, starch 1500, and combinations thereof, the pharmaceutical composition according to claim 10.

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

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

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 regulators, sweeteners, taste masking agents, colorants, and flavors.

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

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