Pharmaceutical composition comprising cap-dependent endonuclease inhibitor

Abstract

A pharmaceutical composition for oral administration is provided comprising a solid dispersion comprising a cap-dependent endonuclease inhibitor or a pharmaceutically acceptable salt thereof.

Description

[0001] Citation of Related Applications

[0002] This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 355,742, filed on June 27, 2022, under 35 U.S.C. 119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to a pharmaceutical composition comprising a heterocyclic compound or a pharmaceutically acceptable salt thereof. Background Art

[0004] Cap-dependent endonucleases are essential enzymes for the synthesis of influenza virus mRNA. Cap-dependent endonucleases inhibitors have been found to be effective against influenza A and B viruses. Several compounds have been found to effectively exhibit antiviral activity against influenza viruses by inhibiting the activity of cap-dependent endonucleases. PCT Publication Application No. WO2019 / 144089 discloses for the first time a novel heterocyclic compound that can effectively inhibit the activity of cap-dependent endonucleases. Effective therapeutic interventions usually rely on the ability to administer drug compounds in a convenient and patient-friendly manner. Oral administration is the preferred route for drug administration because it is non-invasive, easy to use, and patient-compliant. The aforementioned novel anti-influenza heterocyclic compounds have shown considerable potency in preclinical studies. However, there are some challenges to their oral administration, including low solubility and poor stability. Therefore, the development of suitable drug formulations is important to ensure the therapeutic effect of the compound. The formulations herein can improve solubility to enhance patient compliance and maximize therapeutic benefits in different age groups. Summary of the invention

[0005] The present disclosure provides a pharmaceutical composition comprising a solid dispersion, wherein 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; 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. In the compound of formula (II), G represents hydrogen or -C(R2R2')-O-CO-O-R3, wherein each R2 and R2' are independently hydrogen or C 1-4 Alkyl; R3 is C 1-4 Alkyl; the asterisk "*" represents a chiral center,

[0006]

[0007] In another aspect, provided herein is a method for preparing a pharmaceutical composition comprising a solid dispersion of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0008] Also provided herein is a method for treating influenza, comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and providing a pharmaceutical composition for treating influenza. In addition, also provided herein is the use of the pharmaceutical composition in the preparation of a medicament for treating influenza.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present disclosure may be more fully understood by reading the following description of the embodiments with reference to the accompanying drawings.

[0011] Figure 1 are the dissolution profiles of the granular formulation and ASD powder itself.

[0012] Figure 2 These are the dissolution profiles of the orally disintegrating dosage form and the ASD powder itself. DETAILED DESCRIPTION

[0013] To facilitate understanding of the inventive content described herein, a number of terms are defined below.

[0014] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0015] The term "about" means within the acceptable error range of a particular value measured by a person of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. As used herein, when referring to measurable or calculated values ​​such as amounts, durations, concentrations, ratios, etc., variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% relative to a particular value may be included, and such variations are suitable for the disclosed methods.

[0016] The term "treat" is meant to include alleviating or eliminating a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition; or alleviating or eradicating the cause of the disorder, disease or symptom itself.

[0017] The term "prevent" or "preventing" is intended to include: delaying and / or excluding the onset of a disorder, disease or condition and / or its attendant symptoms; preventing a subject from developing a disorder, disease or condition; or methods of reducing a subject's risk of developing a disorder, disease or condition.

[0018] The term "patient", "individual" or "subject" refers to a human or 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.

[0019] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response or other problematic complications for contact with human and animal tissues, and are consistent with a reasonable benefit / risk ratio.

[0020] The term "one or more" refers to one or a number greater than one (eg, 2, 3, 4, 5, 6, 7 or more).

[0021] The term "C 1-4 "Alkyl" refers to a branched or straight chain saturated hydrocarbon group containing 1 to 4 carbon atoms. 1-4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like, but are not limited thereto.

[0022] The term "C 1-4 "Alkoxy" refers to a group -OR, where R is C 1-4 Alkyl. C 1-4 Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0023] The term "C 1-4 "Alkylamino" refers to a -NHR' group, where R' is C 1-4 Alkyl, C 1-4 Examples of the alkylamino group include a methylamino group, an ethylamino group, and an isopropylamino group, but are not limited thereto.

[0024] The term "carbocycle" refers to a C3 to C 10 Cyclic hydrocarbon groups include aromatic carbocyclic rings and non-aromatic carbocyclic rings.

[0025] The term "aromatic carbocycle" refers to a monocyclic or polycyclic aromatic cyclic hydrocarbon group having two or more rings, and examples of the aromatic carbocycle include benzene, naphthalene, anthracene, phenanthryl and the like, but are not limited thereto.

[0026] The term "non-aromatic carbocycle" refers to a cyclic hydrocarbon group that is fully saturated or contains one or more units of unsaturation but does not have aromatic character.

[0027] The term "heterocycle" refers to aromatic and non-aromatic heterocycles containing one or more heteroatoms independently selected from the group consisting of O, S, N, and any combination thereof.

[0028] The term "aromatic heterocycle" refers to an aromatic cyclic group containing one or more heteroatoms independently selected from the group consisting of O, S, N and any combination thereof, and may be a monocyclic ring or a polycyclic structure containing two or more rings.

[0029] The term "non-aromatic heterocycle" refers to a non-aromatic cyclic group containing one or more heteroatoms independently selected from the group consisting of O, S, N and any combination thereof, and may be a monocyclic ring or a polycyclic structure containing two or more rings.

[0030] The term "pharmaceutically acceptable salt" includes non-toxic acid and base addition salts or the compounds to which the term refers. Pharmaceutically acceptable salts include those derived from organic and inorganic acids or bases known in the art.

[0031] The term "solid dispersion" refers to a molecular dispersion of a compound, particularly a drug substance, in a pharmaceutically acceptable carrier (e.g., a polymer). A solid dispersion generally refers to a solid system comprising at least two components, one of which is substantially uniformly dispersed in the other components. For example, a solid dispersion may be a dispersion of one or more active ingredients in a solid inert carrier or matrix, which may be prepared by methods such as spray drying, hot melt extrusion, fluidized bed or freeze drying. The formation of a solid dispersion may provide a means of reducing particle size to near molecular level.

[0032] As used herein, polyvinylpyrrolidone (also referred to as PVP) refers to a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone. Examples of polyvinylpyrrolidone include PVP-K17, PVP-K25, PVP-K30, PVP-K40, PVP-K50, PVP-K60, PVP-K70, PVP-K80, PVP-K85, PVP-K90, and PVP-K120, but are not limited thereto.

[0033] As used herein, polyvinylpyrrolidone / vinyl acetate copolymer (also referred to as PVP-VA) refers to a copolymer of vinylpyrrolidone (also referred to as VP) and vinyl acetate (also referred to as VA) monomers, and examples of polyvinylpyrrolidone / vinyl acetate copolymers include PVP-VA64, Kollidon SR, etc., but are not limited thereto.

[0034] As used herein, methacrylic acid and methyl methacrylate copolymer refers to a copolymer derived from an ester of acrylic acid and methacrylic acid. is a brand name for various methacrylic acid methyl methacrylate copolymers. Examples of methacrylic acid methyl methacrylate copolymers include etc., but not limited to.

[0036] 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-, and examples of polyethylene glycol include PEG1000, PEG1500, PEG2000, PEG2500, PEG3000, PEG3350, PEG3500, PEG4000, PEG5000, PEG6000, PEG8000, etc., but are not limited thereto.

[0037] As used herein, 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 series of surfactants (available from BASF), The series of surfactants can be named by the CTFA name Poloxamer 108, 124, 188, 217, 237, 238, 288, 338, 407, 101, 105, 122, 123, 124, 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.

[0038] As used herein, hydroxypropyl cellulose is also referred to as HPC, and examples of hydroxypropyl cellulose may include HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H according to the average molecular weight thereof.

[0039] As used herein, hydroxypropyl methyl cellulose is also referred to as HPMC, and examples of hydroxypropyl methyl cellulose may include E3, E5, E6, E15, E50Lv, etc. according to its viscosity, but are not limited thereto.

[0040] As used herein, hydroxypropyl methylcellulose acetate succinate (also referred to as HPMCAS) refers to a mixture of hydroxypropyl methylcellulose acetate and monosuccinate. In a specific embodiment, HPMCAS includes multiple types, such as HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-MG, HPMCAS-HF and HPMCAS-HG, but is not limited thereto.

[0041] As used herein, hydroxypropyl methylcellulose phthalate is also referred to as HPMCP, and examples of HPMCP include HPMCP HP-50, HPMCP HP-55, and HPMCP HP-55S, but are not limited thereto.

[0042] The term "amorphous" refers to a solid form of a molecule that is not crystalline. Specifically, an amorphous solid does not exhibit a well-defined X-ray diffraction pattern.

[0043] The term "therapeutically effective amount" refers to the amount or dosage of an active compound or salt thereof sufficient to prevent the development of one or more symptoms of a disease, disease or condition or to alleviate one or more symptoms of the treated disease, disease or condition to a certain extent. Compound A (oral, 5 mg / kg) herein was tested in an in vivo mouse (BALB / c) model infected with influenza virus (A / PR / 8 / 34) and showed good antiviral efficacy in survival rate and weight change. In addition, one day after infecting mice with virus A / PR / 8 / 34 at a low infection dose (100 pfu / each), the effect of compound A on the growth of influenza virus in the lungs of BALB / c mice was tested, and the virus titers (virustiters) of the groups treated with compound A (5 and 25 mg / kg) were significantly lower than those of the blank control group. In a 14-day repeated dose oral toxicology study, when the dose of compound A was given to 300 mg / kg / day, no death or toxic effects were caused. Therefore, based on these preliminary in vivo animal study results, it is estimated that a reasonable therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be about 5 to 200 mg, about 5 to 150 mg, about 5 to 100 mg, about 10 to 80 mg, about 10 to 40 mg, about 10 to 30 mg, about 10 to 20 mg, about 5 to 10 mg, about 5 to 20 mg, about 20 to 40 mg, or about 40 to 80 mg. For example, but not limited to, a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is about 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.

[0044] The present disclosure relates to a pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises:

[0045] i) A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0046]

[0047] Wherein, G is hydrogen, a prodrug group or an appropriate substituent group; R1 is halogen, C 1-4 alkyl or deuterium; m is an integer from 1 to 9; the asterisk "*" represents a chiral center; and

[0048] ii) Pharmaceutically acceptable polymers:

[0049] wherein the weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the pharmaceutically acceptable polymer is from about 1:1 to about 1:5; and the compound of formula (I) or its pharmaceutically acceptable salt is present in a therapeutically effective amount of from about 5 mg to about 200 mg, from about 5 mg to about 150 mg, from about 5 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 40 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 20 mg to about 40 mg, or from about 40 mg to about 80 mg.

[0050] In one embodiment, R1 is halogen and m is an integer from 1 to 3; in another embodiment, R1 is fluorine and m is an integer from 1 to 2.

[0051] A method of treating a patient suffering from influenza comprises administering an oral pharmaceutical composition as described herein. In one embodiment, the method comprises administering to the patient about 1 mg / kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a dosage form. In another embodiment, the method comprises administering to the patient about 2 mg / kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a dosage form.

[0052] In one embodiment, in formula (I), the formula: The cyclic group represented is a cyclic group represented by any of the following structures:

[0053]

[0054] In one embodiment, the compound of formula (I) is represented by formula (II):

[0055]

[0056] In one embodiment, G is selected from the group consisting of hydrogen, -C(R2R2')-O-CO-R3, -C(R2R2')-O-CO-O-R3, -C(R2R2')-NR4-C(=O)-CO-O-R3

[0057] -C(R2R2')-O-CO-C(R2R2')-NR4-CO-O-R3, -C(R2R2')-C(R2R2')-O-CO-R3, -C(R2R2')-R3, -CO-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), wherein R2, R2' and R4 are each independently hydrogen or C 1-8 Alkyl; R3 is C 1-4 Alkyl, C 3-10 Carbocyclic or C 3-10 Heterocyclic group; R5 is OH, NH2, C 1-4 Alkyl or C 1-4 Alkoxy; and R6 is OH, C 1-4 Alkoxy or C 1-4 In another embodiment, G is hydrogen or -C(R2R2')-O-CO-O-R3. In one embodiment, each of R2 and R2' is independently hydrogen or C 1-8 In another embodiment, each of R2 and R2' is independently hydrogen or C 1-4 alkyl.

[0058] In one embodiment, G is selected from the group consisting of hydrogen,

[0059] 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 methoxyformate) or its metabolite 1'-((11S)-7,8-difluoro-6H,11H-dibenzo[b,e]thiepin-11-yl)-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione (1'-((11S)-7,8-difluoro-6H,11H-dibenzo[b,e]thiepin-11-yl)-1',2'-dihydro-5'-hydrox y-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione) or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compounds herein can be prepared according to the methods / procedures disclosed in PCT Published Application No. WO2019 / 144089 or WO2021 / 239126, which are incorporated herein by reference in their entirety.

[0061] In one embodiment, provided herein is an amorphous solid dispersion of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may further comprise a pharmaceutically acceptable polymer.

[0062] In another embodiment, disclosed herein is an amorphous solid dispersion 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 dispersed in a polymer matrix formed by a solid pharmaceutically acceptable polymer.

[0063] The pharmaceutically acceptable polymer used in the amorphous solid dispersion herein is a water-soluble polymer. Suitable water-soluble polymers should be used as water-soluble carriers to make the active ingredient hydrophilic so as to improve its solubility and help to keep the solid dispersion in an amorphous state. Some common examples of water-soluble polymers include, but are not limited to, vinyl polymers and copolymers, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone / vinylacetate copolymer (PVP-VA), polyvinyl alcohol (PVA), polyvinyl alcohol polyvinyl acetate copolymers, polyethylene polyvinyl alcohol copolymers, polyvinyl caprolactam and polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (also known as Soluplus), acrylate and methacrylate copolymers, methacrylic acid and methyl methacrylate copolymers. copolymer; for example, Eudragit), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene copolymers (also known as poloxamers), hydroxypropylmethyl cellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPMC).HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxymethylethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), carboxymethylcellulose acetate butyrate (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), carboxymethylcellulose acetate butyrate (CMEC), butyrate; CMCAB), calcium CMC, sodium CMC, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, docusate sodium, cellacefate, and the like. ;

[0064] In one embodiment, the pharmaceutically acceptable polymer is polyvinyl pyrrolidone / vinyl acetate copolymer (PVP-VA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), methacrylic acid methyl methacrylate copolymer (such as Eudragit), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), or a combination thereof.

[0065] In one embodiment, the pharmaceutically acceptable polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a combination thereof. In another embodiment, the pharmaceutically acceptable polymer is hydroxypropyl cellulose (HPC), which includes HPC-SSL, HPC-SL, HPC-L, HPC-M or HPC-H.

[0066] In one embodiment, the pharmaceutically acceptable polymer is Soluplus, HPC-SSL, HPMCAS, or a combination thereof.

[0067] In one embodiment, disclosed herein is an amorphous solid dispersion 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, 1:1 to 1:1.5. In one embodiment, the weight ratio is about 1:1 to about 1:5. In another embodiment, the weight ratio is about 1:1 to about 1:3.5. In another embodiment, the weight ratio is about 1:1 to about 1:3. In another embodiment, the weight ratio is about 1:3.

[0068] In one embodiment, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the amorphous solid dispersion is generally 10 to 60%, 10 to 55%, 10 to 50%, 10 to 45%, 10 to 40%, 15 to 60%, 15 to 55%, 15 to 50%, 15 to 45% or 15 to 40% by weight, for example, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the amorphous solid dispersion (drug loading) is about 15%, 25%, 33%, 40% or 50% by weight.

[0069] In one embodiment, the solid dispersions described herein have a D in the range of about 4 μm to 15 μm. 50 Particle size, or D with a range of about 15 μm to 50 μm 90 granularity.

[0070] The solid dispersions described herein can be orally administered to a subject (eg, a human) in need thereof to treat or prevent infectious diseases, such as influenza.

[0071] In one embodiment, the amorphous solid dispersion herein can be prepared by methods well known in the art, such as spray drying, hot melt extrusion, fluidized bed or freeze drying technology. In one embodiment, the amorphous solid dispersion is prepared by spray drying technology.

[0072] In one embodiment, the amorphous solid dispersion herein is prepared by dissolving the compound of formula (I) or its pharmaceutically acceptable salt in a sufficient amount of an organic solvent, and mixing the resulting solution with a solution containing a pharmaceutically acceptable polymer, thereby preparing a spray solution. The solvent can then be evaporated, leaving the drug dispersed / dissolved in the matrix. Any organic solvent capable of dissolving or dispersing the compound of formula (I) or its pharmaceutically acceptable salt and the aforementioned pharmaceutically acceptable polymer can be used in the present disclosure, and examples of organic solvents include low-carbon alcohols (e.g., methanol, ethanol, propanol or isopropanol), ketones (e.g., acetone, butanone or methyl isobutyl ketone), halogenated alkanes (e.g., dichloromethane, chloroform or carbon tetrachloride), acetic acid, ethyl acetate, N,N-dimethylformamide, DMSO, tetrahydrofuran or a mixture thereof.

[0073] In one embodiment, the preparation of the amorphous solid dispersion comprises the following steps: (i) dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer in a solvent, and (ii) drying the solution obtained in step (i).

[0074] In one embodiment, step (i) comprises: dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a sufficient amount of an organic solvent; dissolving a pharmaceutically acceptable polymer in the solvent, and mixing the two solutions.

[0075] In one embodiment, step (ii) comprises spray drying; in another embodiment, step (ii) comprises spray drying in combination with a fluidized bed; in yet another embodiment, step (ii) comprises evaporating the solvent using a rotary evaporator.

[0076] In one embodiment, the solvent can be evaporated by spray drying technology. The term "spray drying" is used conventionally and widely, and refers to the process of breaking a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the liquid mixture in a spray drying device (e.g., a nozzle), where there is a strong driving force to evaporate the solvent from the droplets. In a typical spray drying process, the feed liquid can be a solution, slurry, emulsion, gel or paste, as long as it is pumpable and can be atomized.

[0077] In one embodiment, the pharmaceutical composition comprising the solid dispersion of the present disclosure further comprises one or more pharmaceutically acceptable excipients, which excipients can be selected from binders, disintegrants, fillers, diluents, lubricants, glidants, surfactants, wetting agents, release rate modifiers, sweeteners, taste masking agents, colorants, flavoring agents, and combinations thereof.

[0078] 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.

[0079] In one embodiment, the filler includes but is not limited to mannitol, microcrystalline cellulose, lactose, maltitol, calcium hydrogen 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, hydrogenated starch hydrolysate, etc. In another specific embodiment, the filler includes mannitol, microcrystalline cellulose, lactose, mantitol, calcium hydrogen phosphate, etc. In another embodiment, the filler includes D-mannitol, MCC 101, or a combination thereof.

[0080] In one embodiment, the binder comprises hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, carboxycellulose, polyvinyl alcohol, starch, sucrose, lactose, lactose monohydrate, maltol, sorbitol, xylitol, poloxamer, gelatin, sugars, colloids (e.g., xanthan gum, gum arabic or gum arabic), calcium hydrogen phosphate, dicalcium phosphate, glycerides, baicalin, sodium alginate, and the like. In another embodiment, the binder comprises hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, or a mixture thereof. In certain embodiments, the binder comprises HPMC, HPC, PEG-4000, Povidone K30, PVP-VA64, or a mixture thereof.

[0081] In one embodiment, the disintegrant includes cross-linked sodium carboxymethylcellulose (croscarmellose), cross-linked polyvinylpyrrolidone (crospovidone), copovidone (copovidone), microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch (carboxymethyl starch), pregelatinized starch, sodium carboxymethyl starch (sodium starch glycolate), starch, carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose or calcium carboxymethyl cellulose), sodium carmellose (sodium carmellose), potassium polyacrylate (polacrilin potassium), alginic acid, and the like, but not limited thereto. In another embodiment, the disintegrant includes cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch, sodium carboxymethyl starch, starch, carboxymethyl cellulose, alginic acid, or a mixture thereof, but not limited thereto. In certain embodiments, the disintegrant includes cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, starch 1500, or a mixture thereof, but not limited thereto.

[0082] Suitable diluents include, but are not limited to, lactose, mannitol, maltitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum magnesium silicate, or the like.

[0083] 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, or the like.

[0084] Suitable surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or polyoxyethylene sorbate, dioctyl sodium sulfonate (DOSS), lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylene castor oil, polyoxyethylene fatty acid glycerides, poloxamers, or any other commercially available co-processing surfactant, e.g. or or its analogue.

[0085] Suitable sweeteners include, but are not limited to, sucralose, aspartame, neotame, acesulfame-K, or the like.

[0086] Suitable glidants include, but are not limited to, silicon dioxide, stearic acid, magnesium stearate, calcium hydroxide, talc, sodium stearate fumarate, polyvinyl alcohol, polyvinyl alcohol, magnesium or sodium lauryl sulfate, colloidal silicon dioxide, starch, or the like.

[0087] The pharmaceutical composition comprises about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 16%, 20%, 25%, 30%, 35% or 40% by weight of the 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 the solid dispersion. In another embodiment, the pharmaceutical composition contains about 3% (w / w) to about 30% (w / w) of the solid dispersion. In other embodiments, the pharmaceutical composition contains about 3% (w / w) to about 20% (w / w) of the solid dispersion.

[0088] In one embodiment, the pharmaceutical composition containing a solid dispersion may further include one or more fillers. The pharmaceutical composition may contain about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 92% or 95% weight of filler, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains about 40% (w / w) to about 95% (w / w) of filler. In another embodiment, the pharmaceutical composition contains about 50% (w / w) to about 95% (w / w) of filler. In other embodiments, the pharmaceutical composition contains about 50% (w / w) to about 92% (w / w) of filler.

[0089] In one embodiment, the pharmaceutical composition containing a solid dispersion and one or more fillers may further include one or more binders and / or disintegrants. The pharmaceutical composition may contain about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30% or 35% by weight of a binder and / or disintegrant, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains about 1% (w / w) to about 35% (w / w) of a binder and / or disintegrant. In another embodiment, the pharmaceutical composition contains about 1% (w / w) to about 10% (w / w) of a binder and / or disintegrant. In other embodiments, the pharmaceutical composition contains about 10% (w / w) to about 30% (w / w) of a binder and / or disintegrant.

[0090] In one embodiment, the pharmaceutical composition containing the solid dispersion may also include one or more fillers, binders and disintegrants. The pharmaceutical composition may contain about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 92%, 95% or 98% by weight of fillers, binders and disintegrants, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains about 50% (w / w) to about 98% (w / w) of fillers, binders and disintegrants. In another embodiment, the pharmaceutical composition contains about 70% (w / w) to about 95% (w / w) of fillers, binders and disintegrants. In other embodiments, the pharmaceutical composition contains about 80% (w / w) to about 92% (w / w) of fillers, binders and disintegrants.

[0091] In one embodiment, the pharmaceutical composition contains 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 contains 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 contains 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.

[0092] In one embodiment, the pharmaceutical composition contains about 3% (w / w) to about 40% (w / w) of a solid dispersion, about 40% (w / w) to about 95% (w / w) of a filler, and about 1% (w / w) to about 35% (w / w) of a binder and / or a disintegrant. In another embodiment, the pharmaceutical composition contains about 3% (w / w) to about 30% (w / w) of a solid dispersion, about 50% (w / w) to about 95% (w / w) of a filler, and about 1% (w / w) to about 30% (w / w) of a binder and / or a disintegrant. In other embodiments, the pharmaceutical composition contains about 3% (w / w) to about 20% (w / w) of a solid dispersion, about 50% (w / w) to about 92% (w / w) of a filler, and about 2% (w / w) to about 30% (w / w) of a binder and / or a disintegrant.

[0093] In one embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of granules, orally disintegrating tablets (ODT), suspensions, powders, solutions, suspensions or solutions reconstituted from granules or powders, syrups, elixirs, dispersible / effervescent tablets, chewable tablets, lozenges, orodispersible wafers, powder sachets, microparticles, pills, capsules, spray oral powders, or inhalants.

[0094] In one embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration to pediatric patients.

[0095] The pharmaceutical compositions provided herein can also be subjected to film coating. The film coating contains 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.

[0096] The present disclosure will be further understood by the following non-limiting examples.

[0097] Example 1: Preparation of [1-((11S)-7,8-difluoro(6H,11H-dibenzo[c,f]thiophen-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyrido[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methyl methoxycarboxylate (Compound A)

[0098] Compound A was prepared according to the synthetic route and scheme reported in WO2019 / 144089 of Hsu et al. The mass spectrometry (MS) and nuclear magnetic resonance (NMR) data of Compound A are as follows: MS: m / z 541.0 (M + +1); 1H 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,1 H),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). In addition, the metabolite of compound A, 1'-((11S)-7,8-difluoro-6H,11H-dibenzo[b,e]thiophen-11-yl)-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyrido[1,2-b]pyridazine-4',6'-dione, was also prepared by a similar synthetic route and scheme. The mass spectrometry (MS) and nuclear magnetic resonance (NMR) data of the metabolite of compound A are as follows: 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,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).

[0099] Example 2: Preparation of amorphous solid dispersion

[0100] The amorphous solid dispersion of the present invention is prepared by spray drying as is known in the art, for example, see Singh et al., Advanced Drug Delivery Reviews, 2016, 100, 27-50. Different pharmaceutically acceptable polymers, such as PVP-VA64, Soluplus, HPMCAS-MG, HPMCAS-HG, EPO, HPC-SSL, HPMCP HP-55, Kollidon SR and PEG3350 are used to prepare the amorphous solid dispersion of the present disclosure, and the amorphous solid dispersion is prepared using a spray dryer 4M8-Trix. The spray drying concentration of compound A is set to 25 mg / mL, and compound A is mixed with different pharmaceutically acceptable polymers in different proportions in a glass bottle and dissolved in a solvent (e.g., acetone) to provide a feed solution, and the obtained feed solution is made into a fine spray through a nozzle into a chamber, in which the solvent is rapidly evaporated to produce particles containing compound A and the corresponding polymer, and the resulting spray-dried powder is further dried in a static dryer to remove residual solvent.

[0101] Example 3: Dissolution Evaluation

[0102] A certain amount of compound A (about 6 mg) and amorphous solid dispersion (with the equivalent of about 6 mg of compound A) were weighed and placed in 8 ml bottles, and 6 ml of FaSSIF (fasting state simulated intestinal fluid) was added, with a target concentration of 1.0 mg / ml. The suspension was then stirred in a thermal mixer at 37 ° C and 600 rpm, and 200 μL of the suspension was taken out at a preset time interval (e.g., 5 minutes), and then centrifuged at 14000 rpm for 4 minutes. Then, 100 μL of supernatant was diluted with 500 μL of acetonitrile to prevent precipitation, and analyzed by HPLC. Compound A has low water solubility.

[0103] The preparation steps of FaSSIF are as follows: 1) Place 0.1024 g of sodium hydroxide, 0.7518 g of anhydrous sodium dihydrogen phosphate and 1.5470 g of sodium chloride in a 250 ml volumetric flask, add about 225 ml of water, and adjust the pH to 6.5 with 1N sodium hydroxide or 1N hydrochloric acid. Make up to 250 ml with pure water. 2) Dissolve 0.4480 g of SIF Powder Original and 100 ml of buffer (from step 1) in a 200 ml flask, add water to make up to volume and mix well.

[0104] Table 1 lists the solubility of Compound A and the amorphous solid dispersion in FaSSIF at 5 minutes and 15 minutes.

[0105] Table 1

[0106]

[0107] Example 4: Stability study of amorphous solid dispersion

[0108] The amorphous solid dispersion was stored at 4°C (closed state) or 40°C / 75%RH (closed and open state), and after 10 days or 4 weeks, the samples were observed with a camera, characterized by XRPD, and analyzed for purity and kinetic solubility using HPLC. All samples under closed storage conditions were placed in clear glass vials with gaskets and screw caps, while all samples under open storage conditions were placed in clear glass vials without caps, and the mouths of the vials were covered with aluminum foil with pinholes to avoid cross contamination.

[0109] Table 2 shows the total impurity levels (ie, TRS%; total related substances) of Compound A and ASDs after stability testing. The sample numbers in Table 2 correspond to the sample numbers in Table 1.

[0110] Table 2

[0111]

[0112] Example 5: Formulation and preparation

[0113] The formulation of the solid dispersion containing compound A is shown in Table 3 and Table 4. The amorphous solid dispersion (ASD) containing compound A is as described in Example 2. The granular dosage form is prepared by roller compaction. ASD and an equal amount of mannitol are manually mixed and stirred for 2 minutes, then mannitol is added to the bag of ASD, shaken for 2 minutes to remove the remaining ASD, and then other excipients are added using an equal amount stepwise method, and finally, in a shaker mixer (shaker mixer, ) and stirred the mixture at 46 rpm for 10 min.

[0114] Table 3

[0115]

[0116]

[0117] The dissolution curves of granules and ASD powder are as follows: Figure 1 The granules tested reached about 80% dissolution within 15 minutes.

[0118] Table 4

[0119]

[0120] The dissolution profiles of D9 preparation and ASD powder itself are as follows Figure 2 The dosage form tested achieved about 80% dissolution within 15 minutes.

[0121] Other Implementations

[0122] All features disclosed in the specification can be combined in any combination. The various features disclosed in the specification can be replaced by features that serve the same, equivalent or similar purposes. Therefore, unless otherwise specified, the various features disclosed are merely examples of a series of equivalent or similar features. Through the above description, those skilled in the art can easily determine the main features of the present invention, and can make various changes and improvements to the present invention without departing from the spirit and scope of the present invention to make it suitable for various applications and conditions. Therefore, other embodiments are also within the scope of the attached patent application.

Claims

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: in, G is hydrogen or -C(R2R2')-O-CO-O-R3, wherein each R2 and R2' are independently hydrogen or C 1-4 Alkyl; R3 is C 1-4 Alkyl; the asterisk "*" represents a chiral center; as well as ii) a pharmaceutically acceptable polymer; 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 1:5; 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.

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]thiophen-11-yl))-4,6-dioxospiro[1,2,3,9-tetrahydropyridinium[1,2-e]pyridazine-3,1'-cyclopropane]-5-yloxy]methyl methoxyformate or 1'-((11S)-7,8-difluoro-6H,11H-dibenzo[b,e]thiophen-11-yl)-1',2'-dihydro-5'-hydroxy-spiro[cyclopropane-1,3'-(3H)pyridinium[1,2-b]pyridazine-4',6'-dione; The pharmaceutically acceptable polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof.

3. The pharmaceutical composition according to claim 2, wherein The pharmaceutically acceptable polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), 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 about 1:1 to about 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 about 5 mg to about 100 mg.

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

7. The pharmaceutical composition according to claim 1, wherein The solid dispersion has a D ranging from about 4 μm to 15 μm. 50 Particle size, or D with a range of about 15 μm to 50 μm 90 granularity.

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

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

10. The pharmaceutical composition according to claim 9, wherein The filler is selected from mannitol, microcrystalline cellulose, lactose, maltitol, calcium hydrogen phosphate, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, starch, glucose, fructose, sucrose, dicalcium phosphate, calcium sulfate, cellulose, kaolin, sodium chloride, sorbitol, trehalose, mannito, lactitol, xylitol, isomalt, erythritol and hydrogenated starch hydrolysate, and combinations thereof; the binder is selected from hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), povidone, polyvinyl pyrrolidone (PVP), polyhydroxypropyl cellulose (HPC), methyl cellulose, and combinations thereof; and the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, copovidone, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl starch, sodium carboxymethyl starch, starch, carboxymethyl cellulose, alginic acid, and combinations thereof.

11. The pharmaceutical composition according to claim 10, wherein The filler is selected from D-mannitol, MCC 101, and combinations thereof; the binder is selected from HPMC, HPC, PEG-4000, Povidone K30, PVP-VA64, and combinations thereof; the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch 1500, and combinations thereof.

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

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

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

15. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition is in a dosage form selected from the group consisting of granules, orally disintegrating tablets (ODT), suspensions, powders, solutions, suspensions or solutions reconstituted from granules or powders, syrups, elixirs, dispersible / effervescent tablets, chewable tablets, lozenges, orodispersible wafers, powder sachets, microparticles, pills, capsules, spray oral powders, and inhalants.

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