Pharmaceutical composition containing a 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide derivative and its use

Abstract

This specification provides solid dosage forms comprising a 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide derivative (e.g., vorixibat or a pharmaceutically acceptable salt thereof). This specification also provides embodiments of methods for treating cholestatic liver disease, hyperlipidemia, arteriosclerosis, or syndrome X, or for lowering serum cholesterol levels, in subjects where required, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition comprising vorixibat in solid dosage form to the subject.

Description

Cross-reference of related applications

[0001] This application asserts the interests under § 119(e) of U.S. Patent Act, as of U.S. Provisional Application No. 63 / 467,823, filed 19 May 2023 (which is incorporated herein by reference in its entirety). [Technical Field]

[0002] This specification provides solid dosage forms comprising 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide derivatives (e.g., vorixibat or a pharmaceutically acceptable salt thereof). [Background technology]

[0003] Hypercholestasis and cholestatic liver disease are liver diseases associated with intracellular accumulation of bile acids / salts in hepatocytes, often followed by impaired bile secretion (i.e., cholestasis). Hypercholestasis is characterized by elevated serum concentrations of bile acids or bile salts. Cholestasis can be classified clinicopathologically into two main categories: obstructive, often extrahepatic, cholestasis, and non-obstructive or intrahepatic cholestasis. Non-obstructive intrahepatic cholestasis can be further classified into two main subgroups: primary intrahepatic cholestasis, resulting from constitutively defective bile secretion, and secondary intrahepatic cholestasis, resulting from hepatocyte damage. Primary intrahepatic cholestasis includes benign recurrent intrahepatic cholestasis, an adult form that primarily presents with similar clinical symptoms, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which affect children. While pediatric cholestatic liver disease affects only a small percentage of children, treatment incurs significant annual medical costs. Currently, many cases of pediatric cholestatic liver disease require invasive and expensive treatments such as liver transplantation or surgery.

[0004] Volixibat (also known as SHP626, LUM002, or ((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate) is an ileal bile acid transporter (IBAT) inhibitor for treating hyperbilirubinemia and cholestatic liver diseases. There is still a need to find a suitable dosage form of volixibat that has good dissolution and pharmacokinetic profiles and also shows good storage stability. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0005] In the present specification, a compound of formula (I):

Chemical formula

[0006] In some embodiments, the compound of formula (I) is a compound having the structure of formula (II), which is vorixibate: [ka] or a pharmaceutically acceptable salt thereof.

[0007] Furthermore, embodiments of methods for treating cholestatic liver disease, hyperlipidemia, arteriosclerosis, or Syndrome X, or for lowering serum cholesterol levels, in subjects where such methods include administering a therapeutically effective amount of the pharmaceutical composition described herein to the subject.

[0008] Further provided herein are embodiments of a method for producing a pharmaceutical composition in solid form, the method being: A therapeutically effective amount of the compound of formula (I), (i) Diluent or filler, (ii) Disintegrant, (iii) Channeling agent, (iv) Flow promoters, and (v) Lubricants The process includes the steps of: forming an admixture by combining one or more excipients selected from the group consisting of; mixing the admixture; and filling the admixture into a capsule shell or compressing the admixture to form a pharmaceutical composition.

[0009] Furthermore, embodiments relating to a kit for treating cholestatic liver disease or hyperlipidemia in subjects requiring such treatment, the kit comprising a therapeutically effective amount of the composition described herein. [Brief explanation of the drawing]

[0010] [Figure 1] NaCl: shows aggregation of the sample with porixibat. [Figure 2] This shows the aggregation of PEG1500:porixivat samples. [Figure 3] The appearance of the sample under ambient temperature / 60%RH conditions is shown. [Figure 4] The appearance of the sample under 40°C / 75%RH conditions is shown. [Figure 5] The dissolution data for 20 mg capsules of formulations 1 and 2 in 900 mL of phosphate buffer (pH 6.8) is shown. [Figure 6] The dissolution data for 40 mg capsules of formulations 1, 3, and 4 in 500 mL of phosphate buffer (pH 6.8) is shown. [Figure 7] Dissolution data for 20 mg capsules of formulation 5 is shown: T=0, tamped fill vs. bulk fill. [Figure 8] Dissolution data for the 20 mg capsule of formulation 5 is shown: Effect of over-lubrication. [Figure 9] The dissolution data for a 20 mg capsule of formulation 5 in 500 mL of acetate buffer (pH 4.5) is shown. [Figure 10] The dissolution data for 20 mg capsules of formulations 1 and 3-6 in 500 mL of phosphate buffer (pH 6.8) is shown. [Figure 11] The dissolution data for 20 mg capsules of formulations 1 and 3-6 in 500 mL of 0.01 N HCl is shown. [Figure 12] The dissolution data for 20 mg capsules of formulation 5 in each dissolution medium is shown. [Figure 13] The dissolution data for 20 mg capsules of formulation 7 in each dissolution medium is shown. [Modes for carrying out the invention]

[0011] Unless otherwise defined, all technical and scientific terms have the same meanings as those commonly understood by those skilled in the art in the field to which the disclosed embodiments belong.

[0012] As used herein, the terms "a" or "an" mean "at least one" or "one or more" unless the context explicitly indicates otherwise.

[0013] Where used herein, the term “about” means that a numerical value is an approximation and small variations will not significantly affect the execution of the described embodiment. Where numerical limitations are used, unless otherwise indicated by the context, “about” means that the numerical value may vary by ±10% and remain within the scope of the disclosed embodiment.

[0014] As used herein, the term “alkenyl” means a linear or branched alkyl group having one or more double carbon-carbon bonds and 2 to 20 carbon atoms, and includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In some embodiments, the length of the alkenyl chain is 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0015] As used herein, the terms “active pharmaceutical ingredient” or “API” refer to a biologically active compound. An example API is vorixibat. Vorixibat is known as SHP626, LUM002, or ((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)bisulfate). The structure of vorixibat potassium is shown below: [ka]

[0016] The terms “alkoxy,” “phenyloxy,” “benzoxy,” and “pyrimidinyloxy” refer to an optionally substituted alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, bonded via an oxygen atom. For example, the term “alkoxy” means a linear or branched -O-alkyl group having 1 to 20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, etc. In some embodiments, the length of the alkoxy chain is 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0017] As used herein, the term “alkyl” means a saturated hydrocarbon group that is linear or branched. Alkyl groups may contain 1 to 20, 2 to 20, 1 to 10, 2 to 10, 1 to 8, 2 to 8, 1 to 6, 2 to 6, 1 to 4, 2 to 4, 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl, 2-methyl Examples include, but are not limited to, 2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, and 2-ethyl-1-butyl.

[0018] As used herein, the terms “alkylene” or “alkylenyl” mean a divalent alkyl linking group. Examples of alkylenes (or alkylenyls) are methylene or methyleneyl (-CH2-).

[0019] As used herein, the term "alkynyl" means a linear or branched alkyl group having one or more triple carbon-carbon bonds and 2 to 20 carbon atoms, including but not limited to acetylene, 1-propylene, 2-propylene, and the like. In some embodiments, the length of the alkynyl chain is 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0020] As used herein, the term "amino" means -NH2.

[0021] As used herein, the term "aminoalkoxy" means an alkoxy group substituted with an amino group. An example of an aminoalkoxy is -OCH2CH2NH2.

[0022] As used herein, the term "aminoalkyl" means an alkyl group substituted with an amino group. An example of an aminoalkyl group is -CH2CH2NH2.

[0023] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0024] As used herein, the term "aminoalkylthio" means an alkylthio group substituted with an amino group. An example of an aminoalkylthio is -SCH2CH2NH2.

[0025] As used herein, the term “amphiphilic” refers to a three-dimensional structure having separate hydrophobic and hydrophilic regions. Amphiphilic compounds appropriately possess both hydrophobic and hydrophilic elements.

[0026] As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates (e.g., wild animals, livestock and farm animals).

[0027] As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic (e.g., having two, three, or four fused rings) aromatic hydrocarbon that optionally contains a heteroatom. In some embodiments, the aryl group has 6 to 20 carbon atoms or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, indenyl, and tetrahydronaphthyl. In some embodiments, the aryl group includes heteroaryl groups as defined in other embodiments. In some embodiments, the aryl group has a heteroatom. In some embodiments, the aryl group has a heteroatom selected from the group consisting of N, S, O, and P atoms. Examples of aryl groups include, but are not limited to: [ka] [ka]

[0028] As used herein, “binder” is an excipient that imparts enhanced cohesiveness or tensile strength (e.g., hardness) to a pharmaceutical composition.

[0029] As used herein, the term “carrier” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the active ingredient to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a patient.

[0030] As used herein, the term “composition” generally refers to a composition of two or more components, typically one or more drugs (e.g., vorixibat) and one or more pharmaceutical excipients.

[0031] As used herein, the term “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0032] As used herein, the terms “comprising” (and all forms of “comprising,” e.g., “comprise,” “comprises,” and “comprised,” etc.), “having” (and all forms of “having,” e.g., “have” and “has,” etc.), “including” (and all forms of “including,” e.g., “includes” and “include,” etc.), or “containing” (and all forms of “containing,” e.g., “contains” and “contain,” etc.) are inclusive or open-ended and do not exclude additional elements or method steps not enumerated.

[0033] As used herein, the term “bring into contact” means bringing two elements into close proximity to each other in an in vitro or in vivo system.

[0034] As used herein, the term "cyano" means -CN.

[0035] As used herein, the term “ring” means a ring which is optionally substituted, having 1 to 5 heteroatoms independently selected from 6 to 20-membered aryls, N, O, and S; a 3 to 20-membered saturated or partially unsaturated cycloalkyl; or a 3 to 20-membered saturated or partially unsaturated heterocycloalkyl having 1 to 5 heteroatoms independently selected from N, O, and S.

[0036] As used herein, the term “cycloalkyl” means a non-aromatic cyclic hydrocarbon comprising a cyclized alkyl, alkenyl, and alkynyl group, containing up to 20 ring-forming carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic systems, such as fused ring systems, bridging ring systems, and spiro-ring systems. In some embodiments, polycyclic systems contain two, three, or four fused rings. Cycloalkyl groups may contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted with oxo or sulfide. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. Furthermore, the definition of a cycloalkyl group includes substructures in which one or more aromatic rings are fused to a cycloalkyl ring (sharing a common bond), such as benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl, or 1H-inden-2(3H)-on-1-yl).

[0037] As used herein, “disintegrant” is an excipient that hydrates a pharmaceutical composition and helps disperse tablets.

[0038] As used herein, “diluent” or “filler” is an excipient that adds bulk to a pharmaceutical composition.

[0039] As used herein, "DS" refers to the drug substance.

[0040] As used herein, “excipients” include functional and non-functional components in a pharmaceutical composition.

[0041] As used herein, “glidant” is an excipient that imparts enhanced flow properties to a pharmaceutical composition.

[0042] As used herein, the term "halo" means a halogen group, including, but not limited to, fluoro, chloro, bromo, and iodo groups.

[0043] As used herein, the term "haloalkoxy" means an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0044] As used herein, the term "haloalkyl" refers to a C atom having one or more halogen substituents. 1-6 This refers to alkyl groups. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, C2Cl5, and CH2CF3.

[0045] As used herein, the term “heteroatom” refers to an atom that is neither a carbon atom nor a hydrogen atom. In some embodiments, the “heteroatom” is a nitrogen, oxygen, phosphorus, or sulfur atom.

[0046] As used herein, the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and at least one heteroatom ring member (ring-forming atom) (e.g., sulfur, oxygen, or nitrogen). In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each independently of sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (indole-3-yl, etc.), pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolinyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, prinyl, carbazolyl, benzimidazolyl, and in Examples include drinnyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolidinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinazolinyl, phenanthiazolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, and phenoxazinyl groups.Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

[0047] As used herein, the term “heteroarylalkyl” means C substituted with a heteroaryl group. 1-6 It means alkyl group.

[0048] As used herein, the term “heterocyclic” or “heterocyclic ring” means a monocyclic or bicyclic ring system of 5 to 7 members or a bicyclic or heterocyclic ring system of 7 to 10 members, any of which rings may be saturated or unsaturated and consist of a carbon atom and 1 to 3 heteroatoms selected from N, O, and S, wherein the N and S heteroatoms may be optionally oxidized, and the N heteroatom may be optionally quaternized, and also includes any bicyclic group in which any of the above-defined heterocyclic rings are fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur atom, 1 to 3 nitrogen atoms, or one oxygen or sulfur atom in combination with one or two nitrogen atoms. Heterocyclic rings may be bonded to any heteroatoms or carbon atoms that result in the formation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperizinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, Examples include morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranil, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranil, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

[0049] As used herein, the term “heterocycloalkyl” means a non-aromatic heterocycle having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more of the ring-forming carbon atoms are replaced by heteroatoms such as O, N, or S atoms. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., condensed, bridging, or spiro systems). In some embodiments, heterocycloalkyl groups have 1 to 20 carbon atoms, or 3 to 20 carbon atoms. In some embodiments, heterocycloalkyl groups contain 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, and pyrrolidine-2-on-3-yl. Furthermore, the ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may be substituted with oxo or sulfide atoms. For example, the ring-forming S atom may be substituted with one or two oxo atoms (forming S(O) or S(O)2). As another example, the ring-forming C atom may be substituted with an oxo atom (forming a carbonyl group).Furthermore, the definition of heterocycloalkyl includes substructures having one or more aromatic rings fused (sharing a common bond) to a non-aromatic heterocycle, which include, but are not limited to, heterocyclic pyridinyl, thiophenyl, phthaliumidyl, naphthaliumidyl, and benzo derivatives such as indolene, isoidolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridine-7(4H)-on-5-yl, isoindorin-1-on-3-yl, and 3,4-dihydroisoquinorin-1(2H)-on-3-yl groups. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may optionally be substituted with oxo or sulfide groups.

[0050] As used herein, the terms "hydroxy" or "hydroxyl" mean the -OH group.

[0051] As used herein, the terms "hydroxyalkyl" or "hydroxylalkyl" mean an alkyl group substituted with a hydroxyl group. Examples of hydroxylalkyls include, but are not limited to, -CH2OH and -CH2CH2OH.

[0052] As used herein, the terms “individual” and “patient” are interchangeable and mean any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or mammals such as primates (e.g., humans).

[0053] As used herein, the term “inhibitor” means a substance that reduces the activity of an enzyme or receptor by a measurable amount. The term “inhibit” means reducing the activity of an enzyme or receptor by a measurable amount.

[0054] As used herein, the phrase “needs it” means that an animal or mammal has been identified as having a need for a particular method or treatment. In some embodiments, the identification may be by any diagnostic means. In any of the methods and treatments described herein, an animal or mammal may need it. In some embodiments, an animal or mammal is in or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.

[0055] As used herein, the phrase "an integer from X to Y" means any integer including the endpoint. For example, the phrase "an integer from 1 to 5" means 1, 2, 3, 4, or 5.

[0056] As used herein, the phrase “optionally substituted” means that the substitution is optional and therefore includes both unsubstituted and substituted atoms and substructures. “Substituted” atom or substructure indicates that any hydrogen of the specified atom or substructure may be replaced with one of the indicated substituents, provided that the substitution does not exceed the normal valence of the specified atom or substructure and that the substitution results in a stable compound. For example, if a methyl group may be optionally substituted, then three hydrogen atoms on the carbon atom may be replaced with substituents.

[0057] As used herein, “lubricant” is an excipient added to a pharmaceutical composition to be compressed into a tablet. The lubricant assists in the compression of granules into tablets and the discharge of the tablets of the pharmaceutical composition from the die press.

[0058] As used herein, the terms “percent” or “%” mean a percentage by weight relative to the total weight of the composition (i.e., a proportion of the total weight of the composition).

[0059] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that is suitable, within the bounds of sound medical judgment, for use in contact with human and animal tissues. In some embodiments, “pharmaceutically acceptable” means that it is approved by a federal or state regulatory authority, or that it is listed in the United States Pharmacopeia or other generally accepted pharmacopoeia with respect to use in animals, more specifically in humans.

[0060] As used herein, the term “pharmaceutically acceptable salt” includes, but is not limited to, salts of acidic or basic groups. Compounds that are inherently basic can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, and such salts include, but are not limited to, sulfates, thiosulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, bisulfites, phosphates, acidic phosphates, isonicotinates, borates, acetates, lactates, salicylates, citrates, acidic citrates, tartrates, oleates, tannates, pantothenates, Examples include tartarates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, bicarbonates, malons, mesylates, esylates, napsydisylates, tosylates, besylates, orthophosphates, trifluoroacetates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds containing an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids listed above. Compounds that are inherently acidic can form basic salts with various pharmaceutically acceptable cations. Examples of such salts include, but are not limited to, alkali metal salts or alkaline earth metal salts, particularly salts of calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron. This embodiment includes pharmaceutically acceptable salts of the compounds described herein. This embodiment also includes quaternary ammonium salts of the compounds described herein, wherein the compound has one or more tertiary amine moieties.

[0061] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two, or three preferred substituents.

[0062] As used herein, the term “prodrug” means a derivative of a known direct-acting drug, which has enhanced delivery properties and therapeutic value compared to the drug and is converted to an active drug by an enzymatic or chemical process.

[0063] As used herein, the term “purified” means that, when isolated, the isolate contains at least 90% by weight, at least 95% by weight, at least 98% by weight, or at least 99% by weight of the compound described herein.

[0064] As used herein, the term “solid dosage form” generally refers to a pharmaceutical composition that, when used in an oral administration mode, includes capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier.

[0065] As used herein, the term "solubilizing agent" means an agent that results in the formation of a micelle or true solution of a drug.

[0066] As used herein, the term “solution / suspension” means a liquid composition in which a first portion of the active substance is present in a solution and a second portion of the active substance is suspended in a liquid matrix in particulate form.

[0067] As used herein, the phrase “substantially isolated” means a compound that has been separated at least partially or substantially from the environment in which it was formed or detected.

[0068] As used herein, “surfactant” is an excipient that imparts improved solubility and / or wetting properties to a pharmaceutical composition.

[0069] As used herein, “preferred substituent,” “substituent,” “optional substituent,” or a substituent of any optionally substituted group means a group that does not impair the synthetic or pharmaceutically useful properties of the compounds described herein or intermediates useful for preparing them. Examples of “preferred substituent,” “substituent,” “optional substituent,” or a substituent of any optionally substituted group include, but are not limited to, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, phenyl, C3-C5 heteroaryl, C3-C 10 Examples include cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -NH(phenyl), -N(phenyl)2, -CHO, -CO(C1-C6 alkyl), -CO(phenyl), -CO2(C1-C6 alkyl), and -CO2(phenyl). In some embodiments, a "preferred substituent," "substituent," "optional substituent," or substituents of any optionally substituted group may be C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, phenyl, C3-C5 heteroaryl, C3-C 10 The compounds are further substituted with one or more groups selected from cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -NH(phenyl), -N(phenyl)2, -CHO, -CO(C1-C6 alkyl), -CO(phenyl), -CO2(C1-C6 alkyl), or -CO2(phenyl). Those skilled in the art can easily select suitable substituents based on the stability and pharmacokinetic and synthetic activity of the compounds described herein.

[0070] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that elicits a biological or pharmacokinetic response in a tissue, system, animal, individual, or human, as sought by researchers, veterinarians, physicians, or other clinicians. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect may be a reduction in the severity of symptoms associated with the disorder, and / or a suppression (partial or complete) of the progression of the disorder, or treatment, cure, elimination, or improvement of the disorder, or improvement of side effects. The amount required to elicit a therapeutic response may be determined based on the age, health status, size, and sex of the subject. The optimal amount may also be determined based on monitoring the subject's response to the treatment.

[0071] As used herein, the terms “treat,” “treated,” “treatment,” or “treating” mean both therapeutic actions whose purpose is to delay (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the severity of a condition, disorder, or disease; a stabilized (i.e., non-worsening) state of a condition, disorder, or disease; delay of the onset or slowing of the progression of a condition, disorder, or disease; improvement or remission (whether partial or whole) of a condition, disorder, or disease, whether detectable or undetectable; improvement or improvement of at least one measurable physical parameter, or improvement of a condition, disorder, or disease, which is not necessarily identifiable by the patient. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the expected survival without treatment.

[0072] In various parts of this specification, substituents of a compound may be described by group or range. Embodiments are specifically intended to include any and all individual subcombinations of members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0073] In compounds where a variable appears multiple times, each variable may be a different substructure selected from the Markush group that defines the variable. For example, if a structure is described that has two R groups present on the same compound, the two R groups can represent different substructures selected from the Markush group defined for R. Another example is, for instance, [ka] In this form, when multiple substituents are specified by arbitrary choice, it is understood that substituent R can appear s times on the ring, and that R can be a different substructure in each appearance. Furthermore, in the above example, the variable T 1 If it is defined to contain hydrogen (for example, T 1 However, if the molecule is CH2, NH, etc., any H can be replaced with a substituent.

[0074] Furthermore, it should be understood that certain features described herein, which are described in the context of separate embodiments for clarity, can also be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for simplification can also be provided individually or in any suitable subcombination.

[0075] This embodiment is understood to encompass, where applicable, the use of stereoisomers, diastereomers, and optical stereoisomers of a compound, as well as mixtures thereof. Furthermore, stereoisomers, diastereomers, and optical stereoisomers of a compound, as well as mixtures thereof, are understood to be within the scope of this embodiment. As a non-limiting example, the mixture may be a racemate, or the mixture may contain certain stereoisomers in unequal proportions to other particular stereoisomers. Furthermore, the compound may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (such as epimers).

[0076] The compounds described herein may be asymmetric (for example, they may have one or more chiral centers). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by the separation or stereoselective synthesis of racemic mixtures. Many geometric isomers, such as olefins and C=N double bonds, may also exist in the compounds described herein, but all such stable isomers are intended in these embodiments. Cis and trans geometric isomers of compounds are also included within the scope of the embodiments and can be isolated as mixtures of isomers or as separated isomers. When a compound capable of stereoisomerism or geometric isomerism is specified by its structure or name without referring to a specific R / S or cis / trans configuration, all such isomers are intended to be included.

[0077] The restructuring of racemic mixtures of compounds can be carried out by any of the many methods known in the art, including, for example, chiral HPLC and fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and D and L forms of various optically active camphorsulfonic acids (e.g., β-camphorsulfonic acid). Other suitable resolving agents for fractional recrystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. Racemic mixtures can also be separated by elution using a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0078] Split compounds may also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond and the associated transfer of protons. Tautomers include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system (e.g., but are not limited to, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles). Tautomers can exist in equilibrium or can be sterically fixed into one form by appropriate substitution.

[0079] The compounds include hydrates and solvates, as well as anhydrous and non-solvated forms.

[0080] A compound may also contain all isotopes of the atoms present in the intermediate or final compound. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0081] In some embodiments, the compound or its salts are substantially isolated. Partial isolation includes, for example, an enriched composition of the compound of the embodiment. Substantial isolation may include a composition containing at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or its salt of the embodiment. Methods for isolating compounds and their salts are common in the art.

[0082] While the disclosed compounds are appropriate, other functional groups can be incorporated into the compounds for similar results. In particular, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometric pattern of the compound, and this distance can be altered by incorporating aliphatic chains of varying lengths (which may be optionally substituted and may include amino acids, dicarboxylic acids, or diamines). By replacing the amide bond with a substitute having additional atoms, the distance between monomers in the compound and the relative orientation of the monomers can also be altered. Thus, replacing a carbonyl group with a dicarbonyl changes the distance between monomers and the tendency of the dicarbonyl unit to adopt an anti-arrangement of the two carbonyl moieties, thereby altering the periodicity of the compound. Pyromellitic anhydrides represent yet another substitute for a simple amide bond, which can alter the conformation and physical properties of the compound. Modern methods in solid-phase organic chemistry (E. Atherton and RC Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford 1989) now enable the synthesis of homodisperse compounds with molecular weights close to 5,000 daltons. Other substitution patterns are equally effective.

[0083] The compounds also include derivatives called prodrugs.

[0084] Embodiments of various compounds and their salts are provided. Unless otherwise specified, variables may be any of the options described herein.

[0085] Pharmaceutical composition When used as a pharmaceutical, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. Such a composition can be prepared by methods well known in the pharmaceutical field and contains at least one active compound.

[0086] In this specification, compounds of formula (I): [ka] [In the formula, X is NH; R 1 It is (C1~C6)-alkyl; R 2 is OH; R 2 ' is H; R 3 , R 3’ , R 4 , R 4’ , R 5 , R 5’ These are independently H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O) p -R 6 OS(O) p -R 6 (C1~C6)-alkylene-S(O) p -R 6 (C1~C6)-alkylene-OS(O) p -R 6 COOH, COO(C1~C6)alkyl, CONH2, CONH(C1~C6)alkyl, CON[(C1~C6)alkyl]2, (C1~C6)-alkyl, (C2~C6)alkenyl, (C2~C6)-alkynyl, O-(C1~C6)-alkyl (where one, one or more, or all hydrogens in the alkyl radical may be replaced by fluorine); phenyl, -(CH2)-phenyl, -(CH2)2-phenyl, O-phenyl, O-(CH2) m -phenyl, -(CH2)-O-(CH2) m -phenyl (where the phenyl ring may be substituted 1 to 3 times with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1~C6)-alkyl, (C1~C6)-alkyl, NH2, NH(C1~C6)-alkyl, N((C1~C6)-alkyl)2, SO2-CH3, COOH, COO-(C1~C6)-alkyl, or CONH2); Radical R3 , R 3’ , R 4 , R 4’ , R 5 , and R 5’ At least one of them is (C1~C6)-alkylene-OS(O) p -R 6 It has the meaning of -O-(CH2) m -Having the meaning of phenyl, where the phenyl ring may be substituted 1 to 3 times with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1~C6)-alkyl, (C1~C6)-alkyl, NH2, NH(C1~C6)-alkyl, N((C1~C6)-alkyl)2, SO2-CH3, COOH, COO-(C1~C6)-alkyl, or CONH2; R 6 These are H, OH, (C1~C6)-alkyl, NH2, NH(C1~C6)-alkyl, or N((C1~C6)-alkyl)2; n is 2, 3, 4, 5, or 6; m is 1, 2, 3, 4, 5, or 6; p is 0, 1, or 2. or a pharmaceutically acceptable salt thereof, as (i) Diluents or fillers, and (ii) Disintegrant The present invention provides embodiments relating to a pharmaceutical composition comprising one or more excipients selected from the group consisting of the following.

[0087] Typically, the compound of formula (I) is administered in a therapeutically effective dose. The actual amount of compound administered is typically determined by the physician in light of relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound being administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0088] Pharmaceutical compositions of the compound of formula (I) can be administered by various routes, including orally, rectally, intraocularly, transdermally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, directly into the cerebrospinal fluid, intratracheally, and intranasally. Depending on the intended delivery route, the compound of formula (I) is preferably formulated as an oral composition.

[0089] Oral compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are presented in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physically distinct unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the active compound is usually a trace component, with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0090] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffers, suspending agents and dispersants, colorants, flavors, etc. Solid forms may include, for example, any of the following components or compounds of similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch or lactose; disintegrants, e.g., alginic acid, Primogel, or corn starch; lubricants, e.g., magnesium stearate; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose or saccharin; or flavoring agents, e.g., peppermint, methyl salicylate, or orange flavor.

[0091] Pharmaceutical compositions containing the compound of formula (I) can be prepared in combination with one or more pharmaceutically acceptable carriers. In the preparation of the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, caches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders.

[0092] In some embodiments, the composition comprising the compound of formula (I) further comprises a channeling agent.

[0093] In some embodiments, compositions comprising the compound of formula (I) further include a flow promoter, a lubricant, or a combination thereof.

[0094] In some embodiments, the composition is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (ii) Disintegrant, (iii) Channeling agent, (iv) Flow promoters, and (v) Lubricants Includes one or more selected from the group consisting of the following.

[0095] In some embodiments, the composition is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (ii) Disintegrant, (iii) Channeling agent, (iv) Flow promoters, and (v) Lubricants Includes.

[0096] In some embodiments, the composition further includes a binder.

[0097] In some embodiments, the compound of formula (I) is (C1~C6)-alkylene-S(O)2-R 6 R is 5’ It has.

[0098] In some embodiments, the compound of formula (I) has a structure selected from the group consisting of formulas (II), (III), or (IV), or is a pharmaceutically acceptable salt thereof: [ka]

[0099] In some embodiments, the compound of formula (I) has a structure selected from the group consisting of formulas (II) or (III), or is a pharmaceutically acceptable salt thereof: [ka]

[0100] In some embodiments, the compound of formula (I) is having the structure of formula (II) or a pharmaceutically acceptable salt thereof: [ka]

[0101] In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is an ammonium salt.

[0102] In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.

[0103] In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a potassium salt.

[0104] In some embodiments, the composition comprises the compound of formula (II) as potassium ethanolate hydrate: [ka]

[0105] In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a zinc salt.

[0106] In some embodiments, the composition is a compound of formula (I) having the structure of formula (II), or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (II) Disintegrant, (iii) Optional channeling agent, (iv) Flow promoters, and (v) Lubricants Includes.

[0107] This specification provides embodiments relating to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, less than 45% by weight, less than 40% by weight, less than 35% by weight, less than 30% by weight, less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 12.5% ​​by weight, less than 10% by weight, less than 7.5% by weight, less than 5%, less than 3% by weight, less than 2% by weight, or less than 1% by weight of the total composition. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 70% by weight, 65% by weight, 60% by weight, 55% by weight, 50% by weight, 45% by weight, 40% by weight, 35% by weight, 30% by weight, 25% by weight, 20% by weight, 15% by weight, 12.5% ​​by weight, 10% by weight, 7.5% by weight, 5% by weight, 3% by weight, 2% by weight, or 1% by weight of the total composition. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in amounts of about 1% to 30% by weight, 3% to 30% by weight, 5% to 30% by weight, 7.5% to 30% by weight, 10% to 30% by weight, 15% to 30% by weight, 20% to 30% by weight, 1% to 25% by weight, 3% to 25% by weight, 5% to 25% by weight, 7.5% to 25% by weight, 10% to 25% by weight, 15% to 25% by weight, 20% to 25% by weight, 1% to 20% by weight, and 3% to 20% by weight. The values ​​are %, 5% to 20% by weight, 7.5% to 20% by weight, 10% to 20% by weight, 15% to 20% by weight, 1% to 15% by weight, 3% to 15% by weight, 5% to 15% by weight, 7.5% to 15% by weight, 10% to 15% by weight, 1% to 12.5% ​​by weight, 3% to 12.5% ​​by weight, 5% to 12.5% ​​by weight, 7.5% to 12.5% ​​by weight, 10% to 12.5% ​​by weight, 1% to 10% by weight, 3% to 10% by weight, 5% to 10% by weight, or 7.5% to 10% by weight.

[0108] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, constitutes less than about 60% by weight of the total composition.

[0109] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, constitutes less than about 50% by weight of the total composition.

[0110] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5% to about 20% by weight of the total composition.

[0111] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 7.5% to about 15% by weight, about 2% to about 10% by weight, about 3% to about 10% by weight, or about 10% to about 20% by weight of the total composition.

[0112] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 7.5% by weight of the total composition.

[0113] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in about 15% by weight of the total composition.

[0114] This specification provides embodiments relating to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of less than approximately 200 mg, less than 180 mg, less than 150 mg, less than 120 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, less than 3 mg, less than 2 mg, or less than 1 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in amounts of about 200 mg, 180 mg, 150 mg, 120 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, 3 mg, 2 mg, or 1 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in doses of approximately 1 mg to 150 mg, 3 mg to 150 mg, 5 mg to 150 mg, 7.5 mg to 150 mg, 10 mg to 150 mg, 12.5 mg to 150 mg, 15 mg to 150 mg, 20 mg to 150 mg, 25 mg to 150 mg, 30 mg to 150 mg, 35 mg to 150 mg, 40 mg to 150 mg, 1 mg to 120 mg, 3 mg to 120 mg, 5 mg to 120 mg, 7.5 mg to 120 mg, 10 mg to 120 mg, 12.5 mg to 120 mg, and 15 mg to 1 20mg, 20mg~120mg, 25mg~120mg, 30mg~120mg, 35mg~120mg, 40mg~120mg, 1mg~100mg, 3mg~100mg, 5mg~100mg, 7.5mg~100mg, 10mg~100mg, 12.5mg~1 00mg, 15mg~100mg, 20mg~100mg, 25mg~100mg, 30mg~100mg, 35mg~100mg, 40mg~100mg, 1mg~80mg, 3mg~80mg, 5mg~80mg, 7.5mg~80mg, 10mg~80mg, 12.5mg~80mg, 15mg~80mg, 20mg~80mg, 25mg~80mg, 30mg~80mg, 35mg~80mg, 40mg~80mg, 1mg~60mg, 3mg~60mg, 5mg~ 60mg, 7.5mg~60mg, 10mg~60mg, 12.5mg~60mg, 15mg~60mg, 20mg~60mg, 25mg~60mg, 30mg~60mg, 35mg~60mg, 40m g~60mg, 1mg~50mg, 3mg~50mg, 5mg~50mg, 7.5mg~50mg, 10mg~50mg, 12.5mg~50mg, 15mg~50mg, 20mg~50mg, 25mg ~50mg, 30mg~50mg, 35mg~50mg, 40mg~50mg, 1mg~40mg, 3mg~40mg, 5mg~40mg, 7.5mg~40mg, 10mg~40mg, 12.5mg~4 0mg, 15mg~40mg, 20mg~40mg, 25mg~40mg, 30mg~40mg, 35mg~40mg, 1mg~30mg, 3mg~30mg, 5mg~30mg, 7.5mg~30mg , 10mg~30mg, 12.5mg~30mg, 15mg~30mg, 20mg~30mg, 25mg~30mg, 1mg~20mg, 3mg~20mg, 5mg~20mg, 7.5mg~20mg, 1 The dosages are 0mg-20mg, 12.5mg-20mg, 15mg-20mg, 1mg-15mg, 3mg-15mg, 5mg-15mg, 7.5mg-15mg, 10mg-15mg, 12.5mg-15mg, 1mg-10mg, 3mg-10mg, 5mg-10mg, 7.5mg-10mg, 1mg-7.5mg, 3mg-7.5mg, 5mg-7.5mg, 1mg-5mg, or 3mg-5mg.

[0115] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of less than approximately 100 mg.

[0116] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of less than approximately 50 mg.

[0117] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg to about 20 mg.

[0118] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg.

[0119] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 20 mg.

[0120] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in amounts of less than about 5 mg, about 5 mg to 20 mg, or more than about 20 mg.

[0121] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in amounts of less than about 10 mg, about 10 mg to 40 mg, or more than about 40 mg.

[0122] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 10 mg to about 40 mg.

[0123] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 10 mg.

[0124] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 40 mg.

[0125] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 80 mg.

[0126] In some embodiments, the diluent or filler is selected from the group consisting of sugars, dextrates, dextrins, dextrose, lactose, mannitol, sorbitol, starch, cellulose, and modified cellulose, or combinations thereof.

[0127] In some embodiments, the diluent or filler is microcrystalline cellulose (MCC), lactose, mannitol, or a combination thereof.

[0128] In some embodiments, the diluent or filler is a mixture of MCC and lactose, a mixture of MCC and mannitol, or a mixture of lactose and mannitol.

[0129] In some embodiments, the diluent or filler is less than about 99% by weight, less than 97% by weight, less than 95% by weight, less than 93% by weight, less than 90% by weight, less than 86% by weight, less than 85% by weight, less than 80% by weight, less than 75% by weight, less than 73% by weight, less than 71% by weight, less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 59% by weight, less than 55% by weight, less than 50% by weight, less than 45% by weight, less than 40% by weight, less than 35% by weight, or less than 30% by weight of the total composition. In some embodiments, the diluent or filler is about 99% by weight, 97% by weight, 95% by weight, 93% by weight, 90% by weight, 86% by weight, 85% by weight, 80% by weight, 75% by weight, 73% by weight, 71% by weight, 70% by weight, 65% by weight, 60% by weight, 59% by weight, 55% by weight, 50% by weight, 45% by weight, 40% by weight, 35% by weight, or 30% by weight of the total composition. In some embodiments, the diluent or filler is approximately 30% to 95% by weight, 40% to 95% by weight, 50% to 95% by weight, 60% to 95% by weight, 65% to 95% by weight, 70% to 95% by weight, 80% to 95% by weight, 90% to 95% by weight, 30% to 90% by weight, 40% to 90% by weight, 50% to 90% by weight, 60% to 90% by weight, 65% to 90% by weight, 70% to 90% by weight, 80% to 90% by weight, 30% to 80% by weight, 40% to 80% by weight, 50% to 80% by weight, 60% to 80% by weight, 65% to 80% by weight, 70% by weight The values ​​are 30% to 80% by weight, 30% to 85% by weight, 40% to 85% by weight, 50% to 85% by weight, 60% to 85% by weight, 65% to 85% by weight, 70% to 85% by weight, 30% to 75% by weight, 40% to 75% by weight, 50% to 75% by weight, 60% to 75% by weight, 65% to 75% by weight, 70% to 75% by weight, 30% to 70% by weight, 40% to 70% by weight, 50% to 70% by weight, 65% to 70% by weight, 30% to 65% by weight, 40% to 65% by weight, 50% to 65% by weight, 60% to 65% by weight, or 60% to 70% by weight.

[0130] In some embodiments, the total amount of diluent or filler and channeling agent is less than about 99% by weight, less than 97% by weight, less than 95% by weight, less than 93% by weight, less than 90% by weight, less than 86% by weight, less than 85% by weight, less than 80% by weight, less than 75% by weight, less than 73% by weight, less than 71% by weight, less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 59% by weight, less than 55% by weight, less than 50% by weight, less than 45% by weight, less than 40% by weight, less than 35% by weight, or less than 30% by weight of the total composition. In some embodiments, the total amount of diluent or filler and channeling agent is about 99% by weight, 97% by weight, 95% by weight, 93% by weight, 90% by weight, 86% by weight, 85% by weight, 80% by weight, 75% by weight, 73% by weight, 71% by weight, 70% by weight, 65% by weight, 60% by weight, 59% by weight, 55% by weight, 50% by weight, 45% by weight, 40% by weight, 35% by weight, or 30% by weight of the total composition. In some embodiments, the total amount of diluent or filler and channeling agent is approximately 30% to 95% by weight, 40% to 95% by weight, 50% to 95% by weight, 60% to 95% by weight, 65% to 95% by weight, 70% to 95% by weight, 80% to 95% by weight, 90% to 95% by weight, 30% to 90% by weight, 40% to 90% by weight, 50% to 90% by weight, 60% to 90% by weight, 65% to 90% by weight, 70% to 90% by weight, 80% to 90% by weight, 30% to 80% by weight, 40% to 80% by weight, 50% to 80% by weight, 60% to 80% by weight, 65% to 80% by weight The values ​​are 100%, 70%-80% of weight, 30%-85% of weight, 40%-85% of weight, 50%-85% of weight, 60%-85% of weight, 65%-85% of weight, 70%-85% of weight, 30%-75% of weight, 40%-75% of weight, 50%-75% of weight, 60%-75% of weight, 65%-75% of weight, 70%-75% of weight, 30%-70% of weight, 40%-70% of weight, 50%-70% of weight, 65%-70% of weight, 30%-65% of weight, 40%-65% of weight, 50%-65% of weight, 60%-65% of weight, or 60%-70% of weight.

[0131] In some embodiments, the diluent or filler constitutes less than about 97% by weight of the total composition.

[0132] In some embodiments, the diluent or filler is present in an amount of about 55% to about 90% by weight of the total composition.

[0133] In some embodiments, the diluent or filler is about 59% by weight, about 71% by weight, about 73% by weight, or about 86% by weight of the total composition.

[0134] In some embodiments, the diluent or filler comprises MCC and / or lactose. In some embodiments, the diluent or filler, which is MCC or lactose, is present in amounts of about 70%, 65%, 60%, 58%, 56%, 50%, 46%, 48%, 44%, 40%, 30%, 25%, 20%, 15%, 14%, 10%, 5%, 3%, or 1%. In some embodiments, the diluent or filler, which is MCC or lactose, is approximately 30%-95%, 40%-95%, 50%-95%, 60%-95%, 65%-95%, 70%-95%, 80%-95%, 90%-95%, 30%-90%, 40%-90%, 50%-90%, 60%-90%, 65%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 60%-80%, 65% These are amounts of %~80%, 70%~80%, 30%~85%, 40%~85%, 50%~85%, 60%~85%, 65%~85%, 70%~85%, 30%~75%, 40%~75%, 50%~75%, 60%~75%, 65%~75%, 70%~75%, 30%~70%, 40%~70%, 50%~70%, 65%~70%, 30%~65%, 40%~65%, 50%~65%, 60%~65%, or 60%~70%. In some embodiments, the diluent or filler, which is MCC or lactose, is present in amounts of approximately 5%-70%, 10%-70%, 15%-70%, 20%-70%, 40%-70%, 50%-70%, 5%-60%, 10%-60%, 15%-60%, 20%-60%, 40%-60%, 50%-60%, 5%-50%, 10%-50%, 15%-50%, 20%-50%, 40%-50%, 5%-40%, 10%-40%, 15%-40%, 20%-40%, 5%-30%, 10%-30%, 15%-30%, 20%-30%, 5%-20%, 10%-20%, or 15%-20%.

[0135] In some embodiments, the diluent or filler comprises MCC in an amount of about 40% to about 60% by weight of the total composition.

[0136] In some embodiments, the diluent or filler comprises MCC in an amount of about 44% by weight, about 46% by weight, about 48% by weight, about 56% by weight, or about 58% by weight of the total composition.

[0137] In some embodiments, the diluent or filler contains lactose in an amount of about 10% to about 40% by weight of the total composition.

[0138] In some embodiments, the diluent or filler contains lactose in an amount of about 14% by weight, about 15% by weight, about 25% by weight, or about 40% by weight of the total composition.

[0139] In some embodiments, the diluent or filler comprises mannitol in an amount of about 10% to about 20% by weight of the total composition.

[0140] In some embodiments, the diluent or filler comprises mannitol in an amount of about 14% by weight of the total composition.

[0141] In some embodiments, the channeling agent is selected from the group consisting of sodium chloride and polyethylene glycol (PEG), or a combination thereof.

[0142] In some embodiments, the channeling agent is sodium chloride, sugar, citric acid, sodium citrate, sodium bicarbonate, potassium chloride, potassium citrate, dextrin, fructose, sodium saccharin, or xylitol.

[0143] In some embodiments, the channeling agent is PEG.

[0144] In some embodiments, the channeling agent is PEG1500.

[0145] In some embodiments, the channeling agent is in an amount of less than about 30% by weight, less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, less than 3% by weight, or less than 1% by weight of the total composition. In some embodiments, the channeling agent is in an amount of about 30% by weight, 25% by weight, 20% by weight, 15% by weight, 14% by weight, 10% by weight, 5% by weight, 3% by weight, or 1% by weight of the total composition. In some embodiments, the channeling agent is present in amounts of approximately 1% to 30% by weight, 5% to 30% by weight, 10% to 30% by weight, 15% to 30% by weight, 20% to 30% by weight, 25% to 30% by weight, 1% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, 15% to 20% by weight, 1% to 15% by weight, 5% to 15% by weight, 10% to 15% by weight, 1% to 10% by weight, 5% to 10% by weight, or 1% to 5% by weight of the total composition.

[0146] In some embodiments, the channeling agent is present in an amount less than about 20% by weight of the total composition.

[0147] In some embodiments, the channeling agent is present in an amount of about 5% to about 15% by weight of the total composition.

[0148] In some embodiments, the channeling agent is present in an amount of about 5% by weight, about 14% by weight, or about 15% by weight of the total composition.

[0149] In some embodiments, the amount of the disintegrant is less than about 30% by weight, less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, or less than 1% by weight of the total composition. In some embodiments, the amount of the disintegrant is about 30% by weight, 25% by weight, 20% by weight, 15% by weight, 10% by weight, 5% by weight, 3% by weight, 2% by weight, or 1% by weight. In some embodiments, the disintegrant is present in amounts of 2% to 30% by weight, 5% to 30% by weight, 10% to 30% by weight, 15% to 30% by weight, 20% to 30% by weight, 2% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, 15% to 20% by weight, 2% to 15% by weight, 5% to 15% by weight, 10% to 15% by weight, 2% to 10% by weight, 5% to 10% by weight, or 2% to 5% by weight of the total composition.

[0150] In some embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, starch, and sodium starch glycolate, or combinations thereof.

[0151] In some embodiments, the amount of disintegrant is less than approximately 30%.

[0152] In some embodiments, the amount of the disintegrant is less than about 20% by weight of the total composition.

[0153] In some embodiments, the disintegrant is present in an amount of about 2% to about 10% by weight of the total composition.

[0154] In some embodiments, the disintegrant is present in an amount of about 5% by weight or about 10% by weight of the total composition.

[0155] In some embodiments, the flow enhancer is selected from the group consisting of silicon dioxide, magnesium stearate, talc, and corn starch, or a combination thereof.

[0156] In some embodiments, the flow enhancer includes silicon dioxide.

[0157] In some embodiments, the amount of the flow accelerator is less than about 10%, less than 5%, less than 2%, or less than 1%. In some embodiments, the amount of the flow accelerator is about 0.1%, 0.3%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 8%, or 10%. In some embodiments, the amount of the flow accelerator is about 0.1% to 10%, 0.3% to 10%, 0.5% to 10%, 1% to 10%, 2% to 10%, 0.1% to 5%, 0.3% to 5%, 0.5% to 5%, 1% to 5%, 2% to 5%, 0.1% to 2%, 0.3% to 2%, 0.5% to 2%, 1% to 2%, 0.1% to 1%, 0.3% to 1%, or 0.5% to 1%.

[0158] In some embodiments, the amount of the flow promoter is less than about 2% by weight of the total composition.

[0159] In some embodiments, the flow promoter is present in an amount of about 1% by weight of the total composition.

[0160] In some embodiments, the lubricant is selected from the group consisting of magnesium stearate, talc, calcium stearate, zinc stearate, sodium stearate, sodium stearyl fumarate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil, or combinations thereof.

[0161] In some embodiments, the lubricant includes magnesium stearate.

[0162] In some embodiments, the amount of lubricant is less than 10%, less than 5%, less than 2%, or less than 1%. In some embodiments, the amount of lubricant is about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 8%, or 10%. In some embodiments, the amount of lubricant is about 0.1% to 10%, 0.3% to 10%, 0.5% to 10%, 1% to 10%, 2% to 10%, 0.1% to 5%, 0.3% to 5%, 0.5% to 5%, 1% to 5%, 2% to 5%, 0.1% to 2%, 0.3% to 2%, 0.5% to 2%, 1% to 2%, 0.1% to 1%, 0.3% to 1%, or 0.5% to 1%.

[0163] In some embodiments, the amount of the lubricant is less than about 2% by weight of the total composition.

[0164] In some embodiments, the lubricant is present in an amount of about 0.5% by weight or about 1% by weight of the total composition.

[0165] In some embodiments, the composition further comprises a binder selected from the group consisting of polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch, and modified cellulose, or a combination thereof.

[0166] Embodiments relating to compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80%. In some embodiments, the composition comprises a compound of formula (I) in amounts of about 5% to 80%, 10% to 80%, 15% to 80%, 20% to 80%, 25% to 80%, 30% to 80%, 40% to 80%, 5% to 60%, 10% to 60%, and 15% to 60%. Contains in amounts of 20%-60%, 25%-60%, 30%-60%, 40%-60%, 5%-40%, 10%-40%, 15%-40%, 20%-40%, 25%-40%, 30%-40%, 5%-20%, 10%-20%, 15%-20%, or 5%-10%.

[0167] Embodiments relating to compositions containing the compound of formula (II) or a pharmaceutically acceptable salt thereof in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80% are also provided herein. In some embodiments, the composition contains the compound of formula (II) or a pharmaceutically acceptable salt thereof in amounts of about 5% to 80%, 10% to 80%, 15% to 80%, 20% to 80%, 25% to 80%, 30% to 80%, 40% to 80%, 5% to 60%, 10% to 60%, 15% to 60%, 20% to 60%, 25% to 60%, 30% to 60%, 40% to 60%, 5% to 40%, 10% to 40%, 15% to 40%, 20% to 40%, 25% to 40%, 30% to 40%, 5% to 20%, 10% to 20%, 15% to 20%, or 5% to 10%.

[0168] Embodiments relating to compositions containing the compound of formula (III) or a pharmaceutically acceptable salt thereof in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80% are also provided herein. In some embodiments, the composition contains the compound of formula (III) or a pharmaceutically acceptable salt thereof in amounts of about 5% to 80%, 10% to 80%, 15% to 80%, 20% to 80%, 25% to 80%, 30% to 80%, 40% to 80%, 5% to 60%, 10% to 60%, 15% to 60%, 20% to 60%, 25% to 60%, 30% to 60%, 40% to 60%, 5% to 40%, 10% to 40%, 15% to 40%, 20% to 40%, 25% to 40%, 30% to 40%, 5% to 20%, 10% to 20%, 15% to 20%, or 5% to 10%.

[0169] Embodiments relating to compositions containing the compound of formula (IV) or a pharmaceutically acceptable salt thereof in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80% are also provided herein. In some embodiments, the composition contains the compound of formula (IV) or a pharmaceutically acceptable salt thereof in amounts of about 5% to 80%, 10% to 80%, 15% to 80%, 20% to 80%, 25% to 80%, 30% to 80%, 40% to 80%, 5% to 60%, 10% to 60%, 15% to 60%, 20% to 60%, 25% to 60%, 30% to 60%, 40% to 60%, 5% to 40%, 10% to 40%, 15% to 40%, 20% to 40%, 25% to 40%, 30% to 40%, 5% to 20%, 10% to 20%, 15% to 20%, or 5% to 10%.

[0170] In some embodiments, the composition contains about 5% to about 60% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants If a channeling agent is not present, the amount of diluent or filler is approximately 70% to 90% by weight of the total composition, or if a channeling agent is present, the total amount of diluent or filler and channeling agent is approximately 70% to 90% by weight of the total composition.

[0171] In some embodiments, the composition contains about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants If a channeling agent is not present, the amount of diluent or filler is approximately 70% to 90% by weight of the total composition, or if a channeling agent is present, the total amount of diluent or filler and channeling agent is approximately 70% to 90% by weight of the total composition.

[0172] In some embodiments, the composition contains about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants If a channeling agent is not present, the amount of diluent or filler is approximately 70% to 90% by weight of the total composition, or if a channeling agent is present, the total amount of diluent or filler and channeling agent is approximately 70% to 90% by weight of the total composition.

[0173] In some embodiments, the composition contains about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler in an amount of about 65% to about 85% by weight of the total composition (ii) A channeling agent in an amount of about 10% to about 20% by weight of the total composition, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants Includes.

[0174] In some embodiments, the composition contains about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Diluent or filler in an amount of about 65% to about 75% by weight of the total composition, (ii) A channeling agent in an amount of about 10% to about 20% by weight of the total composition, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants Includes.

[0175] In some embodiments, the composition A disintegrant in an amount of approximately 5% to 10% by weight of the total composition. A flow promoter in an amount of approximately 0.5% to approximately 2% by weight of the total composition, and Lubricant in an amount of approximately 0.5% to 2% by weight of the total composition Includes.

[0176] In some embodiments, the composition contains about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 44% MCC, (ii) Approximately 14% lactose, (iii) Approximately 14% sodium chloride, (iv) Approximately 10% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0177] In some embodiments, the composition contains about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 44% MCC, (ii) Approximately 14% mannitol, (iii) Approximately 14% sodium chloride, (iv) Approximately 10% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0178] In some embodiments, the composition contains about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 48% MCC, (ii) Approximately 25% lactose, (iii) Approximately 5% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0179] In some embodiments, the composition contains about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 58% MCC, (ii) Approximately 15% lactose, (iii) Approximately 5% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0180] In some embodiments, the composition contains about 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 56% MCC, (ii) Approximately 15% lactose, (iii) Approximately 15% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 0.5% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0181] In some embodiments, the composition contains about 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 46% MCC, (ii) Approximately 40% lactose, (iii) Approximately 5% sodium starch glycolate, (iv) about 1% silicon dioxide, and (v) Approximately 0.5% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0182] In some embodiments, the composition contains about 6.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 56% MCC, (ii) Approximately 15% lactose, (iii) Approximately 15% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 0.5% magnesium stearate This includes, where each percentage is a weight percentage of the total composition.

[0183] This specification provides embodiments relating to pharmaceutical compositions containing a compound of formula (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in an amount of less than about 200 mg, less than 180 mg, less than 150 mg, less than 120 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, less than 3 mg, less than 2 mg, or less than 1 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in an amount of about 200 mg, 180 mg, 150 mg, 120 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, 3 mg, 2 mg, or 1 mg. In some embodiments, compounds of formula (II), (III), or (IV), or pharmaceutically acceptable salts thereof, are present in amounts of approximately 1 mg to 150 mg, 3 mg to 150 mg, 5 mg to 150 mg, 7.5 mg to 150 mg, 10 mg to 150 mg, 12.5 mg to 150 mg, 15 mg to 150 mg, 20 mg to 150 mg, 25 mg to 150 mg, 30 mg to 150 mg, 35 mg to 150 mg, 40 mg to 150 mg, 1 mg to 120 mg, 3 mg to 120 mg, 5 mg to 120 mg, 7.5 mg to 120 mg, 10 mg to 120 mg, and 12.5 mg to 120 mg. mg, 15mg~120mg, 20mg~120mg, 25mg~120mg, 30mg~120mg, 35mg~120mg, 40mg~120mg, 1mg~100mg, 3mg~100mg, 5mg~100mg, 7.5mg~100mg, 10mg~100mg, 12.5 mg~100mg, 15mg~100mg, 20mg~100mg, 25mg~100mg, 30mg~100mg, 35mg~100mg, 40mg~100mg, 1mg~80mg, 3mg~80mg, 5mg~80mg, 7.5mg~80mg, 10mg~80mg, 12.5mg~80mg, 15mg~80mg, 20mg~80mg, 25mg~80mg, 30mg~80mg, 35mg~80mg, 40mg~80mg, 1mg~60mg, 3mg~60mg, 5mg~ 60mg, 7.5mg~60mg, 10mg~60mg, 12.5mg~60mg, 15mg~60mg, 20mg~60mg, 25mg~60mg, 30mg~60mg, 35mg~60mg, 40m g~60mg, 1mg~50mg, 3mg~50mg, 5mg~50mg, 7.5mg~50mg, 10mg~50mg, 12.5mg~50mg, 15mg~50mg, 20mg~50mg, 25mg ~50mg, 30mg~50mg, 35mg~50mg, 40mg~50mg, 1mg~40mg, 3mg~40mg, 5mg~40mg, 7.5mg~40mg, 10mg~40mg, 12.5mg~4 0mg, 15mg~40mg, 20mg~40mg, 25mg~40mg, 30mg~40mg, 35mg~40mg, 1mg~30mg, 3mg~30mg, 5mg~30mg, 7.5mg~30mg , 10mg~30mg, 12.5mg~30mg, 15mg~30mg, 20mg~30mg, 25mg~30mg, 1mg~20mg, 3mg~20mg, 5mg~20mg, 7.5mg~20mg, 1 The dosages are 0mg-20mg, 12.5mg-20mg, 15mg-20mg, 1mg-15mg, 3mg-15mg, 5mg-15mg, 7.5mg-15mg, 10mg-15mg, 12.5mg-15mg, 1mg-10mg, 3mg-10mg, 5mg-10mg, 7.5mg-10mg, 1mg-7.5mg, 3mg-7.5mg, 5mg-7.5mg, 1mg-5mg, or 3mg-5mg.

[0184] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of less than approximately 100 mg.

[0185] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of less than approximately 50 mg.

[0186] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg to about 20 mg.

[0187] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in amounts of less than about 5 mg, about 5 mg to 20 mg, or more than about 20 mg.

[0188] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in amounts of less than about 10 mg, about 10 mg to 40 mg, or more than about 40 mg.

[0189] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 10 mg to about 40 mg.

[0190] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg.

[0191] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 10 mg.

[0192] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 20 mg.

[0193] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 40 mg.

[0194] In some embodiments, the composition further comprises at least one further active ingredient, the at least one further active ingredient being a compound that normalizes lipid metabolism.

[0195] In some embodiments, the composition comprises at least one further active ingredient, the at least one further active ingredient being one or more antidiabetic drugs, blood glucose-lowering active ingredients (hypoglycemic active ingredients). (ingredient), HMGCoA reductase inhibitor, cholesterol absorption inhibitor, PPARγ agonist, PPARα agonist, PPARα / γ agonist, PPARδ agonist, fibrate, MTP inhibitor, bile acid absorption inhibitor, MTP inhibitor, CETP inhibitor, high molecular weight bile acid adsorbent, LDL receptor inducer, ACAT inhibitor, antioxidant, lipoprotein lipase inhibitor, ATP-citrate lyase inhibitor, squalene synthase inhibitor, lipoprotein (a) antagonist, HM74A receptor agonist, lipase inhibitor, insulin, sulfonylurea, biguanide, meglitinide, thiazolidinedione, α-glucosidase inhibitor, active ingredient acting on ATP-dependent potassium channels in β cells, glycogen phosphorylase inhibitor, glucagon receptor antagonist, glucokinase activator, gluconeogenesis inhibitor, fructose-1,Inhibitors of 6-bisphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amide transferase, inhibitors of dipeptidyl peptidase IV, inhibitors of 11-β-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of sodium-dependent glucose transporter 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3β, inhibitors of protein kinase Cβ, endothelin A receptor antagonists, inhibitors of IκB kinase, modulators of glucocorticoid receptors, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF The group includes BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, diphenylazetidinone derivatives, leptin agonists, DA agonists (bromocriptine, doplexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators, or TR-β agonists or amphetamines.

[0196] In some embodiments, the compositions or unit dosage forms described herein are administered as emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, dissolving tablets, dissolving wafers, capsules, gel capsules, solids, semi-solids, solid forma gels, gel matrices, creams, pastes, tablets, granules, sachets, powders, and the like.

[0197] In some embodiments, the composition is in a solid dosage form.

[0198] In some embodiments, the solid dosage form is a capsule, pill, cachet, tablet, granule, or powder.

[0199] In some embodiments, the composition is stable for at least 9 weeks at room temperature and 60% relative humidity (RH).

[0200] In some embodiments, the composition is stable for at least 8 weeks at 40 °C and 75% RH.

[0201] In some embodiments, the composition is stable for at least about 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 58, or 64 months. In some embodiments, the composition is stable for about 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 58, or 64 months

[0202] In some embodiments, the composition is stable for at least 3 months.

[0203] In some embodiments, the composition is stable for at least 4 months.

[0204] In some embodiments, the composition is stable for at least 36 months.

[0205] Methods of treatment Embodiments are provided herein related to methods of treating cholestatic liver disease in a subject that needs it, the method comprising administering to the subject a therapeutically effective amount of the above pharmaceutical composition.

[0206] In an embodiment, the cholestatic liver disease is pediatric cholestatic liver disease.

[0207] In an embodiment, the cholestatic liver disease is adult cholestatic liver disease.

[0208] In this embodiment, cholestatic liver disease includes non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition associated cholestasis, and paraneoplastic cholestasis. These include cholestasis, Stauffer syndrome, pregnancy-related intrahepatic cholestasis (ICP), contraceptive-associated cholestasis, drug-associated cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai procedure, biliary atresia after liver transplant, cholestasis after liver transplant, post-liver transplant-associated liver disease, intestinal failure-associated liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

[0209] In this embodiment, cholestatic liver disease is selected from the group consisting of ALGS, PFIC, BA, ICP, BRIC, PSC, and PBC.

[0210] In this embodiment, cholestatic liver disease is PSC.

[0211] In this embodiment, cholestatic liver disease is PBC.

[0212] In one embodiment, cholestatic liver disease is ICP.

[0213] In this embodiment, cholestatic liver disease is characterized by pruritus.

[0214] In some embodiments, the subjects have elevated total serum bile acid (sBA) levels prior to administration of the pharmaceutical composition.

[0215] In this embodiment, the compound of formula (I) is an ileal bile acid transporter (IBAT) inhibitor.

[0216] In this embodiment, the compound of formula (I) has the structure of the compound of formula (II), which is an ileal bile acid transporter (IBAT) inhibitor.

[0217] Embodiments of methods for treating hyperlipidemia in subjects requiring such treatment are also provided herein, the methods comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to the subject.

[0218] Embodiments of methods for lowering serum cholesterol levels in subjects requiring such reduction are also provided herein, and these methods include administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to the subject.

[0219] Furthermore, embodiments of methods for treating arteriosclerosis in subjects requiring such treatment are also provided herein, the methods comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to the subject.

[0220] Furthermore, embodiments of methods for treating X syndrome in subjects requiring such treatment are also provided herein, the methods comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to the subject.

[0221] The pharmaceutical compositions of the present invention can be administered by various routes, including orally, rectally, intraocularly, transdermally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, directly into the cerebrospinal fluid, intratracheally, and intranasally. In some embodiments, the composition is administered orally to the subject.

[0222] Method for manufacturing pharmaceutical compositions and kits Embodiments regarding methods for manufacturing the above pharmaceutical composition are provided herein. The method comprises combining a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with (i) a diluent or filler; (ii) a disintegrant; (iii) a channeling agent; (iv) a flow promoter; and (v) a lubricant selected from the group consisting of one or more excipients to form a mixture, mixing the mixture, and filling the mixture into a capsule shell or compressing the mixture to form a pharmaceutical composition.

[0223] Furthermore, embodiments regarding a kit for treating cholestatic liver diseases in a subject in need thereof are provided herein. The kit comprises at least one unit dosage of the above composition at a therapeutically effective amount and an instruction for its administration.

[0224] In some embodiments, the kit is for treating cholestatic liver diseases, which are non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, central venous nutrition-related cholestasis, tumor-associated cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive pill-related cholestasis, drug-related cholestasis, infection-related cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai operation, biliary atresia after liver transplantation, cholestasis after liver transplantation, liver diseases related to liver transplantation, intestinal failure complicated with liver damage, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

[0225] In some embodiments, cholestatic liver disease is ALGS, PFIC, BA, ICP, BRIC, PSC, or PBC.

[0226] In some embodiments, the kit is intended for treating cholestatic liver disease, which is PSC.

[0227] In some embodiments, the kit is for treating cholestatic liver disease, which is PBC.

[0228] In some embodiments, the kit is for treating cholestatic liver disease, which is ICP.

[0229] Furthermore, embodiments relating to a kit for treating hyperlipidemia in a subject of interest are provided herein, the kit comprising a therapeutically effective amount of the above composition.

[0230] Furthermore, embodiments relating to a kit for lowering serum cholesterol levels in a subject requiring such reduction, the kit comprising a therapeutically effective amount of the above composition.

[0231] Furthermore, embodiments relating to a kit for treating arteriosclerosis in subjects requiring it, the kit comprising a therapeutically effective amount of the above composition.

[0232] Furthermore, embodiments relating to a kit for treating X syndrome in subjects requiring it, the kit comprising a therapeutically effective amount of the above composition, [Examples]

[0233] The following examples are provided to further illustrate some of the embodiments disclosed herein. The examples are intended to illustrate, and not limit, the embodiments disclosed.

[0234] Example 1. Compatibility of excipients Binary formulations of vorixibat potassium were prepared with the excipients outlined in Table 1.1 in either a 1:1 or 10:1 ratio. Powder-grade excipients were used to maximize surface area interactions between the excipients and the drug substance.

[0235] Each formulation was prepared with a total sample size of 300 mg. Vorixibat and each excipient were weighed into glass vials and mixed by vortex mixing. Single vials of each formulation were loosely sealed and stored under two storage conditions: ambient temperature / 60%RH and 40°C / 75%RH. Humidity control was achieved by using a saturated salt solution in a sealed container. Samples were taken from single vials of each formulation at all three planned time points (T=2, 4, and 8 weeks). A standard solution of Vorixibat DS prepared at nominal concentration in analytical diluent was used as the data point at T=0. Undiluted neat, loose drug substance powder was stored in the same vial configuration and used as a control under each storage condition.

[0236] At the specified time, approximately 50 mg of each formulation was sampled and diluted with 50 mL (for 1:1 formulations) or 100 mL (for 1:10 formulations and undiluted (neat) DS) of analytical diluent to a target nominal analytical concentration of 0.5 mg / mL of vorixivate. HPLC analysis was performed using the above parameters with HPLC parameters (gradient elution). [Table 1-1]

[0237] The potency of the samples varied significantly at each time point. This variability is expected considering sampling variability, potential water absorption under open-dish conditions, and the effect of insoluble excipients on dilution. Although the potency data were not used to trend stability, they were reported as supporting data for evaluation along with the impurity profile.

[0238] For all samples, purity remained stable under both storage conditions; samples stored at 40°C / 75%RH showed a slightly greater increase in the associated substances. The overall peak purity of porixibat remained stable for all samples under both storage conditions, demonstrating acceptable compatibility with all excipients tested. [Table 1-2] [Table 1-3]

[0239] The NaCl:porixibat mixture exhibited significant water uptake under storage conditions of 40°C / 75%RH, resulting in sample aggregation and stickiness (Figure 1). Samples of NaCl:porixibat at room temperature (RT) / 60%RH did not show physical aggregation or a significant increase in RRT 0.86.

[0240] PEG1500:vorixivate formulations stored at 40°C / 75%RH showed some formation of hard aggregates by 2 weeks (see Figure 2), but remained unchanged throughout the remainder of the study period. This aggregation was not evident in the RT / 60%RH samples. Under both storage conditions, there was no change in the associated substance profile of PEG1500:vorixivate over 8 weeks.

[0241] All other samples remained white loose powder throughout the testing process. No color changes or significant aggregation were observed under any storage conditions (Figures 3-4).

[0242] Example 2. Formulation Development Overview of the formulation [Table 2-1] [Table 2-2]

[0243] Formulations 1 and 2 were prepared using 15% w / w vorixibat potassium (without applying any correction factors). These two formulations were first tested as 20 mg capsules. Since the flow characteristics and dissolution results were similar for both formulations, the diluent system of Formulation 1 was selected. Formulations 3 and 4 were prepared by reducing the levels of the channeling agent and disintegrant, and compensating for the reduction by increasing either lactose (Formulation 3) or Avicel® (Formulation 4). In this case as well, there was no significant effect on the flow characteristics or dissolution characteristics of the 20 mg capsules. The dissolution profiles of Formulations 3 and 4 were consistent with each other and also with Formulation 1. This confirmed that the levels of sodium chloride and sodium starch glycolate in the final formulation could be reduced as needed. Formulation 3 (with increased lactose) showed lower release in phosphate buffer than Formulation 4 (with increased Avicel®), therefore, for Formulation 5, it was determined that increasing the amount of Avicel® is preferable when adapting to formulation changes.

[0244] Formulation 5 was prepared using a lower concentration of potassium porixibat in the formulation. Magnesium stearate was also reduced in Formulation 5. Formulation 5 exhibited acceptable dissolution and flow characteristics, and segregation and dissolution changes due to excessive lubrication were also evaluated. Content uniformity maintained a low %RSD when tested on day 0 and day 7 after formulation preparation (no segregation was observed), and over-mixing of the formulation did not affect the dissolution profile.

[0245] Formulation 6 was formulated without NaCl, and all 20 mg capsules were tested in the same medium set. Increased dose of Avicel® (Formulation 4) resulted in higher release in phosphate buffer (pH 6.8), but the elution results in the acidic medium (acetate buffer, pH 4.5) were improved with higher levels of lactose (Formulation 3). Formulation 6 did not achieve complete release in 0.1N HCl despite solubility data indicating that sink conditions were met. Further investigation concluded that porixivat extraction was limited in 0.1N HCl even without the excipient (Example 2). The acidic medium was changed to 0.01N HCl. Formulation 6 was further evaluated in each medium (0.01N HCl, phosphate buffer, and acetate buffer) to provide information on the effect of NaCl in the formulation.

[0246] Evaluation of the target dose of formulation 1-2: 40 mg, and the diluent system. Formulations 1 and 2 were prepared using 15% w / w vorixibat potassium. The diluent system for Formulation 1 was representative of existing vorixibat capsule formulations, while Formulation 2 contained mannitol instead of lactose. Historical dissolution data for vorixibat capsules showed that higher active ingredient content (dosage strength) (20 mg) resulted in gelation and slowed release. For each formulation, the effect of tamping on capsule release was determined by filling the capsules using either tamping or loose-fill methods. Dissolution tests were performed in 900 mL of phosphate buffer (pH 6.8). Both formulations showed immediate dissolution, and the capsule contents dispersed within 7–10 minutes. No gelation was observed, and there were no significant differences in release between formulations or between tamped and loose-fill capsules. Figure 5 shows the superposition of dissolution profiles for Formulation 1 and Formulation 2 (n=6, including both tamped and bulk capsules). Formulations 1 and 2 were equivalent, so the diluent system was maintained as Avicel® lactose for consistency with existing capsule formulations. Subsequent formulations 3 and 4 were evaluated for reductions in the channeling agent (NaCl) and disintegrant (sodium starch glycolate).

[0247] Formulation 3-4: Optimization of channeling agent and disintegrant Formulations 3 and 4 were prepared using reduced levels of NaCl and sodium starch glycolate. To compensate for the reduction in these components, formulation 3 had an increased proportion of Avicel®, while formulation 4 had an increased amount of lactose. Furthermore, the target weight of boroxybat potassium during formulation preparation was determined by including the potency (0.9165) and salt correction factor in the calculation to reach a wt% (%w / w) of boroxybat potassium. The bulk density / tap density and angle of repose indicated that each of these formulations had similar flow characteristics to formulations 1 and 2 (Table 2.1). [Table 2-3]

[0248] The dissolution of a 40 mg dose was tested using size 0 gelatin capsules in phosphate buffer (pH 6.8) to evaluate the effects of dose reductions in the channeling and disintegrating agents. The filled weight of these capsules was 280 mg. To align with the current analytical method, the dissolution solution volume was changed from 900 mL to 500 mL. Considering the high water solubility of vorixibat (>200 mg / mL at 25°C), the sink conditions were still met even with a 40 mg capsule (0.08 mg / mL) in 500 mL. As a control, vorixibat formulation 1 was also retested in 500 mL of dissolution medium, but the filled weight of the 40 mg capsule was adjusted to 304.7 mg to include potency correction.

[0249] Formulations 1, 3, and 4 showed similar dissolution in 500 mL of phosphate buffer (pH 6.8) (Figure 6). Formulation 3 (with increased lactose) had the lowest overall recovery rate and the highest variability. For Formulation 5, the lactose level was maintained at 15%, and Avicel® was increased to accommodate the formulation change. For Formulations 3 and 4, there was no impact on the visual dissolution of the capsules or the overall dissolution rate, and it was confirmed that the channeling and disintegrants in the formulations could be reduced as needed without affecting the release profile of the 40 mg capsules.

[0250] Target dose of formulation 5:20 mg Formulation 5 has a similar composition to Formulation 1, but is designed to have a lower drug load and to reduce sodium starch glycolate (disintegrant) from 10% to 5%. NaCl (channeling agent) was maintained at the original level of 15%. Magnesium stearate was reduced to 0.5% based on the excessive lubrication problem previously observed with other vorixibat formulations. Based on the results observed with Formulations 3-4 (a slight improvement in dissolution with increased Avicel® compared to lactose), the wt% (%w / w) of Avicel® was increased to accommodate the weight changes of the other components. As with Formulations 3-4, the amount of vorixibat potassium added was corrected to correspond to the salt and purity coefficient. See Table 2.4. [Table 2-4]

[0251] Evaluation of Formulation 5 for segregation and excessive lubrication. Formulation 5 was used to evaluate potential segregation and over-lubrication studies. The formulation was tested for assay, content unity ("CU"), and dissolution at T=0, and then allowed to stand for 7 days (stored in a sealed glass bottle in an aluminum bag). After 7 days, CU was retested to evaluate segregation. CU was tested by sampling 280 mg from 10 different locations in the jar (total batch size in the jar was 50 g). The formulation was then mixed in a turbol for a further 5 minutes to create over-lubrication. The over-mixed formulation was filled into size 0 capsules and tested for dissolution in 500 mL of phosphate buffer (pH 6.8). The filtration step was not used in the dissolution tests at T=0 or T=7.

[0252] The T=0 assay for formulation 5 yielded 97.30% LC and 99.85% purity. Dissolution tests were performed at T=0 on a total of six capsules (n=3 bulk-filled and n=3 tamped-filled). Consistent with previous formulations, the level of tamping did not affect the capsule dissolution profile: the capsules dissolved, the contents dispersed within 10 minutes, and the majority of the release was obtained by 15 minutes (Figure 7).

[0253] Table 2.5 includes CU results for T=0 and after 7 days of standing on a benchtop. CU samples at T=0 and T=7 days had a lower RSD of approximately 3%. USP <905> The Acceptance Value (AV) calculated according to the instructions was 4.78 at T=0 and 7.50 at T=7 days. Despite the slight increase in AV, both values ​​were within the USP <905> The values ​​were below the recommended limit of 15 outlined, and similar RSDs at both time points indicate that batch uniformity did not change significantly after 7 days of storage.

[0254] After testing the formulation for CU at T=7 days, the formulation was mixed for an additional 5 minutes in a tarbeller to over-slip the mixture. Capsules were filled to a 20 mg dose (tamping), and dissolution in phosphate buffer (pH 6.8) was evaluated. Dissolution was consistent with the T=0 result, indicating that the additional mixing did not significantly over-slip the mixture. See Figure 8. It is surprising and unexpected that lower magnesium stearate levels may be beneficial in the final formulation. [Table 2-5]

[0255] Example 3. Elution in various media Formulations 1, 3, 4, and 5 were tested for elution in three different media: phosphate buffer (pH 6.8), acetate buffer (pH 4.5), and 0.1N HCl.

[0256] Elution in acetate buffer (pH 4.5) Figure 9 shows a superposition of the elution results in acetate buffer (pH 4.5). This release was consistent with visual observations during the test; the capsules dissolved completely, and the contents dispersed easily within 10–15 minutes. No aggregation or gelation was observed in any of the formulations in acetate buffer (pH 4.5).

[0257] Elution in phosphate buffer (pH 6.8) Formulations 1, 3, 4, 5, and 6 were filled into size 1 capsules to a target dose of 20 mg, and their dissolution in 500 mL of phosphate buffer (pH 6.8) was tested.

[0258] Similar to acetate buffer, the elution profiles were similar for all formulations, although formulations 5 and 6 achieved the best overall release (Figure 10). [Table 3-1]

[0259] Elution in acidic media First, we examined the evaluation of all formulations in 0.1N HCl. [Table 3-2] [Table 3-3]

[0260] Similar to the dissolution tests in phosphate buffer and acetate buffer, dissolution tests in 0.01N HCl were performed using each formulation filled to a target dose of 20 mg in size 1 gelatin capsules. The medium volume was 500 mL, a transparent container was used, and neutralization was performed immediately after each sample (0.5 mL of 0.01N NaOH was added to 0.5 mL of the elution sample) to limit degradation between sampling and analysis. The results are summarized in Figure 11 and Table 3.4.

[0261] Summary of elution results Table 3.4 shows the 60-minute dissolution results (average of 6 containers) for each formulation in three different media. In phosphate buffer (pH 6.8), all formulations yielded similar vorixibat capsule release profiles and final recovery percentages. Differences between formulations were more pronounced in lower pH media. All formulations showed generally slower release profiles and lower final recovery percentages in 0.01N HCl, although formulation 4 had a significantly lower overall recovery percentage. Formulations 1, 3, and 4 had higher drug loads (15% vorixibat compared to 7.5% in formulations 5 and 6). Formulations 3 and 4 also had lower levels of sodium chloride (5% compared to 15% in the other formulations), formulation 3 had a higher percentage of lactose, and formulation 4 had a higher level of Avicel® to compensate for the lower NaCl level. Formulation 4 showed higher recovery rates than Formulation 3 in the nominal medium (phosphate buffer, pH 6.8) when tested at both 20 mg and 40 mg doses; therefore, Formulation 5 was subjected to a higher Avicel® load to adapt to the formulation change. Formulation 4 performed better than Formulation 3 in phosphate buffer (pH 6.8), but showed lower recovery rates in both acetate buffer and 0.01N HCl, suggesting that an increase in lactose may be beneficial for porixivat elution at lower pH values. Based on these results, Formulation 6 was prepared by removing NaCl and increasing lactose to adapt to the desired elution in the 0.1N HCl medium. Formulation 6 did not show improved elution in 0.1N HCl, so the acidic medium used for elution screening was changed to 0.01N HCl. Formulation 5 maintained a higher Avicel®:lactose ratio based on improved elution in the nominal phosphate buffer (pH 6.8). As shown in Table 3.4, formulations 5 and 6 exhibited similar performance in all three media tested. [Table 3-4]

[0262] Example 4. Testing of Formulation 7 Formulation 7 was developed using 6.55% VLX and filled into size 4 and size 0 capsules (see Table 4.1). For a 5 mg dose in size 4 capsules, the filling amount was 80 mg, and for a 20 mg dose in size 0 capsules, the filling amount was 320 mg. Pro-filled formulation 7 was successful with these target filling amounts and capsule sizes. All capsules were weight-sorted within a tolerance of ±5% of the target filling weight.

[0263] The flow characteristics and elution results for formulation 7 are shown in Table 4.2 and Figure 12. Elution in each medium was very consistent for formulations 5 and 7, with approximately 95% released in phosphate buffer (pH 6.8) and acetate buffer (pH 4.5), and only 85% released in 0.01N HCl. [Table 4-1] [Table 4-2]

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, X is NH; R １ is (C １ ~C ６ ) - Alkyl; R ２ is OH; R ２ ' is H; R ３ 、R ３’ 、R ４ 、R ４’ 、R ５ 、R ５’ are each independently H, Cl, Br, I, OH, -(CH ２ )-OH, CF ３ , NO ２ , N ３ , CN, S(O) ｐ -R ６ , O-S(O) ｐ -R ６ , (C １ ~C ６ )-alkylene-S(O) ｐ -R ６ , (C １ ~C ６ )-alkylene-O-S(O) ｐ -R ６ , COOH, COO(C １ ~C ６ )alkyl, CONH ２ , CONH(C １ ~C ６ )alkyl, CON[(C １ ~C ６ )alkyl] ２ , (C １ ~C ６ )-alkyl, (C ２ ~C ６ )alkenyl, (C ２ ~C ６ )-alkynyl, O-(C １ ~C ６ )-alkyl (where one, one or more, or all of the hydrogens in the alkyl radical may be replaced by fluorine); phenyl, -(CH ２ )-phenyl, -(CH ２ ) ２ -phenyl, O-phenyl, O-(CH ２ ) ｍ -phenyl, -(CH ２ )-O-(CH ２ ) ｍ -phenyl (where the phenyl ring is F, Cl, Br, I, OH, CF ３ , NO ２ , CN, OCF ３ , O-(C １ ~C ６ )-alkyl, (C １ ~C ６ )-alkyl, NH ２ NH(C １ ~C ６ )-alkyl, N((C １ ~C ６ )-alkyl) ２ SO ２ -CH ３ , COOH, COO-(C １ ~C ６ )-alkyl, or CONH ２ (It may be substituted one to three times by; Radical R ３ 、R ３’ 、R ４ 、R ４’ 、R ５ 、and R ５’ at least one of which has the meaning of (C １ ~C ６ )-alkylene-O-S(O) ｐ -R ６ ; another has the meaning of -O-(CH ２ ) ｍ -phenyl, where the phenyl ring is substituted 1 to 3 times by F, Cl, Br, I, OH, CF ３ , NO ２ , CN, OCF ３ , O-(C １ ~C ６ )-alkyl, (C １ ~C ６ )-alkyl, NH ２ , NH(C １ ~C ６ )-alkyl, N((C １ ~C ６ )-alkyl) ２ , SO ２ -CH ３ , COOH, COO-(C １ ~C ６ )-alkyl, or CONH ２ and may be substituted 1 to 3 times; R ６ H, OH, (C １ ~C ６ )-alkyl, NH ２ NH(C １ ~C ６ )-alkyl, or N((C １ ~C ６ )-alkyl) ２ And; n is 2, 3, 4, 5, or 6; m is 1, 2, 3, 4, 5, or 6; p is 0, 1, or 2. or a pharmaceutically acceptable salt thereof, as (i) Diluents or fillers, and (ii) Disintegrant A pharmaceutical composition comprising one or more excipients selected from the group consisting of the following:

2. The composition according to claim 1, further comprising a channeling agent.

3. The composition according to claim 1 or 2, further comprising a flow promoter, a lubricant, or a combination thereof.

4. Compounds of formula (I) or pharmaceutically acceptable salts thereof, as well as (i) Diluent or filler, (ii) Disintegrant, (iii) Channeling agent, (iv) Flow promoters, and (v) Lubricants A composition according to any one of claims 1 to 3, comprising:

5. The composition according to claims 1 to 3, further comprising a binder.

6. R ５’ is (C １ ~C ６ )-alkylene-S(O) ２ -R ６ The composition according to any one of claims 1 to 4.

7. Compounds of formula (I) are those of formula (II), (III), or (IV): 【Chemistry 2】 The composition according to any one of claims 1 to 6, having a structure selected from the group consisting of or a pharmaceutically acceptable salt thereof.

8. Compounds of formula (I) are of formula (II) or (III): 【Transformation 3】 The composition according to any one of claims 1 to 7, having a structure selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

9. The compound of formula (I) is formula (II): 【Chemistry 4】 A composition according to any one of claims 1 to 8, having the structure of or a pharmaceutically acceptable salt thereof.

10. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is an ammonium salt.

11. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.

12. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is a potassium salt.

13. The compound of formula (II) is potassium ethanolate hydrate: 【Transformation 5】 A composition according to any one of claims 1 to 9, comprising as follows:

14. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is a zinc salt.

15. Compounds of formula (I) having the structure of formula (II), or pharmaceutically acceptable salts thereof, and (i) Diluent or filler, (II) Disintegrant, (iii) Optional channeling agent, (iv) Flow promoters, and (v) Lubricants A composition according to any one of claims 1 to 14, comprising:

16. The composition according to any one of claims 1 to 15, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, constitutes less than about 60% by weight of the total composition.

17. The composition according to any one of claims 1 to 16, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, constitutes less than about 50% by weight of the total composition.

18. The composition according to any one of claims 1 to 15, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 5% to about 20% by weight of the total composition.

19. The composition according to any one of claims 1 to 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 7.5% to about 15% by weight, about 2% to about 10% by weight, about 3% to about 10% by weight, or about 10% to about 20% by weight of the total composition.

20. The composition according to any one of claims 1 to 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 7.5% by weight of the total composition.

21. The composition according to any one of claims 1 to 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 15% by weight of the total composition.

22. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of less than about 100 mg.

23. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of less than about 50 mg.

24. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 20 mg.

25. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg.

26. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 20 mg.

27. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in an amount of less than about 5 mg, about 5 mg to 20 mg, or more than about 20 mg.

28. The composition according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in an amount of less than about 10 mg, about 10 mg to 40 mg, or more than about 40 mg.

29. The composition according to any one of claims 1 to 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg to about 40 mg.

30. The composition according to any one of claims 1 to 29, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg.

31. The composition according to any one of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 40 mg.

32. The composition according to any one of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 80 mg.

33. The composition according to any one of claims 1 to 31, wherein the diluent or filler is selected from the group consisting of sugar, dextrate, dextrin, dextrose, lactose, mannitol, sorbitol, starch, cellulose, and modified cellulose, or a combination thereof.

34. The composition according to claim 33, wherein the diluent or filler is microcrystalline cellulose (MCC), lactose, mannitol, or a combination thereof.

35. The composition according to claim 33, wherein the diluent or filler is a mixture of MCC and lactose, a mixture of MCC and mannitol, or a mixture of lactose and mannitol.

36. The composition according to any one of claims 1 to 35, wherein the diluent or filler constitutes less than about 97% by weight of the total composition.

37. The composition according to any one of claims 1 to 36, wherein the diluent or filler is in an amount of about 55% to about 90% by weight of the total composition.

38. The composition according to any one of claims 1 to 37, wherein the diluent or filler is in an amount of about 59% by weight, about 71% by weight, about 73% by weight, or about 86% by weight of the total composition.

39. The composition according to any one of claims 1 to 38, wherein the diluent or filler comprises MCC in an amount of about 40% to about 60% by weight of the total composition.

40. The composition according to any one of claims 1 to 39, wherein the diluent or filler comprises MCC in an amount of about 44% by weight, about 46% by weight, about 48% by weight, about 56% by weight, or about 58% by weight of the total composition.

41. The composition according to any one of claims 1 to 40, wherein the diluent or filler contains lactose in an amount of about 10% to about 40% by weight of the total composition.

42. The composition according to any one of claims 1 to 41, wherein the diluent or filler contains lactose in an amount of about 14% by weight, about 15% by weight, about 25% by weight, or about 40% by weight of the total composition.

43. The composition according to any one of claims 1 to 40, wherein the diluent or filler comprises mannitol in an amount of about 10% to about 20% by weight of the total composition.

44. The composition according to claims 1 to 43, wherein the diluent or filler comprises mannitol in an amount of about 14% by weight of the total composition.

45. The composition according to any one of claims 1 to 44, wherein the channeling agent is selected from the group consisting of sodium chloride, polyethylene glycol (PEG), or a combination thereof.

46. The composition according to any one of claims 1 to 45, wherein the channeling agent is sodium chloride, sugar, citric acid, sodium citrate, sodium bicarbonate, potassium chloride, potassium citrate, dextrin, fructose, sodium saccharin, or xylitol.

47. The composition according to any one of claims 1 to 45, wherein the channeling agent is PEG.

48. The composition according to claim 47, wherein the channeling agent is PEG1500.

49. The composition according to any one of claims 1 to 48, wherein the channeling agent is in an amount of less than about 20% by weight of the total composition.

50. The composition according to any one of claims 1 to 48, wherein the channeling agent is in an amount of about 5% to about 15% by weight of the total composition.

51. The composition according to any one of claims 1 to 48, wherein the channeling agent is in an amount of about 5% by weight, about 14% by weight, or about 15% by weight of the total composition.

52. The composition according to any one of claims 1 to 51, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, starch, and sodium starch glycolate, or a combination thereof.

53. The composition according to any one of claims 1 to 52, wherein the disintegrant is present in an amount less than about 20% by weight of the total composition.

54. The composition according to any one of claims 1 to 53, wherein the disintegrant is present in an amount of about 2% to about 10% by weight of the total composition.

55. The composition according to any one of claims 1 to 54, wherein the disintegrant is in an amount of about 5% by weight or about 10% by weight of the total composition.

56. The composition according to any one of claims 1 to 55, wherein the flow promoter is selected from the group consisting of silicon dioxide, magnesium stearate, talc, and corn starch, or a combination thereof.

57. The composition according to any one of claims 1 to 56, wherein the flow promoter comprises silicon dioxide.

58. The composition according to any one of claims 1 to 57, wherein the amount of the flow promoter is less than about 2% by weight of the total composition.

59. The composition according to any one of claims 1 to 58, wherein the flow promoter is present in an amount of about 1% by weight of the total composition.

60. The composition according to any one of claims 1 to 59, wherein the lubricant is selected from the group consisting of magnesium stearate, talc, calcium stearate, zinc stearate, sodium stearate, sodium stearyl fumarate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil, or a combination thereof.

61. The composition according to any one of claims 1 to 60, wherein the lubricant comprises magnesium stearate.

62. The composition according to any one of claims 1 to 61, wherein the amount of the lubricant is less than about 2% by weight of the total composition.

63. The composition according to any one of claims 1 to 62, wherein the lubricant is in an amount of about 0.5% by weight or about 1% by weight of the total composition.

64. The composition according to any one of claims 1 to 63, further comprising a binder selected from the group consisting of polyvinylpyrrolidone, calcium monohydrogen phosphate, sucrose, corn starch, and modified cellulose, or a combination thereof.

65. The total composition contains approximately 5% to approximately 60% by weight of a compound of formula (II) or a pharmaceutically acceptable salt thereof, as well as (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants The composition according to any one of claims 1 to 64, comprising, if the channeling agent is not present, the amount of the diluent or filler is about 70% to about 90% by weight of the total composition, or if the channeling agent is present, the total amount of the diluent or filler and the channeling agent is about 70% to about 90% by weight of the total composition.

66. The total composition contains approximately 5% to 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, as well as (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants The composition according to any one of claims 1 to 64, comprising, if the channeling agent is not present, the amount of the diluent or filler is about 70% to about 90% by weight of the total composition, or if the channeling agent is present, the total amount of the diluent or filler and the channeling agent is about 70% to about 90% by weight of the total composition.

67. The total composition contains approximately 5% to 10% by weight of a compound of formula (II) or a pharmaceutically acceptable salt thereof, as well as (i) Diluent or filler, (ii) Optional channeling agent, (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants The composition according to any one of claims 1 to 66, comprising, if the channeling agent is not present, the amount of the diluent or filler is about 70% to about 90% by weight of the total composition, or if the channeling agent is present, the total amount of the diluent or filler and the channeling agent is about 70% to about 90% by weight of the total composition.

68. The total composition contains approximately 5% to 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, as well as (i) Diluent or filler in an amount of about 65% to about 85% by weight of the total composition (ii) A channeling agent in an amount of about 10% to about 20% by weight of the total composition. (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants A composition according to any one of claims 1 to 66, comprising:

69. The total composition contains approximately 5% to 10% by weight of a compound of formula (II) or a pharmaceutically acceptable salt thereof, as well as (i) Diluent or filler in an amount of about 65% to about 75% by weight of the total composition (ii) A channeling agent in an amount of about 10% to about 20% by weight of the total composition. (iii) Disintegrant, (iv) Flow promoters, and (v) Lubricants A composition according to any one of claims 1 to 66, comprising:

70. A disintegrant in an amount of approximately 5% to 10% by weight of the total composition. A flow promoter in an amount of about 0.5% to about 2% by weight of the total composition, and Lubricant in an amount of approximately 0.5% to approximately 2% by weight of the total composition A composition according to any one of claims 1 to 69, comprising:

71. Approximately 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 44% MCC, (ii) Approximately 14% lactose, (iii) Approximately 14% sodium chloride, (iv) Approximately 10% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

72. Approximately 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 44% MCC, (ii) Approximately 14% mannitol, (iii) Approximately 14% sodium chloride, (iv) Approximately 10% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

73. Approximately 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 48% MCC, (ii) Approximately 25% lactose, (iii) Approximately 5% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

74. Approximately 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 58% of MCC, (ii) Approximately 15% lactose, (iii) Approximately 5% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 1% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

75. Approximately 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 56% MCC, (ii) Approximately 15% lactose, (iii) Approximately 15% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 0.5% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

76. Approximately 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 46% MCC, (ii) Approximately 40% lactose, (iii) Approximately 5% sodium starch glycolate, (iv) about 1% silicon dioxide, and (v) Approximately 0.5% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

77. Approximately 6.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) Approximately 56% MCC, (ii) Approximately 15% lactose, (iii) Approximately 15% sodium chloride, (iv) Approximately 5% sodium starch glycolate, (v) Approximately 1% silicon dioxide, and (vi) Approximately 0.5% magnesium stearate The composition according to any one of claims 1 to 64, comprising, where each percentage is a weight percentage of the total composition.

78. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of less than about 100 mg.

79. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of less than about 50 mg.

80. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 20 mg.

81. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is in an amount of less than about 5 mg, about 5 mg to 20 mg, or more than about 20 mg.

82. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is in an amount of less than about 10 mg, about 10 mg to 40 mg, or more than about 40 mg.

83. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg to about 40 mg.

84. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg.

85. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg.

86. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 20 mg.

87. The composition according to any one of claims 1 to 77, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of about 40 mg.

88. The composition according to any one of claims 1 to 87, further comprising at least one further active ingredient, wherein the at least one further active ingredient is a compound that normalizes lipid metabolism.

89. The present invention comprises at least one further active ingredient, the at least one further active ingredient being one or more antidiabetic agents, blood glucose lowering active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPARγ agonists, PPARα agonists, PPARα / γ agonists, PPARδ agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, MTP inhibitors, CETP inhibitors, high molecular weight bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipa Lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein (α) antagonists, HM74A receptor agonists, lipase inhibitors, insulin, sulfonylurea drugs, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients acting on ATP-dependent potassium channels in β cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose-1,6-bisphosphatase inhibitors, glucose transporter 4 modulators, glutamine-fructose-6-phosphate amide transferase inhibitors, dipeptidyl peptidase IV inhibitors, 11-β-hydroxysteroid dehydrogenase 1 inhibitors, protein tyrosine phosphatase 1B inhibitors, sodium-dependent glucose transporter 1 or 2 modulators, GPR40 modulators, hormone-sensitive lipase inhibitors, acetyl-CoA carboxylase inhibitors, phosphoenolpyruvate carboxykinase inhibitors, glycogen synthase kinase-3β inhibitors, protein kinase Cβ inhibitors, endothelin A receptor antagonists, IκB kinase inhibitors, glucocorticoid receptor modulators, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF A composition according to any one of claims 1 to 88, selected from the group comprising a BP antagonist, a urocortin agonist, a β3 agonist, a CB1 receptor antagonist, an MSH (melanocyte-stimulating hormone) agonist, a CCK agonist, a serotonin reuptake inhibitor, a mixed serotonergic and noradrenergic compound, a 5HT agonist, a bombesin agonist, a galanin antagonist, a growth hormone, a growth hormone-releasing compound, a TRH agonist, an uncoupling protein 2 or 3 modulator, a diphenylazetidinone derivative, a leptin agonist, a DA agonist (bromocriptine, doplexin), a lipase / amylase inhibitor, a PPAR modulator, an RXR modulator, or a TR-β agonist or amphetamine.

90. A composition according to any one of claims 1 to 89, which is in solid dosage form.

91. The composition according to claim 90, wherein the solid dosage form is a capsule, pill, cachet, tablet, granule, or powder.

92. The composition according to any one of claims 1 to 91, which is stable for at least 9 weeks at room temperature and 60% relative humidity (RH).

93. The composition according to any one of claims 1 to 91, which is stable at 40°C and 75% RH for at least 8 weeks.

94. A composition according to any one of claims 1 to 93, which is stable for at least three months.

95. A composition according to any one of claims 1 to 93, which is stable for at least four months.

96. The composition according to any one of claims 1 to 93, which is stable for at least 36 months.

97. A method for treating cholestatic liver disease in a subject requiring treatment, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 96 to the subject.

98. The method according to claim 97, wherein the cholestatic liver disease is a pediatric cholestatic liver disease.

99. The method according to claim 97, wherein the cholestatic liver disease is adult cholestatic liver disease.

100. The aforementioned cholestatic liver diseases include non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, central venous nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, pregnancy-related intrahepatic cholestasis (ICP), contraceptive-associated cholestasis, and drug-associated cholestasis. The method according to any one of claims 97 to 99, wherein the condition is cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai surgery, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant-associated liver disease, liver injury complicated by intestinal failure, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

101. The method according to any one of claims 97 to 100, wherein the cholestatic liver disease is selected from the group consisting of ALGS, PFIC, BA, ICP, BRIC, PSC, and PBC.

102. The method according to any one of claims 97 to 101, wherein the cholestatic liver disease is PSC.

103. The method according to any one of claims 97 to 101, wherein the cholestatic liver disease is PBC.

104. The method according to any one of claims 97 to 101, wherein the cholestatic liver disease is ICP.

105. The method according to any one of claims 97 to 104, wherein the cholestatic liver disease is characterized by pruritus.

106. The method according to any one of claims 97 to 105, wherein the subject is a patient whose total serum bile acid (sBA) level is elevated before administration of the pharmaceutical composition.

107. The method according to any one of claims 97 to 106, wherein the compound of formula (I) is an ileal bile acid transporter (IBAT) inhibitor.

108. The method according to any one of claims 97 to 107, wherein the compound of formula (I) has the structure of the compound of formula (II) which is an ileal bile acid transporter (IBAT) inhibitor.

109. A method for treating hyperlipidemia in a subject requiring treatment, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 96 to the subject.

110. A method for lowering serum cholesterol levels in a target subject, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 96 to the target subject.

111. A method for treating arteriosclerosis in a target subject, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 96 to the target subject.

112. A method for treating X syndrome in a subject requiring treatment, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 96 to the subject.

113. The method according to any one of claims 97 to 112, wherein the composition is administered orally to a subject.

114. A method for producing a pharmaceutical composition according to any one of claims 1 to 96, comprising a therapeutically effective amount of a compound of formula (I), (i) Diluent or filler, (ii) Disintegrant, (iii) Channeling agent, (iv) Flow promoters, and (v) Lubricants The method comprising: forming a mixture with one or more excipients selected from the group consisting of; mixing the mixture; filling the mixture into a capsule shell or compressing the mixture to form a pharmaceutical composition.

115. A kit for treating cholestatic liver disease in a subject requiring treatment, comprising a therapeutically effective dose of at least one unit of a composition according to any one of claims 1 to 96, and instructions for its administration.

116. The aforementioned cholestatic liver diseases include non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, central venous nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, pregnancy-related intrahepatic cholestasis (ICP), contraceptive-associated cholestasis, and drug-associated cholestasis. The kit according to claim 115, wherein the condition is sequential cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai surgery, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant-associated liver disease, liver injury complicated by intestinal failure, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

117. The kit according to any one of claims 115 to 116, wherein the cholestatic liver disease is ALGS, PFIC, BA, ICP, BRIC, PSC, or PBC.

118. The kit according to any one of claims 115 to 117, wherein the cholestatic liver disease is PSC.

119. The kit according to any one of claims 115 to 118, wherein the aforementioned cholestatic liver disease is PBC.

120. The kit according to any one of claims 115 to 118, wherein the aforementioned cholestatic liver disease is ICP.

121. A kit for treating hyperlipidemia in a subject requiring treatment, comprising a therapeutically effective amount of the composition described in any one of claims 1 to 96.

122. A kit for lowering serum cholesterol levels in a target subject, comprising a therapeutically effective amount of the composition described in any one of claims 1 to 96.

123. A kit for treating arteriosclerosis in a target subject, comprising a therapeutically effective amount of the composition described in any one of claims 1 to 96.

124. A kit for treating X syndrome in a subject requiring treatment, comprising a therapeutically effective amount of the composition described in any one of claims 1 to 96.

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