Pharmaceutical compositions comprising 2,3,4,5-tetrahydro-benzothiepin-1,1-dioxide derivatives and the use thereof

Abstract

Provided herein are solid dosage forms comprising a 2, 3, 4, 5-tetrahydro-benzothiaheptyl-1, 1-dioxide (2, 3, 4, 5-tetrahydro-benzothiaheptyl-1, 1-dioxide) derivative, for example, a voxibat (voxibat), or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical composition comprising the same. Also provided herein are embodiments relating to a method of treating cholestatic liver disease, hyperlipidemia, arteriosclerosis, or syndrome X or reducing serum cholesterol levels in a subject in need thereof, wherein the method comprises administering to the subject a solid dosage form of a therapeutically effective amount of a pharmaceutical composition comprising voxibatide.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480032291.4 (22) Application Date 2024.05.17 (30) Priority Data 63 / 467,823 2023.05.19 US (85) PCT International Application Entering National Phase Date 2025.11.13 (86) PCT International Application Application Data PCT / US2024 / 029906 2024.05.17 (87) PCT International Application Publication Data WO2024 / 243023 EN 2024.11.28 (71) Applicant Milrum Pharmaceuticals Company Address California, USA (72) Inventor P. Wade (74) Patent Agency Beijing Law Alliance Intellectual Property Agency Co., Ltd. 11287 Patent Attorney Shen Jinhua (51) Int.Cl. A61K 31 / 38(2006.01) A61K 31 / 70(2006.01) A61K 31 / 7028(2006.01) A61K 31 / 33(2006.01) (54) Invention Title Pharmaceutical Compositions Containing 2,3,4,5-Tetrahydro-benzothiepin-1,1-dioxide Derivatives and Their Uses (57) Abstract This document provides solid dosage forms containing 2,3,4,5-tetrahydro-benzothiepin-1,1-dioxide derivatives, such as volixibat or pharmaceutically acceptable salts thereof. This article also provides examples of methods relating to treating cholestatic liver disease, hyperlipidemia, arteriosclerosis or syndrome X, or lowering serum cholesterol levels in subjects in need, wherein the methods comprise administering to the subject a therapeutically effective amount of a solid dosage form of a pharmaceutical composition comprising voxibarb. Claims (13 pages), Description (38 pages), Drawings (9 pages), CN 121175041 A 2025.12.19 CN 1 21 17 50 41 A 1. A pharmaceutical composition comprising a compound of formula (I), wherein: X is NH; R1 is (C1-C6)-alkyl; R2 is OH; R2' is H; R3, R3', R4, R4', R5, R5' are independently H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-alkylene-S(O)p-R6, (C1-C6)-alkylene-O-S(O)p-R6, COOH, COO(C1-C6)alkyl,CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)alkenyl, (C2-C6)-ynyl, O-(C1-C6)-alkyl, wherein one, more than one, or all of the hydrogens in the alkyl group can be replaced by: fluorine, phenyl, -(CH2)-phenyl, -(CH2)2-phenyl, O-phenyl, O-(CH2)m-phenyl, -(CH2)-O-(CH2)m-phenyl, wherein the phenyl ring can be replaced 1 to 3 times by: 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; wherein at least one of the groups R3, R3', R4, R4', R5 and R5' has the meaning of (C1-C6)-alkylene-O-S(O)p-R6, and the other has the meaning of -O-(CH2)m-phenyl, wherein the phenyl ring may be substituted 1 to 3 times with the following: 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; R6 is 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; and one or more excipients selected from the group consisting of: (i) diluents or fillers, and (ii) disintegrants. 2. The composition according to claim 1, further comprising a channel forming agent. 3. The composition according to any one of claims 1 and 2, further comprising a flow aid, a lubricant, or a combination thereof. 4. The composition according to any one of claims 1 to 3, wherein the composition comprises (I) a chemical compound or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, (ii) a disintegrant, (iii) a channel-forming agent, (iv) a flow aid, and (v) a lubricant. 5. The composition according to any one of claims 1 to 3, further comprising a binder. 6. The composition according to any one of claims 1 to 4, wherein R5' is (C1-C6)-alkylene-S(O)2-R6.7. The composition according to any one of claims 1 to 6, wherein the compound of formula (I) has a structure selected from the group consisting of formulas (II), (III) or (IV) or a pharmaceutically acceptable salt thereof: . 8. The composition according to any one of claims 1 to 7, wherein the compound of formula (I) has a structure selected from the group consisting of formulas (II) or (III) or a pharmaceutically acceptable salt thereof: Claims 2 / 13 page 3 CN 121175041 A . 9. The composition according to any one of claims 1 to 8, wherein the compound of formula (I) has a structure of formula (II) or a pharmaceutically acceptable salt thereof: . 10. The composition according to any one of claims 1 to 9, comprising the pharmaceutically acceptable salt of the 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 the 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. 12. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a potassium salt. 13. The composition according to any one of claims 1 to 9, comprising a compound of formula (II) in the form of potassium ethoxide hydrate: Claims 3 / 13 page 4 CN 121175041 A. 14. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a zinc salt. 15. The composition according to any one of claims 1 to 14, wherein the composition comprises a compound of formula (I) having the structure of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, (ii) a disintegrant, (iii) optionally a channel forming agent, (iv) a flow aid, and (v) a lubricant. 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 constitutes 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 constitutes less than about 50% by weight of the total composition.The pharmaceutically acceptable salt comprises 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 comprises 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 comprises about 15% by weight of the total composition. 22. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 100 mg. Claims 4 / 13 pages 5 CN 121175041 A 23. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 50 mg. 24. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 5 mg to about 20 mg. 25. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 5 mg. 26. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 20 mg. 27. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 5 mg, from about 5 mg to 20 mg, or greater than about 20 mg. 28. The composition according to any one of claims 1 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 10 mg, from about 10 mg to 40 mg, or greater than about 40 mg. 29. The composition according to any one of claims 1 to 28, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 40 mg. 30. The composition according to any one of claims 1 to 29, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 10 mg. 31. The composition according to any one of claims 1 to 22, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 40 mg. 32. The composition according to any one of claims 1 to 22, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 80 mg. 33. The composition according to any one of claims 1 to 31, wherein the diluent or the filler...The composition is selected from the group consisting of: sugars, glucose dextrorates, dextrins, dextrose, lactose, mannitol, sorbitol, starch, cellulose, and modified cellulose, or combinations thereof. 34. The composition of claim 33, wherein the diluent or filler is microcrystalline cellulose (MCC), lactose, mannitol, or a combination thereof. 35. The composition of 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 of 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 of any one of claims 1 to 36, wherein the amount of the diluent or filler is from about 55% by weight to about 90% by weight of the total composition. 38. The composition of any one of claims 1 to 37, wherein the diluent or filler constitutes 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 the filler comprises about 40% to about 60% by weight of MCC in the total composition. 40. The composition according to any one of claims 1 to 39, wherein the diluent or the filler comprises about 44%, about 46%, about 48%, about 56%, or about 58% by weight of MCC in the total composition. 41. The composition according to any one of claims 1 to 40, wherein the diluent or the filler comprises about 10% to about 40% by weight of lactose in the total composition. Claims 5 / 13 Page 6 CN 121175041 A 42. The composition according to any one of claims 1 to 41, wherein the diluent or the filler comprises about 14%, about 15%, about 25%, or about 40% by weight of lactose in the total composition. 43. The composition of any one of claims 1 to 40, wherein the diluent or the filler comprises mannitol in an amount of about 10% to about 20% by weight of the total composition. 44. The composition of any one of claims 1 to 43, wherein the diluent or the filler comprises mannitol in an amount of about 14% by weight of the total composition. 45. The composition of any one of claims 1 to 44, wherein the channel forming agent is selected from the group consisting of sodium chloride and polyethylene glycol (PEG) or combinations thereof. 46. The composition of any one of claims 1 to 45, wherein the channel forming agent is a chloride...Sodium, 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 channel forming agent is PEG. 48. The composition according to claim 47, wherein the channel forming agent is PEG 1500. 49. The composition according to any one of claims 1 to 48, wherein the amount of the channel forming agent is less than about 20% by weight of the total composition. 50. The composition according to any one of claims 1 to 48, wherein the amount of the channel forming agent is from about 5% by weight to about 15% by weight of the total composition. 51. The composition according to any one of claims 1 to 48, wherein the amount of the channel forming agent is 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, croscarmellose, starch, and sodium starch glycolate, or combinations thereof. 53. The composition of any one of claims 1 to 52, wherein the amount of the disintegrant is less than about 20% by weight of the total composition. 54. The composition of any one of claims 1 to 53, wherein the amount of the disintegrant is from about 2% to about 10% by weight of the total composition. 55. The composition of any one of claims 1 to 54, wherein the amount of the disintegrant is about 5% by weight or about 10% by weight of the total composition. 56. The composition of any one of claims 1 to 55, wherein the flow aid is selected from the group consisting of silica, magnesium stearate, talc, and corn starch or combinations thereof. 57. The composition of any one of claims 1 to 56, wherein the flow aid comprises silica. 58. The composition of any one of claims 1 to 57, wherein the amount of the flow aid is less than about 2% by weight of the total composition. 59. The composition of any one of claims 1 to 58, wherein the amount of the flow aid is 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 stearoyl fumarate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil or combinations thereof. 61. The composition according to any one of claims 1 to 60, wherein the lubricant comprises magnesium stearate. Claims 6 / 13 pages 7 CN 121175041 A 62. The composition according to any one of claims 1 to 61, wherein the amount of the lubricant is a percentage of the total composition.63. The composition according to any one of claims 1 to 62, wherein the amount of the lubricant is 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, wherein the composition further comprises an adhesive selected from the group consisting of: polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch, and modified cellulose, or combinations thereof. 65. The composition according to any one of claims 1 to 64, wherein the composition comprises about 5% to about 60% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, (ii) optionally a channel forming agent, (iii) a disintegrant, (iv) a flow aid, and (v) a lubricant, wherein when the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition. 66. The composition according to any one of claims 1 to 64, wherein the composition comprises about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, (ii) optionally a channel forming agent, (iii) a disintegrant, (iv) a flow aid, and (v) a lubricant, wherein when the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition. 67. The composition according to any one of claims 1 to 66, wherein the composition comprises about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, (ii) optionally a channel forming agent, (iii) a disintegrant, (iv) a flow aid, and (v) a lubricant, wherein when the channel forming agent is absent, the amount of the diluent or the filler comprises about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent comprises about 70% to about 90% by weight of the total composition. 68. The composition according to any one of claims 1 to 66, wherein the composition comprises about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (page 8 of claims 7 / 13).CN 121175041 A (i) a diluent or filler, said diluent or filler being present in an amount of about 65% to about 85% by weight of the total composition, (ii) a channel forming agent being present in an amount of about 10% to about 20% by weight of the total composition, (iii) a disintegrant, (iv) a flow aid, and (v) a lubricant. 69. The composition according to any one of claims 1 to 66, wherein said composition comprises about 5% to about 10% by weight of a compound of formula (II) or a pharmaceutically acceptable salt thereof of the total composition, and (i) a diluent or filler being present in an amount of about 65% to about 75% by weight of the total composition, (ii) a channel forming agent being present in an amount of about 10% to about 20% by weight of the total composition, (iii) a disintegrant, (iv) a flow aid, and (v) a lubricant. 70. The composition according to any one of claims 1 to 69, wherein the composition comprises: a disintegrant, said disintegrant in an amount of about 5% to about 10% by weight of the total composition; a flow aid, said flow aid in an amount of about 0.5% to about 2% by weight of the total composition; and a lubricant, said lubricant in an amount of about 0.5% to about 2% by weight of the total composition. 71. The composition according to any one of claims 1 to 64, wherein the composition comprises about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 44% MCC, (ii) about 14% lactose, (iii) about 14% sodium chloride, (iv) about 10% sodium starch glycolate, (v) about 1% silica, and (vi) about 1% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. 72. The composition according to any one of claims 1 to 64, wherein the composition comprises about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 44% MCC, (ii) about 14% mannitol, (iii) about 14% sodium chloride, (iv) about 10% sodium starch glycolate, (v) about 1% silica, and (vi) about 1% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. 73. The composition according to any one of claims 1 to 64, wherein the composition comprises about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 48% MCC, (ii) about 25% lactose, (iii) about 5% sodium chloride, (iv) about 5% sodium starch glycolate, (v) about 1% silicon dioxide, and (vi) about 1% magnesium stearate.Each percentage is a weight percentage based on the total composition. 74. The composition according to any one of claims 1 to 64, wherein the composition comprises about 15% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 58% MCC, (ii) about 15% lactose, (iii) about 5% sodium chloride, (iv) about 5% sodium starch glycolate, (v) about 1% silicon dioxide, and (vi) about 1% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. 75. The composition according to any one of claims 1 to 64, wherein the composition comprises about 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 56% MCC, (ii) about 15% lactose, (iii) about 15% sodium chloride, (iv) about 5% sodium starch glycolate, (v) about 1% silica, and (vi) about 0.5% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. 76. The composition according to any one of claims 1 to 64, wherein the composition comprises about 7.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 46% MCC, (ii) about 40% lactose, (iii) about 5% sodium starch glycolate, (iv) about 1% silica, and (v) about 0.5% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. 77. The composition according to any one of claims 1 to 64, wherein the composition comprises about 6.5% of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) about 56% MCC, (ii) about 15% lactose, (iii) about 15% sodium chloride, (iv) about 5% sodium starch glycolate, (v) about 1% silicon dioxide, and (vi) about 0.5% magnesium stearate, wherein each percentage is a weight percentage based on the total composition. Claims 9 / 13 pages 10 CN 121175041 A 78. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 100 mg. 79. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 50 mg. 80. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is from 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...82. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 5 mg, from about 5 mg to 20 mg, or greater than about 20 mg. 83. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 40 mg. 84. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 5 mg. 85. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 10 mg. 86. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 20 mg. 87. The composition according to any one of claims 1 to 77, wherein the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 40 mg. 88. The composition according to any one of claims 1 to 87, wherein the composition further comprises at least one additional active ingredient, wherein the at least one additional active ingredient is a compound that normalizes lipid metabolism. 89. The composition according to any one of claims 1 to 88, comprising at least one additional active ingredient, wherein the at least one additional active ingredient is selected from the group comprising one or more of the following substances: antidiabetic drugs, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPARγ agonists, PPARα agonists, PPARα / γ agonists. Agonists, PPARδ agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulin, sulfonylureas, biguanides, meglitinide, thiazolidinediones, α-glucosidase inhibitors, active components of ATP-dependent potassium channels acting on β cells, glycogen phosphorylation inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose-1,6-bisphosphatase inhibitors, glucose transporter 4 regulators, glutamine-fructose-6-phosphatamidotransferase inhibitors, dipeptidesInhibitors of peptidase IV, inhibitors of 11-β-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, regulators of sodium-dependent glucose transporter 1 or 2, regulators 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, regulators of glucocorticoid receptors, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH (melanocyte-stimulating hormone) agonists. Claims 10 / 13 pages 11 CN 121175041 A CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, serotonin agonists, glycopyridine antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 regulators, diphenylazacyclobutanone derivatives, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR regulators, RXR regulators, or TR-β agonists or amphetamine. 90. The composition according to any one of claims 1 to 89, wherein the composition is in a solid dosage form. 91. The composition according to claim 90, wherein the solid dosage form is a capsule, pill, sachet, tablet, granule, or powder. 92. The composition according to any one of claims 1 to 91, wherein the composition is stable at room temperature and 60% relative humidity (RH) for at least 9 weeks. 93. The composition according to any one of claims 1 to 91, wherein the composition is stable at 40°C and 75% RH for at least 8 weeks. 94. The composition according to any one of claims 1 to 93, wherein the composition is stable for at least 3 months. 95. The composition according to any one of claims 1 to 93, wherein the composition is stable for at least 4 months. 96. The composition according to any one of claims 1 to 93, wherein the composition is stable for at least 36 months. 97. A method for treating cholestatic liver disease in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96. 98. The method according to claim 97, wherein the cholestatic liver disease is pediatric cholestatic liver disease. 99. The method according to claim 97, wherein the cholestatic liver disease is adult cholestatic liver disease.100. The method according to any one of claims 97 to 99, wherein the cholestatic liver disease is 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-related cholestasis, paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, Alagille syndrome. 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. Claims 11 / 13 pages 12 CN 121175041 A 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 has elevated total serum bile acids (sBA) prior to the 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) as an ileal bile acid transporter (IBAT) inhibitor.109. A method of treating hyperlipidemia in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96. 110. A method of lowering serum cholesterol levels in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96. 111. A method of treating arteriosclerosis in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96. 112. A method of treating syndrome X in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96. 113. The method according to any one of claims 97 to 112, wherein the composition is administered orally to the subject. 114. A method for producing a pharmaceutical composition according to any one of claims 1 to 96, the method comprising the steps of: combining a therapeutically effective amount of the compound of formula (I) with one or more excipients selected from the group consisting of: (i) a diluent or filler, (ii) a disintegrant, (iii) a channel-forming agent, (iv) a flow aid, and (v) a lubricant, to form an admixture; mixing the admixture; and filling or compacting the admixture in a capsule shell to form the pharmaceutical composition. 115. A kit for treating cholestatic liver disease in a subject of need, wherein the kit comprises at least one unit dose of a therapeutically effective amount of the composition according to any one of claims 1 to 96 and instructions for its administration. 116. The kit according to claim 115, wherein the cholestatic liver disease is 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-related cholestasis, paraneoplastic cholestasis, Stoffel syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, Durbin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, Aragog syndrome (ALGS), biliary atresia (BA), post-catapulting biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome or rightClaims 12 / 13 pages 13 CN 121175041 A 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 cholestatic liver disease is PBC. 120. The kit according to any one of claims 115 to 118, wherein the cholestatic liver disease is ICP. 121. A kit for treating hyperlipidemia in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96. 122. A kit for lowering serum cholesterol levels in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96. 123. A kit for treating arteriosclerosis in a subject of need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96. 124. A kit for treating syndrome X in a subject of need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96. Claims 13 / 13 pages 14 CN 121175041 A Pharmaceutical composition comprising a 2,3,4,5-tetrahydro-benzothiaheptacyclo-1,1-dioxide derivative and its use

[0001] Cross-Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 467,823, filed May 19, 2023, pursuant to 35 USC §119(e), which is incorporated herein by reference in its entirety. Technical Field

[0003] This document provides solid dosage forms comprising 2,3,4,5-tetrahydro-benzothiepin-1,1-dioxide, such as volixibat or a pharmaceutically acceptable salt thereof. Background Art

[0004] Hypercholesterolemia and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis), which are associated with and usually secondary to the intracellular accumulation of bile acids / bile salts in hepatocytes. Hypercholesterolemia is characterized by elevated serum concentrations of bile acids or bile salts. Cholestasis can be classified in clinicopathology into twoThe main categories are obstructive cholestasis (usually extrahepatic cholestasis) and non-obstructive or intrahepatic cholestasis. Non-obstructive intrahepatic cholestasis can be further classified into two main subgroups: primary intrahepatic cholestasis caused by constitutive defective bile secretion and secondary intrahepatic cholestasis caused by hepatocellular damage. Primary intrahepatic cholestasis includes conditions such as benign recurrent intrahepatic cholestasis (which is primarily an adult form with similar clinical symptoms) and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3 (which are diseases affecting children). Pediatric cholestatic liver disease affects a small percentage of children, but treatments incur significant medical costs annually. Currently, many cases of pediatric cholestatic liver disease require invasive and expensive treatments such as liver transplantation and surgery.

[0005] Voxibat, 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-dioxane-2,3,4,5-tetrahydro-1H-benzo[b]thiaheptacyclo-5-yl)-phenyl]-ureidoyl}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)hydrosulfate), is an ileal bile acid transporter (IBAT) inhibitor used to treat hypercholesterolemia and cholestatic liver disease. There remains a need to discover suitable voxibat formulations with good dissolution rates and pharmacokinetic profiles, which also demonstrate good storage stability. Summary of the Invention

[0006] The embodiments provided herein relate to a pharmaceutical composition comprising a compound of formula (I), Specification 1 / 38 pages 15 CN 121175041 A

[0007]

[0008] wherein:

[0009] X is NH;

[0010] R1 is (C1-C6)-alkyl;

[0011] R2 is OH;

[0012] R2' is H;

[0013] R3, R3', R4, R4', R5, R5' are independently H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-alkylene-S(O)p-R6, (C1-C6)-alkylene-O-S(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)-ynyl, O-(C1-C6)-alkyl, wherein one, more than one, or all of the hydrogen atoms in the alkyl group may be replaced by: fluorine, phenyl, -(CH2)-phenyl, -(CH2)2-phenyl, O-phenyl, O-(CH2)m-phenyl, -(CH2)-O-(CH2)m-phenyl, wherein the phenyl ring may be substituted 1 to 3 times with the following: 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; wherein at least one of the groups R3, R3', R4, R4', R5 and R5' has (C1-C6)-alkylene-O-S(O)p-R6 The meaning of one is that the other has the meaning of -O-(CH2)m-phenyl, wherein the phenyl ring can be substituted 1 to 3 times with the following: 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;

[0014] R6 is H, OH, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl or N((C1-C6)-alkyl)2;

[0015] n is 2, 3, 4, 5 or 6;

[0016] m is 1, 2, 3, 4, 5 or 6;

[0017] p is 0, 1 or 2;

[0018] Or a pharmaceutically acceptable salt thereof, and one or more excipients selected from the group consisting of:

[0019] (i) diluents or fillers,

[0020] (ii) disintegrants,

[0021] (iii) channel-forming agents,

[0022] (iv) flow aids, and

[0023] (v) lubricants.

[0024] In some embodiments, the compound of formula (I) has the structure of formula (II), namely Voxibart: Specification 2 / 38 pages 16 CN 121175041 A

[0025] (II) or a pharmaceutically acceptable salt thereof.

[0026] Examples of methods relating to treating cholestatic liver disease, hyperlipidemia, arteriosclerosis or syndrome X, or lowering serum cholesterol levels in a subject of need are also provided herein, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0027] This document further provides embodiments relating to a method for producing a pharmaceutical composition in solid form, the method comprising the steps of: combining a therapeutically effective amount of a compound of formula (I) with one or more excipients selected from the group consisting of:

[0028] (i) a diluent or filler,

[0029] (ii) a disintegrant,

[0030] (iii) a channel forming agent,

[0031] (iv) a flow aid, and

[0032] (v) a lubricant,

[0033] to form a blend; to mix the blend; and to fill or compact the blend in a capsule shell to form the pharmaceutical composition.

[0034] Additional embodiments provided herein relate to a kit for treating cholestatic liver disease or hyperlipidemia in subjects of need, wherein the kit contains a therapeutically effective amount of the composition as described herein. Brief Description of the Drawings

[0035] Figure 1 shows NaCl:vocibart sample agglomeration.

[0036] Figure 2 shows PEG 1500:vocibart sample agglomeration.

[0037] Figure 3 shows the appearance of the sample under ambient / 60% RH conditions.

[0038] Figure 4 shows the appearance of the sample under 40°C / 75% RH conditions.

[0039] Figure 5 shows dissolution data for formulations 1 and 2, 20 mg capsules, in 900 mL of phosphate at pH 6.8.

[0040] Figure 6 shows the dissolution data for formulations 1, 3, and 4, 40 mg capsules, in 500 mL phosphate buffer at pH 6.8.

[0041] Figure 7 shows the dissolution data for formulation 5, 20 mg capsules: T = 0 tap relative to packing.

[0042] Figure 8 shows the dissolution data for formulation 5, 20 mg capsules: the effect of over-lubrication.

[0043] Figure 9 shows the dissolution data for formulation 5, 20 mg capsules, in 500 mL acetate at pH 4.5.

[0044] Figure 10 shows the dissolution data for formulations 1 and 3-6, 20 mg capsules, in 500 mL phosphate buffer at pH 6.8.

[0045] Figure 11 shows the dissolution data for formulations 1 and 3-6, 20 mg capsules, in 500 mL 0.01 N HCl.

[0046] Figure 12 shows the dissolution rate data for formulation 5, 20 mg capsules in each dissolution medium. Specification 3 / 38 pages 17 CN 121175041 A

[0047] Figure 13 shows the dissolution rate data for formulation 7, 20 mg capsules in each dissolution medium. Detailed Description

[0048] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments pertain.

[0049] As used herein, unless the context explicitly specifies otherwise, the terms “a” or “an” mean “at least one” or “one or more”.

[0050] As used herein, the term “about” means that the numerical values ​​are approximate and small variations do not significantly affect…Practice of the disclosed embodiments. When using numerical limits, unless the context otherwise indicates, “about” means that the numerical value can vary by ±10% and remain within the range of the disclosed embodiments.

[0051] As used herein, the term “alkenyl” means a straight-chain or branched alkyl group having one or more carbon-carbon bonds and 2 to 20 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In some embodiments, the alkenyl chain is 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0052] As used herein, the term “active pharmaceutical ingredient” or “API” refers to a bioactive compound. Exemplary APIs include Vosibart. Voxibart 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-dioxane-2,3,4,5-tetrahydro-1H-benzo[b]thiheptan-5-yl)-phenyl]-ureidoyl}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate). The structure of potassium Voxibart is shown below:

[0053] .

[0054] The terms "alkoxy", "phenoxy", "benzoyloxy" and "pyrimidinyloxy" refer to alkyl, phenyl, benzyl or pyrimidinyl groups, each optionally substituted, bonded by an oxygen atom. For example, the term "alkoxy" refers to a straight-chain or branched -O-alkyl group having 1 to 20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, and tert-butoxy. In some embodiments, the alkoxy chain has a length of 1 to 10 carbon atoms, a length of 1 to 8 carbon atoms, a length of 1 to 6 carbon atoms, a length of 1 to 4 carbon atoms, a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0055] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. 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, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, tert-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-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, 2-ethyl-1-butyl, etc.

[0056] As used herein, the term "alkylene" or "alkylenyl" means a divalent alkyl linking group. Examples of alkylene (or alkylenyl) are methylene or methylenyl (-CH2-).

[0057] As used herein, the term "alkynyl" means a straight-chain or branched alkyl group having one or more three-carbon bonds and 2 to 20 carbon atoms, including but not limited to acetylene, 1-propene, 2-propene, etc. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0058] As used herein, the term "amino" means -NH2.

[0059] As used herein, the term "aminoalkoxy" means an alkoxy group substituted with an amino group. An example of an aminoalkoxy group is -OCH2CH2NH2.

[0060] As used herein, the term "aminoalkyl" means an alkyl group substituted with an amino group. An example of an aminoalkyl group is -CH2CH2NH2.

[0061] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0062] As used herein, the term “aminoalkylthio” means an alkylthio group substituted with an amino group. An example of an aminoalkylthio group is -SCH2CH2NH2.

[0063] As used herein, the term “amphiphilic” means a three-dimensional structure having discrete hydrophobic and hydrophilic regions. Amphiphilic compounds suitably contain both hydrophobic and hydrophilic elements.

[0064] As used herein, the term “animal” includes, but is not limited to, human and non-human vertebrates, such as wild animals, domestic animals, and farm animals.

[0065] As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings) that optionally contains a heteroatom. In some embodiments, an 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, anthracene, phenanthrene, indenyl, indenyl, tetrahydronaphthyl, etc. In some embodiments, an aryl group includes heteroaryl groups as defined in other embodiments. In some embodiments, the aryl group has heterogeneity.In some embodiments, the aryl group has heteroatoms selected from the group consisting of N, S, O, and P atoms. Examples of aryl groups include, but are not limited to:

[0066]

[0067]

[0068] As used herein, a “binder” is an excipient that imparts enhanced cohesiveness or tensile strength (e.g., hardness) to a pharmaceutical composition.

[0069] 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 allow the formation of a pharmaceutical composition (i.e., a dosage form applicable to a patient).

[0070] As used herein, the term “composition” generally refers to a composition of two or more components, typically one or more pharmaceuticals (e.g., voxibart) and one or more pharmaceutical excipients.

[0071] As used herein, the term “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0072] As used herein, the terms “comprising” (and any form of inclusion, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional unlisted elements or method steps. Specification 7 / 38 pages 21 CN 121175041 A

[0073] As used herein, the term “contact” means bringing two elements together in an in vitro or in vivo system.

[0074] As used herein, the term “cyano” means -CN.

[0075] As used herein, the term “cyclo” means an optionally substituted ring, which is a 6-20 aryl group, a 3-20 heteroaryl group having 1-5 heteroatoms independently selected from N, O, and S; a 3-20 saturated or partially unsaturated cycloalkyl group, or a 3-20 saturated or partially unsaturated heterocycloalkyl group having 1-5 heteroatoms independently selected from N, O, and S.

[0076] As used herein, the term “cycloalkyl” means a non-aromatic cyclic hydrocarbon, including cycloalkyl, alkenyl, and ynyl groups containing up to 20 cyclic carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic systems, such as fused ring systems, bridged ring systems, and spirocyclic systems.Cyclic system. In some embodiments, the polycyclic system comprises 2, 3, or 4 fused rings. The cycloalkyl group may contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 cyclic carbon atoms. The cyclic carbon atoms of the cycloalkyl group may optionally be substituted with oxo or thio. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc. The definition of cycloalkyl also includes portions having one or more aromatic rings fused to (sharing bonds with) a cycloalkyl ring, such as benzo or thiophene derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-keto-1-yl).

[0077] As used herein, a “disintegrant” is an excipient that hydrates a pharmaceutical composition and facilitates tablet dispersion.

[0078] As used herein, a “diluent” or “filler” is an excipient that increases the volume of a pharmaceutical composition.

[0079] As used herein, “DS” refers to a pharmaceutical substance.

[0080] As used herein, “excipient” includes both functional and non-functional components in a pharmaceutical composition.

[0081] As used herein, a “flow aid” is an excipient that imparts enhanced flow properties to a pharmaceutical composition.

[0082] As used herein, the term “halogenated” means a halogen group, including but not limited to fluorine, chlorine, bromine, and iodine.

[0083] As used herein, the term “haloalkoxy” means -O-haloalkyl. An example of a haloalkoxy group is OCF3.

[0084] As used herein, the term “haloalkyl” means a C1-6 alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, C2Cl5, CH2CF3, etc.

[0085] As used herein, the term “heteroatom” or “hetero-atom” means an atom that is not a carbon atom or a hydrogen atom. In some embodiments, a “heteroatom” or “hetero-atom” is a nitrogen atom, an oxygen atom, a phosphorus atom, or a sulfur atom.

[0086] As used herein, the term "heteroaryl" means an aromatic heterocycle having at most 20 cyclic atoms (e.g., C) and at least one heteroatom ring member (cyclic atom), such as sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has at least one or more atoms forming a heteroatom ring, each of which is independently sulfur, oxygen, or nitrogen.In some embodiments, the heteroaryl group has 3 to 20 cyclic atoms, 3 to 10 cyclic atoms, 3 to 6 cyclic atoms, or 3 to 5 cyclic 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, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indoleyl (e.g., indole-3-yl), pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, phenylthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purineyl. (Specification 8 / 38, page 22, CN 121175041 A) Carbazolyl, benzimidazolyl, indololinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thiaanthryl, pyrazolyl, inazinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthaneyl, 2H-pyrroleyl, pyrroleyl, 3H-indolyl, 4H-quinolinazinyl, phthalazinyl, naphridinyl, quinazolinyl, phenanthrynyl, acridineyl, vodiyl, phenanthrynyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenothiazinyl, etc. 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.

[0087] As used herein, the term "heteroarylalkyl" means a C1-6 alkyl group substituted with a heteroaryl group.

[0088] As used herein, the term "heterocycle" or "heterocyclic ring" means a 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic system, any ring of which may be saturated or unsaturated and consists of a carbon atom and one to three heteroatoms selected from N, O, and S, wherein the N heteroatoms and S heteroatoms may optionally be oxidized, and the N heteroatoms may optionally be quaternized, and includes any bicyclic group in which any heterocycle defined above is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur atom, one to three nitrogen atoms, or one oxygen or sulfur atom combined with one or two nitrogen atoms. Heterocycles may be attached at any heteroatom or carbon atom that results in a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-Oxopyrrolyl, 2-Oxazonyl-heptenyl, azaheptenyl, pyrroleyl, 4-piperidinyl, pyrroleyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolinyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, morpholinyl, thiazolyl, thiazolyl, isothiazolyl, quininecycloyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxoxazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, benzothiaphenyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

[0089] As used herein, the term "heterocyclic alkyl" means a non-aromatic heterocycle having up to 20 cyclic atoms, including cycloalkyl, alkenyl, and alkynyl groups, wherein one or more cyclic carbon atoms are replaced by heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic). In some embodiments, a heterocyclic alkyl group has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, a heterocyclic alkyl group contains 3 to 14 cyclic atoms, 3 to 7 cyclic atoms, or 5 or 6 cyclic atoms. In some embodiments, a heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, a heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, a heterocyclic alkyl group contains 0 to 2 triple bonds. Examples of heterocyclic alkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, 2,3-dihydrobenzofuranyl, 1,3-benzo-m-dioxacyclopentene, benzo-1,4-dioxane, piperidinyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, pyrazolyl, thiazolyl, imidazolyl, pyrrolidine-2-one-3-yl, etc. Furthermore, the cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with oxo or thio. For example, the cyclic S atom may be substituted with one or two oxo atoms (forming S(O) or S(O)2). Another example is that the cyclic C atom may be substituted with an oxo group (forming a carbonyl group). The definition of heterocyclic alkyl also includes portions having one or more aromatic rings fused with non-aromatic heterocycles (sharing bonds with them), including but not limited to pyridinyl, thiophene, phthalimide, naphthimide, and heterocyclic benzo[a] derivatives such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindoline-1-one-3-yl, and 3,4-dihydroisoquinoline-1(2H)-one-3-yl. The cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be substituted with oxo or thio.

[0090] As used herein, the term “hydroxyl” or “hydroxyl” means “-OH” group.

[0091] As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl group substituted with a hydroxyl group, as specified in CN 121175041 A, page 9 / 38. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH and -CH2CH2OH.

[0092] As used herein, the interchangeable terms “subject,” “individual,” or “patient” mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates such as humans.

[0093] As used herein, the term “inhibitor” means a measurable amount of a substance that reduces the activity of an enzyme or receptor. The term “inhibition” means a measurable amount that reduces the activity of an enzyme or receptor.

[0094] As used herein, the phrase “in need” means that an animal or mammal has been identified as needing 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, the animal or mammal may be needing it. In some embodiments, the animal or mammal is in or will enter an environment where a particular disease, symptom, or condition is prevalent.

[0095] As used herein, the phrase “integer from X to Y” means any integer including the endpoints. For example, the phrase “integer from X to Y” means 1, 2, 3, 4, or 5.

[0096] As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and portions. A “substituted” atom or portion indicates that any hydrogen atom or portion may be selectively substituted from the indicated substituent, provided that the substitution does not exceed the normal valence of the specified atom or portion and that the substitution produces a stable compound. For example, if a methyl group is optionally substituted, the three hydrogen atoms on the carbon atom may be substituted by the substituent.

[0097] As used herein, a “lubricant” is an excipient added to a pharmaceutical composition compressed into tablets. Lubricants facilitate the compaction of particles into tablets and the ejection of tablets of the pharmaceutical composition from the compression molding machine.

[0098] As used herein, the terms “percentage” or “%” mean a weight percentage of the total weight of the composition (i.e., the total weight of the composition).

[0099] As used herein, the phrase “pharmaceutical acceptable” means those compounds, materials, compositions, and / or dosage forms suitable for tissue exposure in humans and animals to the extent that reasonable medical judgment would allow. In some embodiments, “pharmaceutical acceptable” means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeias.The listed salts are for use in animals and especially for use in humans.

[0100] As used herein, the phrase “pharmaceutically acceptable salt” includes, but is not limited to, salts with acidic or basic groups. Compounds that are basic in nature are capable of forming a variety of salts with a wide range of inorganic and organic acids. Pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfuric acid, thiosulfate, citric acid, maleic acid, acetic acid, oxalic acid, hydrochloride, hydrobromide, hydrogen iodide, nitrates, sulfates, bisulfates, bisulfites, phosphates, acid phosphates, isonicotinate, borates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, bicarbonates, malonates, methanesulfonates, and estolates. Napsydisylate, toluenesulfonate, benzenesulfonate, orthophoshate, trifluoroacetate, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate). In addition to the acids mentioned above, compounds including an amino moiety can form pharmaceutically acceptable salts with various amino acids. Compounds that are acidic in nature can form basic salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts, and specifically calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. Embodiments of the invention include pharmaceutically acceptable salts of the compounds described herein. Embodiments of the invention also include quaternary ammonium salts of the compounds described herein, wherein the compounds have one or more tertiary amine moieties.

[0101] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two, or three suitable substituents.

[0102] As used herein, the term "prodrug" means a derivative of a known directly acting drug that, compared to the drug, has enhanced delivery properties and therapeutic value and is converted into an active drug through an enzymatic or chemical process.

[0103] As used herein, the term "purified" means that, upon separation, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of the compound described herein (by weight of the isolate).

[0104] As used herein, the term "solid dosage form" generally refers to a pharmaceutical composition, when used orally, including 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.

[0105] As used herein, the phrase "solvent" means an agent that causes the formation of a micelle solution or true solution of the drug.

[0106] As used herein, the term "solution / suspension" means a liquid composition in which a first portion of the active pharmaceutical agent is present in solution form and a second portion of the active pharmaceutical agent is present in particulate form in a suspension of a liquid matrix.

[0107] As used herein, the phrase "substantially separated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

[0108] As used herein, "surfactant" is an excipient that imparts enhanced solubility and / or wettability to a pharmaceutical composition.

[0109] As used herein, “suitable substituent,” “substituent,” “optional substituent,” or any substituent of an optionally substituted group means a group that will not render the compound described herein or an intermediate that may be used to prepare the compound ineffective in terms of its synthetic or pharmaceutical value. Examples of substituents of “suitable substituent,” “substituent,” “optional substituent,” or any optionally substituted group include, but are not limited to: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, phenyl, C3-C5 heteroaryl, C3-C10 cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halogenated, 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 "suitable substituent," "substituent," "optional substituent," or any optionally substituted group is further substituted by one or more groups selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, phenyl, C3-C5 heteroaryl, C3-C10 cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halogenated, 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). Those skilled in the art can readily select suitable substituents based on the stability, pharmacological, and synthetic activity of the compounds described herein.

[0110] As used herein, the phrase “therapeutic effective amount” means an amount of an active compound or agent that elicits a biological or pharmaceutical response sought by researchers, veterinarians, physicians, or other clinicians in a tissue, system, animal, individual, or human. The therapeutic effect depends on the condition being treated or the desired biological effect. Thus, a therapeutic effect may be the reduction of the severity of symptoms associated with the condition and / or the inhibition of the progression of the condition (partially or completely), or the improvement of treatment, cure, elimination, or improvement of disease or side effects. The amount required to elicit a therapeutic response may be determined based on the subject’s age, healthy size, and sex. The optimal amount may also be determined based on monitoring the subject’s response to treatment. Specification 11 / 38 pages 25 CN 121175041 A

[0111] As used herein, the terms “treat,” “treated,” “treatment,” or “treating” mean therapeutic treatment in which the aim is to alleviate (reduce) an undesirable physical symptom, condition, 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 condition, symptom, or disease severity; stabilization (i.e., non-deterioration) of condition, symptom, or disease state; delay or slowing of the onset or progression of condition, symptom, or disease; improvement or relief of condition, symptom, or disease state (whether partial or complete) (whether detectable or undetectable); improvement of at least one measurable physical parameter (which the patient may not necessarily perceive); or enhancement or improvement of condition, symptom, or disease. Treatment includes evoking a clinically significant response without producing excessive levels of side effects. Treatment also includes extended survival compared to expected survival without treatment.

[0112] In various places in this specification, substituents of compounds may be disclosed as groups or ranges. It is specifically intended that examples include each individual sub-combination of members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0113] For compounds in which one variable appears more than once, each variable may be a different part of the Markush group of options for defining the variable. For example, when the described structure has two R groups present simultaneously on the same compound, the two R groups can represent different portions selected from the Markush group defined for R. In another instance, when optionally multiple substituents are specified in, for example, it is understood that the substituent R can appear multiple times on the ring, and each time R can be a different portion. Further, in the above examples, when the variable T1 is defined to include hydrogen, such as when T1 is CH2, NH, etc., any H can be substituted by a substituent.

[0114] It should be further understood that certain features described herein, in the context of individual embodiments for clarity, may also be provided in combination in individual embodiments. Conversely, various features described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination.

[0115] It should be understood that embodiments of the invention cover stereoisomers, diastereomers, and optical stereoisomers of compounds, and mixtures thereof, where applicable. Additionally, it should be understood that stereoisomers, diastereomers, and optical stereoisomers of compounds, and mixtures thereof, are all within the scope of the embodiments. As a non-limiting example, a mixture may be a racemic mixture, or a mixture may contain unequal proportions of a particular stereoisomer with another stereoisomer. Additionally, the compound may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (such as epimers).

[0116] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, should be included within the scope of the embodiments. 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 resolution by racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are considered in the embodiments of the invention. 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 separate isomers. Where a compound capable of stereoisomerism or geometric isomerism is specified in its structure or name without mentioning a specific R / S or cis / trans configuration, it means that all such isomers are considered.

[0117] The resolution of racemic mixtures of compounds can be carried out by any of a variety of methods known in the art, including, for example, chiral HPLC, stepwise recrystallization using a chiral resolving acid, which is an optically active salt organic acid. Suitable resolving agents for stepwise recrystallization methods include, but are not limited to, optically active acids such as D- and L-type tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for stepwise recrystallization methods include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. It can also be carried out by using an optically active resolving agent (e.g., ...For example, column dissolution of (dinitrobenzoylphenylglycine) is used to resolve racemic mixtures. Suitable elution solvent compositions can be determined by those skilled in the art.

[0118] The resolved compound may also include tautomeric forms. Tautomeric forms are generated by the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton-transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton tautomers include, but are not limited to, keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, including but not limited to 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomer form may be in equilibrium or spatially locked into one form by appropriate substitution.

[0119] The compound also includes hydrates and solvates, as well as anhydrous and nonsolventized forms.

[0120] The compound may also include isotopes of all atoms present in the intermediate or final compound. Isotopes include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0121] In some embodiments, the compound or its salts are substantially isolated. Partial isolation may include, for example, a composition enriching the compounds of the embodiments. Substantialtive isolation may include a composition containing at least about 50% by weight, 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 compounds of the embodiments or their salts. Methods for separating compounds and their salts are conventional in the art.

[0122] While the disclosed compounds are suitable, other functional groups may be incorporated into the compounds and similar results are expected. Specifically, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometry of a compound and can be altered by incorporating aliphatic chains of varying lengths, which may optionally be substituted or may contain amino acids, dicarboxylic acids, or diamines. The distance and relative orientation between monomers within a compound can also be altered by replacing the amide bond with a substitute having additional atoms. Thus, replacing the carbonyl group with a dicarbonyl group alters the distance between monomers and the tendency of the dicarbonyl unit to adopt an anti-alignment of two carbonyl moieties, and changes the periodicity of the compound. Pyromellitic anhydride represents another alternative to the simple amide bond, which can alter the conformation and physical properties of the compound. Modern solid-phase organic chemistry methods (E. Atherton and R. C. Sheppard)Solid Phase Peptide Synthesis: A Practical Approach (IRL, Oxford, 1989) now allows the synthesis of uniformly dispersed compounds with molecular weights approaching 5,000 Daltons. Other substitution modes are equally effective.

[0123] The compounds also include derivatives referred to as prodrugs.

[0124] Examples of various compounds and their salts are provided. Unless the context otherwise indicates, variables may be any options described herein without specific reference.

[0125] Pharmaceutical Compositions

[0126] When used as pharmaceuticals, the compounds of the present invention are generally administered in the form of pharmaceutical compositions. Such compositions can be prepared in a manner well known in the pharmaceutical industry and contain at least one active compound.

[0127] The embodiments provided herein relate to a pharmaceutical composition comprising a compound of formula (I), Specification 13 / 38 pages 27 CN 121175041 A

[0128]

[0129] wherein:

[0130] X is NH;

[0131] R1 is (C1-C6)-alkyl;

[0132] R2 is OH;

[0133] R2' is H;

[0134] R3, R3', R4, R4', R5, R5' are independently H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-alkylene-S(O)p-R6, (C1-C6)-alkylene-O-S(O)p-R6 6. COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)alkenyl, (C2-C6)-ynyl, O-(C1-C6)-alkyl, wherein one, more than one, or all of the hydrogens in the alkyl group may be replaced by: fluorine, phenyl, -(CH2)-phenyl, -(CH2)2-phenyl, O-phenyl, O-(CH2)m-phenyl, -(CH2)-O-(CH2)m-phenyl, wherein the phenyl ring may be replaced 1 to 3 times by: 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;

[0135] wherein at least one of the groups R3, R3', R4, R4', R5 and R5' has (C1-C6)-alkylene-O-S(O)p-R6.The meaning is defined as follows, and the other has the meaning of -O-(CH2)m-phenyl, wherein the phenyl ring can be substituted 1 to 3 times with the following: 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;

[0136] R6 is H, OH, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl or N((C1-C6)-alkyl)2;

[0137] n is 2, 3, 4, 5 or 6;

[0138] m is 1, 2, 3, 4, 5 or 6;

[0139] p is 0, 1 or 2;

[0140] Or a pharmaceutically acceptable salt thereof, and one or more excipients selected from the group consisting of:

[0141] (i) diluents or fillers, and

[0142] (ii) disintegrants.

[0143] Generally, compounds of formula (I) are administered in a therapeutically effective amount. The amount of compound actually administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated; the route of administration chosen; the actual compound administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms, etc.

[0144] Pharmaceutical compositions of compounds of formula (I) can be administered via a variety of routes, including oral, rectal, intraocular, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, direct into the cerebrospinal fluid, intratracheal, and intranasal. Depending on the intended route of delivery, compounds of formula (I) are preferably formulated as oral compositions. Instructions for use, pages 14 / 38, 28 CN 121175041 A

[0145] Compositions for oral administration may be in the form of a stacked liquid solution or suspension or a stacked powder. However, more commonly, compositions are present in unit dosage forms for precise administration. The term “unit dosage form” refers to a physically discrete unit suitable for administration in a single dose to human subjects and other mammals, each unit containing a predetermined amount of active material calculated to bind with a suitable pharmaceutical excipient to produce the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the active compound is typically a minor component, with the remainder being various mediators or carriers and processing aids that help form the desired delivery form.

[0146] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous mediators having buffers, suspending and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or similar components.Compounds of this type: such as binders like microcrystalline cellulose, tragacanth gum, or gelatin; excipients like starch or lactose; disintegrants like alginic acid, Primogel, or corn starch; lubricants like magnesium stearate; flow aids like colloidal silica; sweeteners like sucrose or saccharin; or flavorings like peppermint, methyl salicylate, or orange flavoring.

[0147] Pharmaceutical compositions containing compounds of formula (I) can be prepared in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated within such a carrier, which is in the form of, for example, capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that can act as a medium, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0148] In some embodiments, the composition comprising the compound of formula (I) further comprises a channel forming agent.

[0149] In some embodiments, the composition comprising the compound of formula (I) further comprises a flow aid, a lubricant, or a combination thereof.

[0150] In some embodiments, the composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more selected from the group consisting of:

[0151] (i) a diluent or filler,

[0152] (ii) a disintegrant,

[0153] (iii) a channel forming agent,

[0154] (iv) a flow aid, and

[0155] (v) a lubricant.

[0156] In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0157] (i) a diluent or filler,

[0158] (ii) a disintegrant,

[0159] (iii) a channel-forming agent,

[0160] (iv) a flow aid, and

[0161] (v) a lubricant.

[0162] In some embodiments, the composition further comprises a binder.

[0163] In some embodiments, the composition of formula (I) has R5', namely (C1-C6)-alkylene-S(O)2-R6.

[0164] In some embodiments, the compound of formula (I) has a structure selected from the group consisting of formulas (II), (III) or (IV) or a pharmaceutically acceptable salt thereof: Specification 15 / 38 pages 29 CN 121175041 A

[0165]

[0166] .

[0167] In some embodiments, the compound of formula (I) has a structure selected from the group consisting of formulas (II) or (III) or a pharmaceutically acceptable salt thereof: Specification 16 / 38 pages 30 CN 121175041 A

[0168] .

[0169] In some embodiments, the compound of formula (I) has a structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0170] .

[0171] In some embodiments, the composition comprises the pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is an ammonium salt.

[0172] In some embodiments, the composition comprises the 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.

[0173] In some embodiments, the composition comprises the pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a potassium salt.

[0174] In some embodiments, the composition comprises a compound of formula (II) in the form of potassium ethoxide hydrate: Specification 17 / 38 pages 31 CN 121175041 A

[0175] .

[0176] 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.

[0177] In some embodiments, the composition comprises a compound of formula (I) having the structure of formula (II) or a pharmaceutically acceptable salt thereof, and

[0178] (i) a diluent or filler,

[0179] (ii) a disintegrant,

[0180] (iii) optionally a channel forming agent,

[0181] (iv) a flow aid, and

[0182] (v) a lubricant.

[0183] The embodiments provided herein relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising less than about 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 12.5 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, 2 wt%, or 1 wt% of the total composition. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises about 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 12.5 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, 2 wt%, or 1 wt% of the total composition. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises less than about 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 12.5 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, 2 wt%, or 1 wt% of the total composition.The salt content of the total composition is approximately 1%-30% by weight, 3%-30% by weight, 5%-30% by weight, 7.5%-30% by weight, 10%-30% by weight, 15%-30% by weight, 20%-30% by weight, 1%-25% by weight, 3%-25% by weight, 5%-25% by weight, 7.5%-25% by weight, 10%-25% by weight, 15%-25% by weight, 20%-25% by weight, 1%-20% by weight, 3%-20% by weight, 5%-20% by weight, 7.5%-20% by weight, 10%-20% by weight, 15%-20% by weight, 1%-15% by weight, 3%-15% by weight, 5%-15% by weight, 7.5%-15% by weight, 10%-15% by weight, 1%-12% by weight. 0.5% by weight, 3% by weight - 12.5% ​​by weight, 5% by weight - 12.5% ​​by weight, 7.5% by weight - 12.5% ​​by weight, 10% by weight - 12.5% ​​by weight, 1% by weight - 10% by weight, 3% by weight - 10% by weight, 5% by weight - 10% by weight or 7.5% by weight - 10% by weight.

[0184] 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.

[0185] 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.

[0186] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof constitutes about 5% by weight to about 20% by weight of the total composition.

[0187] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises less than about 7.5% by weight to about 15% by weight, about 2% by weight to about 10% by weight, about 3% by weight to about 10% by weight, or about 10% by weight to about 20% by weight of the total composition.

[0188] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises about 7.5% by weight of the total composition.

[0189] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof comprises about 15% by weight of the total composition.

[0190] The embodiments provided herein relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in amounts less than 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, etc.mg, 20 mg, 15 mg, 10 mg, 5 mg, 3 mg, 2 mg, or 1 mg. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 1 mg-150 mg, 3 mg-150 mg, 5 mg-150 mg, 7.5 mg-150 mg, 10 mg-150 mg, 12.5 mg-150 mg, 15 mg-150 mg, 20 mg-150 mg, 25 mg-150 mg, 30 mg-150 mg, 35 mg-150 mg, 40 mg-150 mg, 1 mg-120 mg, 3 mg-120 mg, 5 mg-120 mg, 7.5 mg-120 mg, 10 mg-120 mg, 12.5 mg-120 mg, 15 mg-120 mg, 20 mg-120 mg, 25 mg-120 mg, 30 mg-120 mg, 35 mg-120 mg, 40 mg-120 mg, 1 mg-100 mg. mg, 3 mg‑100 mg, 5 mg‑100 mg, 7.5 mg‑100 mg, 10 mg‑100 mg, 12.5 mg‑100 mg, 15 mg‑100 mg, 20 mg‑100 mg, 25 mg‑100 mg, 30 mg‑100 mg, 35 mg‑100 mg, 40 mg‑100 mg, 1 mg‑80 mg, 3 mg‑80 mg, 5 mg‑80 mg, 7.5 mg‑80 mg, 10 mg‑80 mg, 12.5 mg‑80 mg, 15 mg‑80 mg, 20 mg‑80 mg, 25 mg‑80 mg, 30 mg‑80 mg, 35 mg‑80 mg, 40 mg‑80 mg, 1 mg‑60 mg, 3 mg‑60 mg, 5 mg‑60 mg, 7.5 mg‑60 mg, 10 mg‑60 mg, 12.5 mg‑60 mg, 15 mg‑60 mg, 20 mg‑60 mg, 25mg‑60 mg, 30 mg‑60 mg, 35 mg‑60 mg, 40 mg‑60 mg, 1 mg‑50 mg, 3 mg‑50 mg, 5 mg‑50 mg, 7.5 mg‑50 mg, 10 mg‑50 mg, 12.5 mg‑50 mg, 15 mg‑50 mg, 20 mg‑50 mg, 25 mg‑50 mg, 30 mg‑50 mg, 35 mg‑50 mg, 40 mg‑50 mg, 1 mg‑40 mg, 3 mg‑40 mg, 5 mg‑40 mg, 7.5 mg‑40 mg, 10 mg‑40 mg, 12.5 mg‑40 mg, 15 mg‑40 mg, 20 mg‑40 mg, 25 mg‑40 mg, 30 mg‑40 mg, 35 mg‑40 mg, 1 mg‑30 mg, 3 mg‑30 mg, 5 mg‑30 mg, 7.5 mg‑30 mg, 10 mg‑30 mg, 12.5 mg‑30 mg, 15 mg‑30 mg, 20 mg‑30 mg, 25 mg‑30 mg, 1 mg‑20 mg, 3 mg‑20 mg, 5 mg‑20 mg, 7.5 mg‑20 mg, 10 mg‑20 mg, 12.5 mg‑20 mg, 15 mg‑20 mg, 1 mg‑15 mg, 3 mg‑15 mg, 5 mg‑15 mg, 7.5 mg‑15 mg, 10 mg‑15 mg, 12.5 mg‑15 mg, 1 mg‑10 mg, 3 mg‑10 mg, 5 mg‑10 mg, 7.5 mg‑10 mg, 1 mg‑7.5 mg, 3 mg‑7.5 mg, 5 mg‑7.5 mg, 1 mg‑5 mg or 3 mg‑5 mg.

[0191] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 100 mg.

[0192] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 50 mg.

[0193] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 5 mg to about 20 mg.

[0194] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 5 mg.

[0195] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg.

[0196] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 5 mg.mg, from about 5 mg to 20 mg or more than about 20 mg.

[0197] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is less than about 10 mg, from about 10 mg to 40 mg or more than about 40 mg.

[0198] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 40 mg.

[0199] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 10 mg.

[0200] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 40 mg.

[0201] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 80 mg.

[0202] In some embodiments, the diluent or the filler is selected from the group consisting of: sugars, glucose dextrates, dextrins, dextran, lactose, mannitol, sorbitol, starch, cellulose and modified cellulose or combinations thereof.

[0203] In some embodiments, the diluent or the filler is microcrystalline cellulose (MCC), lactose, mannitol, or a combination thereof.

[0204] In some embodiments, the diluent or the filler is a mixture of MCC and lactose, a mixture of MCC and mannitol, or a mixture of lactose and mannitol.

[0205] In some embodiments, the diluent or the filler constitutes less than about 99 wt%, 97 wt%, 95 wt%, 93 wt%, 90 wt%, 86 wt%, 85 wt%, 80 wt%, 75 wt%, 73 wt%, 71 wt%, 70 wt%, 65 wt%, 60 wt%, 59 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, or 30 wt% of the total composition. In some embodiments, the diluent or the filler comprises about 99 wt%, 97 wt%, 95 wt%, 93 wt%, 90 wt%, 86 wt%, 85 wt%, 80 wt%, 75 wt%, 73 wt%, 71 wt%, 70 wt%, 65 wt%, 60 wt%, 59 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, or 30 wt% of the total composition. In some embodiments, the diluent or the filler is about 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%-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%.

[0206] In some embodiments, the combined amount of the diluent or the filler and the channel forming agent is less than about 99 wt%, 97 wt%, 95 wt%, 93 wt%, 90 wt%, 86 wt%, 85 wt%, 80 wt%, 75 wt%, 73 wt%, 71 wt%, 70 wt%, 65 wt%, 60 wt%, 59 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, or 30 wt% of the total composition. In some embodiments, the combined amount of the diluent or the filler and the channel forming agent is about 99 wt%, 97 wt%, 95 wt%, 93 wt%, 90 wt%, 86 wt%, 85 wt%, 80 wt%, 75 wt%, 73 wt%, 71 wt%, 70 wt%, 65 wt%, 60 wt%, 59 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, or 30 wt% of the total composition. In some embodiments, the combined amount of the diluent or the filler and the channel forming agent is about 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%-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%.

[0207] In some embodiments, the diluent or the filler comprises less than about 97% by weight of the total composition.

[0208] In some embodiments, the amount of the diluent or the filler comprises about 55% by weight to about 90% by weight of the total composition.

[0209] In some embodiments, the diluent or the filler comprises about 59% by weight, about 71% by weight, about 73% by weight, or about 86% by weight of the total composition.

[0210] In some embodiments, the diluent or the filler comprises MCC and / or lactose. In some embodiments, the amount of the diluent or the filler as MCC or lactose is about 70%, 65%, 60%, 58%, 56%, 50%, 46%, 48%, 44%, 40%, 30%, 25%, 20%, 15%, 14%, 10%, 5%, 3%, or 1%.

[0211] In some embodiments, the amount of the diluent or filler as MCC or lactose is about 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%-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 amount of the diluent or filler as MCC or lactose is about 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%.

[0212] In some embodiments, the diluent or the filler comprises an amount of MCC of about 40% to about 60% by weight of the total composition.

[0213] In some embodiments, the diluent or the filler comprises about 44% by weight, about 46% by weight, about 48% by weight, about 56% by weight, or about 58% by weight of MCC in the total composition.

[0214] In some embodiments, the diluent or the filler comprises about 10% by weight to about 40% by weight of lactose in the total composition.

[0215] In some embodiments, the diluent or the filler comprises about 14% by weight, about 15% by weight, about 25% by weight, or about 40% by weight of lactose in the total composition.

[0216] In some embodiments, the diluent or the filler comprises about 10% by weight to about 20% by weight of mannitol in the total composition.

[0217] In some embodiments, the diluent or the filler comprises about 14% by weight of mannitol in the total composition.

[0218] In some embodiments, the channel forming agent is selected from the group consisting of sodium chloride and polyethylene glycol (PEG) or combinations thereof.

[0219] In some embodiments, the channel forming agent is sodium chloride, sugar, citric acid, sodium citrate, sodium bicarbonate, potassium chloride, potassium citrate, dextrin, fructose, sodium saccharin, or xylitol.

[0220] In some embodiments, the channel forming agent is PEG.

[0221] In some embodiments, the channel forming agent is PEG 1500. Specification 21 / 38 pages 35 CN 121175041 A

[0222] In some embodiments, the amount of the channel forming agent is less than about 30% by weight, 25% by weight, 20% by weight, 15% by weight, 10% by weight, 5% by weight, 3% by weight, or 1% by weight of the total composition. In some embodiments, the amount of the channel forming agent is less than 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 channel forming agent is present in an amount of about 1%-30% by weight, 5%-30% by weight, 10%-30% by weight, 15%-30% by weight, 20%-30% by weight, 25%-30% by weight, 1%-20% by weight, 5%-20% by weight, 10%-20% by weight, 15%-20% by weight, 1%-15% by weight, 5%-15% by weight, 10%-15% by weight, 1%-10% by weight, 5%-10% by weight, or 1%-5% by weight.

[0223] In some embodiments, the channel forming agent is present in an amount of less than about 20% by weight of the total composition.

[0224] In some embodiments, the channel forming agent is present in an amount of about 5% by weight to about 15% by weight of the total composition.

[0225] In some embodiments, the channel forming agent is present in an amount of about 5% by weight, about 14% by weight, or about 15% by weight of the total composition.

[0226] In some embodiments, the disintegrant is present in an amount of less than 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 of the total composition. In some embodiments, the disintegrant is present in an amount of about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In some embodiments, the amount of the disintegrant is 2%-30% by weight, 5%-30% by weight, 10%-30% by weight, 15%-30% by weight, 20%-30% by weight, 2%-20% by weight, 5%-20% by weight, 10%-20% by weight, 15%-20% by weight, 2%-15% by weight, 5%-15% by weight, 10%-15% by weight, 2%-10% by weight, 5%-10% by weight, or 2%-5% by weight.

[0227] In some embodiments, the disintegrant is selected from the group consisting of: croscarmellose sodium, croscarmellose, starch and sodium starch glycolate, or combinations thereof.

[0228] In some embodiments, the amount of the disintegrant is less than about 30%.

[0229] In some embodiments, the amount of the disintegrant is less than about 20% by weight of the total composition.

[0230] In some embodiments, the amount of the disintegrant is from about 2% to about 10% by weight of the total composition.

[0231] In some embodiments, the amount of the disintegrant is from about 5% by weight or about 10% by weight of the total composition.

[0232] In some embodiments, the flow aid is selected from the group consisting of silica, magnesium stearate, talc, and corn starch or combinations thereof.

[0233] In some embodiments, the flow aid comprises silica.

[0234] In some embodiments, the amount of the flow aid is less than about 10%, 5%, 2%, or 1%. In some embodiments, the amount of the flow aid 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 gliding agent is about 0.1%-10%, 0.3%-10%, 0.5%-10%, 1%-10%, 2%-10%, 5%-10%, 0.1%-5%, 0.3%-5%, 0.5%-5%, 1%-5%, 2%-5%, 0.1%-2%, 0.3%-2%, 0.5%-2%, 1%-2%, 0.1%-1%, 0.3%-1%, or 0.5%-1%.

[0235] In some embodiments, the amount of the gliding agent is less than about 2% by weight of the total composition.

[0236] In some embodiments, the amount of the flow aid is about 1% by weight of the total composition.

[0237] In some embodiments, the lubricant is selected from the group consisting of magnesium stearate, talc, calcium stearate, zinc stearate, sodium stearate, sodium stearoyl fumarate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil or combinations thereof.

[0238] In some embodiments, the lubricant comprises magnesium stearate.

[0239] In some embodiments, the amount of the lubricant is less than about 10%, 5%, 2%, or 1%. In some embodiments, the amount of the 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 the lubricant is about 0.1%-10%, 0.3%-10%, 0.5%-10%, 1%-10%, 2%-10%, 5%-10%, 0.1%-5%, 0.3%-5%, 0.5%-5%, 1%-5%, 2%-5%, 0.1%-2%, 0.3%-2%, 0.5%-2%, 1%-2%, 0.1%-1%, 0.3%-1%, or 0.5%-1%.

[0240] In some embodiments, the amount of the lubricant is less than about 2% by weight of the total composition.

[0241] In some embodiments, the amount of the lubricant is about 0.5% by weight or about 1% by weight of the total composition.

[0242] In some embodiments, the composition further comprises an adhesive selected from the group consisting of: polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch, and modified cellulose or combinations thereof.

[0243] The embodiments provided herein relate to a composition comprising about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80% of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5%–80%, 10%–80%, 15%–80%, 20%–80%, 25%–80%, 30%–80%, 40%–80%, 5%–60%, 10%–60%, 15%–60%, 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% of a compound of formula (I).

[0244] The embodiments provided herein relate to a composition comprising about 5%, 10%, 15%, 20%, 25%,30%, 40%, 50%, 60%, 70%, or 80% of a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5%–80%, 10%–80%, 15%–80%, 20%–80%, 25%–80%, 30%–80%, 40%–80%, 5%–60%, 10%–60%, 15%–60%, 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% of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0245] The embodiments provided herein relate to a composition comprising about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70% or 80% of a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5%-80%, 10%-80%, 15%-80%, 20%-80%, 25%-80%, 30%-80%, 40%-80%, 5%-60%, 10%-60%, 15%-60%, 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% of a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0246] The embodiments provided herein relate to a composition comprising about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70% or 80% of a compound of formula (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5%-80%, 10%-80%, 15%-80%, 20%-80%, 25%-80%, 30%-80%, 40%-80%, 5%-60%, 10%-60%, 15%-60%, 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% of a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the composition comprises about 5% by weight to about 60% by weight of the total composition of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0248] (i) a diluent or filler,

[0249] (ii) optionally a channel forming agent,

[0250] (iii) a disintegrant,

[0251] (iv) a flow aid, and

[0252] (v) a lubricant,

[0253] wherein when the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the combined amount of the diluent or the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

[0254] In some embodiments, the composition comprises about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof of the total composition, and

[0255] (i) a diluent or filler,

[0256] (ii) optionally a channel forming agent,

[0257] (iii) a disintegrant,

[0258] (iv) a flow aid, and

[0259] (v) a lubricant,

[0260] wherein when the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

[0261] In some embodiments, the composition comprises about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof of the total composition, and

[0262] (i) a diluent or filler,

[0263] (ii) optionally a channel forming agent,

[0264] (iii) a disintegrant,

[0265] (iv) a flow aid, and

[0266] (v) a lubricant,

[0267] wherein when the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

[0268] In some embodiments, the composition comprises about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof of the total composition, and

[0269] (i) a diluent or filler in an amount of about 65% to about 85% by weight of the total composition,

[0270] (ii) a channel forming agent in an amount of about 10% to about 20% by weight of the total composition,

[0271] (iii) a disintegrant,

[0272] (iv) a flow aid, and

[0273] (v) a lubricant.

[0274] In some embodiments, the composition comprises about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof of the total composition, and

[0275] (i) a diluent or filler in an amount of about 65% to about 75% by weight of the total composition,

[0276] (ii) a channel forming agent in an amount of about 10% to about 20% by weight of the total composition,

[0277] (iii) a disintegrant,

[0278] (iv) a flow aid, and

[0279] (v) a lubricant.

[0280] In some embodiments, the composition comprises:

[0281] a disintegrant, said disintegrant being present in an amount of about 5% to about 10% by weight of the total composition;

[0282] a flow aid, said flow aid being present in an amount of about 0.5% to about 2% by weight of the total composition; and

[0283] a lubricant, said lubricant being present in an amount of about 0.5% to about 2% by weight of the total composition.

[0284] In some embodiments, the composition comprises about 15% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0285] (i) about 44% of MCC,

[0286] (ii) about 14% of lactose,

[0287] (iii) about 14% of sodium chloride,

[0288] (iv) about 10% of sodium starch glycolate,

[0289] (v) about 1% of silicon dioxide, and

[0290] (vi) about 1% of magnesium stearate,

[0291] wherein each percentage is a weight percentage based on the total weight of the composition.

[0292] In some embodiments, the composition comprises about 15% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0293] (i) about 44% of MCC,

[0294] (ii) about 14% of mannitol,

[0295] (iii) about 14% of sodium chloride,

[0296] (iv) about 10% of sodium starch glycolate,

[0297] (v) about 1% of silicon dioxide, and

[0298] (vi) about 1% of magnesium stearate,

[0299] wherein each percentage is a weight percentage based on the total weight of the composition.

[0300] In some embodiments, the composition comprises about 15% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0301] (i) about 48% MCC,

[0302] (ii) about 25% lactose,

[0303] (iii) about 5% sodium chloride,

[0304] (iv) about 5% sodium starch glycolate,

[0305] (v) about 1% silicon dioxide, and

[0306] (vi) about 1% magnesium stearate,

[0307] Each percentage is a weight percentage based on the total composition.

[0308] In some embodiments, the composition comprises about 15% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0309] (i) about 58% of MCC,

[0310] (ii) about 15% of lactose,

[0311] (iii) about 5% of sodium chloride,

[0312] (iv) about 5% of sodium starch glycolate,

[0313] (v) about 1% of silicon dioxide, and

[0314] (vi) about 1% of magnesium stearate,

[0315] wherein each percentage is a weight percentage based on the total composition. Instructions for Use, pages 25 / 38, 39 CN 121175041 A

[0316] In some embodiments, the composition comprises about 7.5% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0317] (i) about 56% of MCC,

[0318] (ii) about 15% of lactose,

[0319] (iii) about 15% of sodium chloride,

[0320] (iv) about 5% of sodium starch glycolate,

[0321] (v) about 1% of silicon dioxide, and

[0322] (vi) about 0.5% of magnesium stearate,

[0323] wherein each percentage is a weight percentage based on the total weight of the composition.

[0324] In some embodiments, the composition comprises about 7.5% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0325] (i) about 46% of MCC,

[0326] (ii) about 40% of lactose,

[0327] (iii) about 5% of sodium starch glycolate,

[0328] (iv) about 1% of silicon dioxide, and

[0329] (v) about 0.5% of magnesium stearate,

[0330] wherein each percentage is a weight percentage based on the total composition.

[0331] In some embodiments, the composition comprises about 6.5% of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and

[0332] (i) about 56% MCC,

[0333] (ii) about 15% lactose,

[0334] (iii) about 15% sodium chloride,

[0335] (iv) about 5% sodium starch glycolate,

[0336] (v) about 1% silicon dioxide, and

[0337] (vi) about 0.5% magnesium stearate,

[0338] wherein each percentage is a weight percentage based on the total composition.

[0339] The embodiments provided herein relate to a pharmaceutical composition comprising a compound of formula (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, in amounts less than about 200 mg, 180 mg, 150 mg, 120 mg, 100 mg, 95 mg, 90 mg, etc.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, 10 mg, 5 mg, 3 mg, 2 mg, or 1 mg. In some embodiments, the amount of the compound of formula (II), (III), or (IV) or a pharmaceutically acceptable salt thereof is 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 amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 1 mg-150 mg, 3 mg-150 mg, 5 mg-150 mg, 7.5 mg-150 mg, 10 mg-150 mg, 12.5 mg-150 mg, 15 mg-150 mg, 20 mg-150 mg, 25 mg-150 mg, 30 mg-150 mg, 35 mg-150 mg, 40 mg-150 mg, 1 mg-120 mg, 3 mg-120 mg, 5 mg-120 mg, 7.5 mg-120 mg, 10 mg-120 mg, 12.5 mg-120 mg, 15 mg-120 mg, 20 mg-120 mg, 25 mg-120 mg, 30 mg-120 mg, 35 mg-120 mg, 40 mg-120 mg, 1 mg-100 mg. mg, 3 mg‑100 mg, 5 mg‑100 mg, 7.5 mg‑100 mg, 10 mg‑100 mg, 12.5 mg‑100 mg, 15 Instructions 26 / 38 Page 40 CN 121175041 A mg‑100 mg, 20 mg‑100 mg, 25 mg‑100 mg, 30 mg‑100 mg, 35 mg‑100 mg, 40 mg‑100 mg, 1 mg‑80 mg, 3 mg‑80 mg, 5 mg‑80 mg, 7.5 mg‑80 mg, 10 mg‑80 mg, 12.5 mg‑80 mg, 15 mg‑80 mg, 20 mg‑80 mg, 25 mg‑80 mg, 30 mg‑80mg, 35 mg‑80 mg, 40 mg‑80 mg, 1 mg‑60 mg, 3 mg‑60 mg, 5 mg‑60 mg, 7.5 mg‑60 mg, 10 mg‑60 mg, 12.5 mg‑60 mg, 15 mg‑60 mg, 20 mg‑60 mg, 25 mg‑60 mg, 30 mg‑60 mg, 35 mg‑60 mg, 40 mg‑60 mg, 1 mg‑50 mg, 3 mg‑50 mg, 5 mg‑50 mg, 7.5 mg‑50 mg, 10 mg‑50 mg, 12.5 mg‑50 mg, 15 mg‑50 mg, 20 mg‑50 mg, 25 mg‑50 mg, 30 mg‑50 mg, 35 mg‑50 mg, 40 mg‑50 mg, 1 mg‑40 mg, 3 mg‑40 mg, 5 mg‑40 mg, 7.5 mg‑40 mg, 10 mg‑40 mg, 12.5 mg‑40 mg, 15 mg‑40 mg, 20 mg‑40 mg, 25 mg‑40 mg, 30 mg‑40 mg, 35 mg‑40 mg, 1 mg‑30 mg, 3 mg‑30 mg, 5 mg‑30 mg, 7.5 mg‑30 mg, 10 mg‑30 mg, 12.5 mg‑30 mg, 15 mg‑30 mg, 20 mg‑30 mg, 25 mg‑30 mg, 1 mg‑20 mg, 3 mg‑20 mg, 5 mg‑20 mg, 7.5 mg‑20 mg, 10 mg‑20 mg, 12.5 mg‑20 mg, 15 mg‑20 mg, 1 mg‑15 mg, 3 mg‑15 mg, 5 mg‑15 mg, 7.5 mg‑15 mg, 10 mg‑15 mg, 12.5 mg‑15 mg, 1 mg‑10 mg, 3 mg‑10 mg, 5 mg-10 mg, 7.5 mg-10 mg, 1 mg-7.5 mg, 3 mg-7.5 mg, 5 mg-7.5 mg, 1 mg-5 mg, or 3 mg-5 mg.

[0340] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 100 mg.

[0341] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 50 mg.

[0342] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is from about 5 mg to about 20 mg.

[0343] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 5 mg, from about 5 mg to 20 mg, or greater than about 20 mg.

[0344] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is less than about 10 mg, from about 10 mg to 40 mg, or greater than about 40 mg.

[0345] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 40 mg.

[0346] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 5 mg.

[0347] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 10 mg.

[0348] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 20 mg.

[0349] In some embodiments, the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof is about 40 mg.

[0350] In some embodiments, the composition further comprises at least one additional active ingredient, wherein the at least one additional active ingredient is a compound that normalizes lipid metabolism.

[0351] In some embodiments, the composition comprises at least one additional active ingredient, wherein the at least one additional active ingredient is selected from the group comprising one or more of the following: antidiabetic drugs, hypoglycemic 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, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein(a) antagonists, HM74A receptor agonists, lipase inhibitors, insulin, sulfonylureas, biguanides, meglitinide, thiazolidinediones, α-glucosidase inhibitors, active ingredients acting on ATP-dependent potassium channels of β cells, glycogen phosphorylation inhibitors, glucagon receptor antagonists, Activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-bisphosphatase, glucose transporter 4 (Instructions for use, pages 27 / 38, 41 CN 121175041 A), inhibitors of glutamine-fructose-6-phosphatamidotransferase, inhibitors of dipeptidyl peptidase IV, inhibitors of 11-β-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, and sodium-dependent glucose transporter 1 or 2.Regulators, GPR40 regulators, 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 regulators, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH (Melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and norepinephrine compounds, 5HT agonists, serotonin agonists, galactopeptide antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 regulators, diphenylazacyclobutanone derivatives, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR regulators, RXR regulators, or TR-β agonists or amphetamine.

[0352] In some embodiments, the compositions or unit dosage forms described herein are applied in the form of emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, dissolving tablets, dissolving wafers, capsules, gel capsules, solids, semi-solids, solid gels, gel matrices, creams, pastes, tablets, granules, sachets, powders, etc.

[0353] In some embodiments, the compositions are in solid dosage forms.

[0354] In some embodiments, the solid dosage form is a capsule, pill, sachet, tablet, granule, or powder.

[0355] In some embodiments, the composition is stable at room temperature and 60% relative humidity (RH) for at least 9 weeks.

[0356] In some embodiments, the composition is stable at 40°C and 75% RH for at least 8 weeks.

[0357] 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.

[0358] In some embodiments, the composition is stable for at least 3 months.

[0359] In some embodiments, the composition is stable for at least 4 months.

[0360] In some embodiments, the composition is stable for at least 36 months.

[0361] Treatment Method

[0362] The embodiments provided herein relate to a method of treating cholestatic liver disease in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of the above-described pharmaceutical composition.

[0363] In some embodiments, the cholestatic liver disease is pediatric cholestatic liver disease.

[0364] In some embodiments, the cholestatic liver disease is adult cholestatic liver disease.

[0365] In some embodiments, the 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-related cholestasis, paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, and Alagille syndrome. cholestatic liver disease (ALGS), biliary atresia (BA), post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant related liver disease, intestinal failure related liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis. Specification 28 / 38 pages 42 CN 121175041 A

[0366] In some embodiments, the cholestatic liver disease is selected from the group consisting of: ALGS, PFIC, BA, ICP, BRIC, PSC, and PBC.

[0367] In some embodiments, the cholestatic liver disease is PSC.

[0368] In some embodiments, the cholestatic liver disease is PBC.

[0369] In some embodiments, the cholestatic liver disease is ICP.

[0370] In some embodiments, the cholestatic liver disease is characterized by pruritus.

[0371] In some embodiments, the subject has elevated total serum bile acids (sBA) prior to administration of the pharmaceutical composition.

[0372] In some embodiments, the compound of formula (I) is an ileal bile acid transporter (IBAT) inhibitor.

[0373] In some embodiments, the compound of formula (I) has the structure of the compound of formula (II) as an ileal bile acid transporter (IBAT) inhibitor.

[0374] The embodiments provided herein relate to a method of treating hyperlipidemia in a subject of need, wherein the method comprises administering a therapeutically effective amount of the above-described pharmaceutical composition to the subject.

[0375] Further embodiments provided herein relate to a method of lowering serum cholesterol levels in a subject of need, wherein the method comprises administering a therapeutically effective amount of the above-described pharmaceutical composition to the subject.

[0376] Additional embodiments provided herein relate to a method of treating arteriosclerosis in a subject of need, wherein the method comprises administering a therapeutically effective amount of the above-described pharmaceutical composition to the subject.

[0377] Additional embodiments provided herein relate to a method of treating syndrome X in a subject of need, wherein the method comprises administering a therapeutically effective amount of the above-described pharmaceutical composition to the subject.

[0378] The pharmaceutical compositions of the present invention can be administered via a variety of routes, including oral, rectal, intraocular, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, direct into cerebrospinal fluid, intratracheal, and intranasal administration. In some embodiments, the composition is administered orally to the subject.

[0379] Methods and Kits for Generating Pharmaceutical Compositions

[0380] The embodiments provided herein relate to a method for generating the above-described pharmaceutical composition, the method comprising the steps of: combining a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more excipients selected from the group consisting of:

[0381] (i) a diluent or filler,

[0382] (ii) a disintegrant,

[0383] (iii) a channel-forming agent,

[0384] (iv) a flow aid, and

[0385] (v) a lubricant,

[0386] to form an admixture; mixing the admixture; and filling or compacting the admixture in a capsule shell to form the pharmaceutical composition.

[0387] Further embodiments provided herein relate to a kit for treating cholestatic liver disease in a subject of need, wherein the kit comprises at least one unit dose of a therapeutically effective amount of the above-described composition and instructions for its administration.

[0388] In some embodiments, the kit is used to treat the cholestatic liver disease, which 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-related cholestasis, paraneoplastic cholestasis, Stoffel syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive-related cholestasis, and drug-related cholestasis.Cholestasis, infection-associated cholestasis, Durbin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Arageo syndrome (ALGS), biliary atresia (BA), post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant related liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis.

[0389] In some embodiments, the cholestatic liver disease is selected as ALGS, PFIC, BA, ICP, BRIC, PSC, or PBC.

[0390] In some embodiments, the kit is used to treat the cholestatic liver disease, i.e., PSC.

[0391] In some embodiments, the kit is used to treat the cholestatic liver disease, i.e., PBC.

[0392] In some embodiments, the kit is used to treat the cholestatic liver disease, i.e., ICP.

[0393] Further embodiments provided herein relate to a kit for treating hyperlipidemia in a subject in need, wherein the kit comprises a therapeutically effective amount of the above-described composition.

[0394] Further embodiments provided herein relate to a kit for lowering serum cholesterol levels in a subject in need, wherein the kit comprises a therapeutically effective amount of the above-described composition.

[0395] Further embodiments provided herein relate to a kit for treating arteriosclerosis in a subject in need, wherein the kit comprises a therapeutically effective amount of the above-described composition.

[0396] Further embodiments provided herein relate to a kit for treating syndrome X in a subject in need, wherein the kit comprises a therapeutically effective amount of the above-described composition.

[0397] Examples

[0398] The following examples are provided to further describe some embodiments of the examples disclosed herein. The examples are intended to illustrate and not limit the disclosed embodiments.

[0399] Example 1. Excipient Compatibility

[0400] Binary formulations of vosibarb potassium were prepared using the excipients outlined in Table 1.1 at a ratio of 1:1 or 10:1. Powdered excipients were used to maximize the surface area interaction between the excipient and the drug substance.

[0401] Each formulation was prepared in a total sample size of 300 mg. Vocibard and each excipient were weighed into glass vials and mixed by vortexing. Individual vials of each formulation were loosely capped and stored under two storage conditions: ambient / 60% RH and 40°C / 75% RH. Humidity was controlled by using a saturated salt solution in a sealed container. Individual vials of each formulation were sampled at all three planned time points (T = 2 weeks, 4 weeks, and 8 weeks). A Vocibard DS standard solution prepared at nominal concentration in an analytical diluent was used as the T = 0 data point. The pure, loose powder of the drug substance was stored inThe same vial configuration was used as a control for each storage condition.

[0402] At specified time points, approximately 50 mg of each formulation was sampled and diluted with analytical diluent in 50 mL (for 1:1 formulations) or 100 mL (for 1:10 formulations and pure DS) to achieve a nominal analytical concentration of 0.5 mg / mL Vosibart. HPLC analysis (gradient elution) was performed based on the parameters described above under HPLC parameters.

[0403] Table 1.1 Selected Excipients and Target Ratios (Page 30 / 38, CN 121175041 A)

[0404]

[0405] The potency of the samples fluctuated significantly at each time point. This variability is expected considering the variability of sampling, the potential hygroscopicity due to open petri dish conditions, and the effect of insoluble excipients on the diluent. Potency data are not used for trend stability but are reported along with impurity profiles as supporting data for the assessment.

[0406] The purity of all samples remained stable under both storage conditions; the growth of related substances in the samples stored at 40°C / 75% RH was slightly faster. The total peak purity of the Vosibart for all samples remained stable under both storage conditions, indicating acceptable compatibility with all tested excipients.

[0407] Table 1.2 Efficacy results of samples stored at RT / 60% RH (Pages 31 / 38, CN 121175041 A)

[0408]

[0409] Table 1.3 Efficacy results of samples stored at 40°C / 75% RH

[0410]

[0411] The NaCl:Vocibart mixture exhibited significant hygroscopicity under 40°C / 75% RH storage conditions, leading to agglomeration and viscosity of the samples (Figure 1). The NaCl:Vocibart RT / 60% RH samples did not show physical agglomeration or significant growth at RRT 0.86.

[0412] PEG 1500:Vocibart formulations stored at 40°C / 75% RH showed some hard agglomeration formation within 2 weeks (see Figure 2), but remained consistent throughout the remainder of the study. This agglomeration was not noticeable in the RT / 60% RH samples. Under any storage conditions, the relevant material profile of PEG 1500:Vocibart remained unchanged over 8 weeks.

[0413] During the study, all other samples remained as white, loose powders. No color change or significant agglomeration was observed under any storage conditions (Figures 3-4).

[0414] Example 2. Formulation Development

[0415] Overview of Formulations

[0416] Table 2.1 Composition of Formulations Specification 32 / 38 pages 46 CN 121175041 A

[0417]

[0418] Table 2.2 Flow Properties of Formulations

[0419]

[0420] Formulas 1 and 2 were prepared from 15% w / w Vosibart potassium (without correction factors). Both formulas were initially tested as 20 mg capsules. The flow properties and dissolution results for both formulas were similar, therefore the formula 1 diluent system was chosen. Formulas 3–4 reduced the levels of channel-forming agents and disintegrants, decreasing with increasing amounts of lactose (formula 3) or Avicel (formula 4). Again, there was no significant effect on the flow properties or dissolution profiles of the 20 mg capsules. The dissolution profiles of formulas 3 and 4 were consistent with each other and with that of formula 1. This confirms that the levels of sodium chloride and sodium starch glycolate in the final formula can be reduced if desired. Formula 3 (added lactose) showed lower release in phosphate buffer compared to formula 4 (added Avicel), therefore, for formula 5, increasing Avicel is advantageous when adapting to formula modifications.

[0421] Formulation 5 was prepared in a blend with a lower concentration of vosibat potassium. Magnesium stearate was also reduced in formulation 5. Formulation 5 exhibited acceptable dissolution profiles and flow characteristics, and changes in separation and dissolution rate due to excessive lubrication were also evaluated. Content uniformity remained low RSD% (no separation observed) when tested on days 0 and 7 after formulation preparation, and excessive mixing of the formulation did not affect the dissolution profiles.

[0422] Formulation 6 was formulated without NaCl, and 20 mg capsules were tested in all the same media. While the increased Avicel (formulation 4) resulted in increased release in phosphate at pH 6.8, it improved dissolution results in acidic media (acetate at pH 4.5) at higher lactose levels (formulation 3). Although solubility data indicated that sink conditions were met, complete release was not achieved in 0.1 N HCl with formulation 6. Further studies concluded that vocibart extraction in 0.1 N HCl was limited even without excipients (Example 2). The acidic medium was changed to 0.01 N HCl. Formula 6 was evaluated in each of the media (0.01 N HCl, phosphate buffer, and acetate buffer) to inform the effect of NaCl in the formula.

[0423] Formulas 1-2: Evaluation of the diluent system at a target dose of 40 mg

[0424] Formulas 1 and 2 were produced from 15% w / w potassium vocibart. The diluent system in Formula 1 represents existing vocibart capsule formulas, while Formula 2 contains mannitol instead of lactose. Historical dissolution data of vocibart capsules indicate that higher dose strengths (20 mg) exhibit gelling and slow release. For each formula, tapping or loosening was used.The fillers were used to fill capsules to determine the effect of compaction on capsule release. Dissolution tests were performed in 900 mL phosphate buffer at pH 6.8. Both formulations showed immediate dissolution, with the capsule contents dispersing within 7–10 minutes. No gelling was observed, and there were no significant differences in release between formulations or between compacted and loosely filled capsules. The superposition of dissolution curves for formulation 1 versus formulation 2 (n = 6, including both compacted and stacked capsules) can be seen in Figure 5. Since formulations 1 and 2 are comparable, the diluent system was maintained as Avicel:lactose to maintain consistency with existing capsule formulations. Subsequent formulations 3–4 evaluated reduced channel forming agents (NaCl) and disintegrants (sodium starch glycolate, etc.).

[0425] Formulations 3–4: Optimization of channel forming agents and disintegrants

[0426] Formulations 3–4 were prepared from reduced levels of NaCl and sodium starch glycolate. To compensate for the reduction of these components, formulation 3 increased the ratio of Avicel, while formulation 4 increased lactose. Additionally, to achieve the % w / w of vosipat potassium, potency (0.9165) and salt correction (0.9549) were included in the calculations to determine the target weight of vosipat potassium during formulation preparation. The packing / tap density and angle of repose indicate that each of these formulations has flow characteristics similar to those of formulations 1–2 (Table 2.1).

[0427] Table 2.3 Formulation Composition

[0428]

[0429] Dissolution rates of 40 mg doses in gelatin capsules (0) were tested in phosphate buffer (pH 6.8) to assess the effects of reduced channel-forming agents and disintegrants. The fill weight of these capsules was 280 mg. The dissolution volume was then changed from 900 mL to 500 mL to match the current analytical method. Given the high water solubility of vocibarbital (>200 mg / mL at 25°C), 40 mg capsules still met the dissolution conditions in 500 mL (0.08 mg / mL). Vocibarbital formulation 1 was also retested in 500 mL dissolution medium as a control, but the fill weight of the 40 mg capsules was adjusted to 304.7 mg to include potency correction.

[0430] Formulations 1, 3, and 4 showed similar dissolution rates in 500 mL phosphate medium at pH 6.8 (Figure 6). Formulation 3 (with increased lactose) had the lowest overall recovery and the highest variability. For formulation 5, the lactose level was maintained at 15%, and Avicel was increased to accommodate the formulation changes. There was no effect on the visual capsule dissolution rate or overall dissolution rate of formulations 3 and 4, which confirms that the channel forming agents and disintegrants in the formulations can be reduced if necessary without affecting the release profile of the 40 mg capsules on pages 34 / 38 of the instructions.

[0431] Formula 5: 20 mg target dose

[0432] Formula 5 was designed to have a similar composition to Formula 1, but with a lower drug loading and a reduction from 10% to 5% sodium starch glycolate (disintegrant). NaCl (channel forming agent) was maintained at an initial level of 15%. Based on observed over-lubrication issues in other historical Vosibart formulations, magnesium stearate was reduced to 0.5%. Based on observed results from Formulas 3–4 (with a slight increase in dissolution with increased Avicel relative to lactose), the % w / w of Avicel was also increased to accommodate the weight changes of other components. As with Formulas 3–4, the amount of added Vosibart potassium was adjusted to accommodate salt factor and purity factor. See Table 2.4.

[0433] Table 2.4 Composition of Formula 5

[0434]

[0435] Evaluation of Separation and Over-lubrication of Formula 5

[0436] Formula 5 was used to evaluate possible separation and over-lubrication studies. The formulation was tested for uniformity of content (“CU”) and dissolution at T = 0 and then kept undisturbed for 7 days (stored in a glass jar sealed in an aluminum bag). After 7 days, the CU was retested to assess separation. The 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 co-mixed in a turbot for an additional 5 minutes to produce over-lubrication. The over-mixed formulation was filled into capsule No. 0 and its dissolution was tested in 500 mL of phosphate buffer (pH 6.8). No filtration step was used in the dissolution tests at T = 0 or T = 7 days.

[0437] The T = 0 determination of formulation 5 yielded 97.30% LC and 99.85% purity. The dissolution at T = 0 was tested on a total of 6 capsules with n = 3 stacked and n = 3 tapped fillings. Consistent with previous formulations, the level of tapping did not affect the dissolution profile of the capsules: the capsules dissolved within 10 minutes, and the contents dispersed, with most of the release occurring at the 15-minute time point (Figure 7).

[0438] Table 2.5 includes CU results at T = 0 and after undisturbed standing on a benchtop for 7 days. The RSD of the CU samples at T = 0 and T = 7 days was low, at approximately 3%. <905> The acceptable value (AV) calculated in the description is 4.78 at T = 0 and 7.50 at T = 7 days. Although AV increases slightly, both values ​​are below the USP. <905> The recommended limit of 15 is outlined in the specification, and the similar RSD at both time points indicates that there was no significant change in batch uniformity after 7 days of storage. (Pages 35 / 38, CN 121175041 A

[0439] ) At T =After performing a CU test on the formulation at 7 days, the formulation was mixed in a turbula for an additional 5 minutes to over-lubricate the blend. Capsules were filled to a 20 mg dose (tamp-fill) and their dissolution in phosphate at pH 6.8 was evaluated. The dissolution was consistent with the results at T = 0, indicating that the additional mixing did not significantly over-lubricate the blend. See Figure 8. Surprisingly, the lower magnesium stearate level may have been beneficial to the final formulation.

[0440] Table 2.5 Content uniformity of formulation 5, T = 0 relative to T = 7 days

[0441]

[0442] Example 3. Dissolution in various media

[0443] The dissolution of formulations 1, 3, 4 and 5 was tested in three different media: phosphate at pH 6.8, acetate at pH 4.5 and 0.1 N HCl.

[0444] Dissolution in acetate buffer at pH 4.5

[0445] Figure 9 includes a superposition of dissolution results in acetate buffer at pH 4.5. This release is consistent with visual observations during the test: the capsules dissolved completely, and the contents were easily dispersed within 10–15 minutes. No aggregation or gelation of any formulations was observed in acetate buffer at pH 4.5.

[0446] Dissolution in phosphate buffer at pH 6.8

[0447] Formulations 1, 3, 4, 5, and 6 were filled into capsule #1 to a target dose of 20 mg, and their dissolution in 500 mL phosphate buffer at pH 6.8 was tested.

[0448] As with acetate buffer, the dissolution profiles of all formulations were similar, but formulations 5 and 6 achieved the highest total release (Figure 10).

[0449] Table 3.1 Determination of each formulation

[0450]

[0451] Dissolution in acidic media

[0452] Initially, all formulations were studied and evaluated in 0.1 N HCl.

[0453] Table 3.2 Formulation 5 in 0.1 N HCl, Instructions 36 / 38 pages, 50 CN 121175041 A

[0454]

[0455] Table 3.3 Formulation 6 in 0.1 N HCl

[0456]

[0457] Consistent with dissolution tests in phosphate buffer and acetate buffer, each formulation was dissolved in 0.01 N HCl using gelatin capsules filled to a target dose of 20 mg. The media filling volume was 500 mL, using transparent containers, and neutralization was performed immediately after each extraction (0.5 mL of 0.01 N NaOH was added to 0.5 mL of the dissolution sample) to limit degradation between sampling and analysis. The results are shown in Figure 11 and Table 3.4.

[0458] Summary of dissolution results

[0459] Table 3.4 presents the 60-minute dissolution results (average of 6 containers) for each formulation in the three media. In phosphate buffer at pH 6.8, the capsule release profiles and final recovery percentages for vocibarr were similar for all formulations. In lower pH media, the differences between formulations became more pronounced. All formulations exhibited slower overall release profiles and lower final recoveries in 0.01 N HCl, but formulation 4 showed a significantly lower overall recovery. Formulations 1, 3, and 4 had higher drug loadings (15% vocibarr, compared to 7.5% for formulations 5 and 6). Formulations 3 and 4 also had lower sodium chloride levels (5% compared to 15% for the other formulations), with formulation 3 having a higher lactose content and formulation 4 having a higher Avicel level to accommodate the lower NaCl levels. When tested at both 20 mg and 40 mg doses, formulation 4 showed higher recoveries in the nominal medium (phosphate at pH 6.8) than formulation 3, thus formulation 5 implemented a higher Avicel loading to accommodate the formulation change. While formulation 4 performed better than formulation 3 in phosphate at pH 6.8, it showed lower recoveries in both acetate and 0.01 N HCl, suggesting that the increase in lactose may be beneficial for Vosibart dissolution at lower pH values. These results informed the development of formulation 6, which removed NaCl and increased lactose to accommodate this change, aiming to improve dissolution in the desired 0.1 N HCl medium. Formulation 6 did not show an improvement in dissolution in 0.1 N HCl, and the acidic medium used for dissolution screening was changed to 0.01 N HCl. Based on the improved dissolution in the nominal phosphate pH 6.8 buffer, formulation 5 maintained a higher Avicel:lactose ratio. As indicated in Table 3.4, formulations 5 and 6 performed similarly in the three test media.

[0460] Table 3.4 Total dissolution rate of each formulation / media at 60 minutes Instruction manual 37 / 38 pages 51 CN 121175041 A

[0461]

[0462] Example 4. Study of formulation 7

[0463] Formulation 7 was developed with 6.55% VLX and filled into capsules 4 and 0 (see Table 4.1). This resulted in 80 mg of filler at a 5 mg dose in capsule 4 and 320 mg of filler at a 20 mg dose in capsule 0. Prefilled formulation 7 was successful at these filling targets and capsule sizes. All capsules were weight sorted with a tolerance of + / - 5% of the target filler weight.

[0464] The flow characteristics and dissolution results of formulation 7 are included in Table 4.2 and Figure 12. The dissolution rates of formulations 5 and 7 were also very consistent in each medium, particularly at pH 6.8 with phosphate and pH 7.Approximately 95% is released in 4.5% acetate and only 85% in 0.01 N HCl.

[0465] Table 4.1 More capsule-filled formulation 7

[0466]

[0467] Table 4.2 Flow characteristics of formulation 7

[0468] Instruction manual, page 38 / 38, 52 CN 121175041 A, Figure 1; Instruction manual, Figure 1 / 9, page 53 CN 121175041 A, Figure 2; Instruction manual, Figure 2 / 9, page 54 CN 121175041 A, Figure 3; Instruction manual, Figure 3 / 9, page 55 CN 121175041 A, Figure 4; Instruction manual, Figure 4 / 9, page 56 CN 121175041 A, Figure 5; Instruction manual, Figure 5 / 9, page 57 CN 121175041 A, Figure 7; Instruction manual, Figure 8 / 9, page 58 CN 121175041 A, Figure 9; Instruction manual, Figure 10; Instruction manual, Figure 7 / 9, page 59 CN 121175041 A, Figure 11; Instruction manual, Figure 12; Instruction manual, Figure 8 / 9, page 60 CN 121175041 A, Figure 13; Instruction manual, Figure 9 / 9, page 61 CN 121175041 A

Claims

1. A pharmaceutical composition comprising a compound of formula (I), in: X is NH; R 1 It is (C1-C6)-alkyl; R 2 It is OH; R 2 'For H; R 3 R 3' R 4 R 4' R 5 R 5' Independently, it can be H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, or 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, wherein one, more than one, or all of the hydrogen atoms in the alkyl group may be replaced by: fluorine, phenyl, -(CH2)-phenyl, -(CH2)2-phenyl, O-phenyl, O-(CH2) m -phenyl, -(CH2)-O-(CH2) m -Phenyl, wherein the phenyl ring may be substituted 1 to 3 times with the following: 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; Wherein group R 3 R 3' R 4 R 4' R 5 and R 5' At least one of them has (C1-C6)-alkylene-OS(O) p -R 6 The meaning of , and the other has -O-(CH2) m -The meaning of phenyl, wherein the phenyl ring can be substituted 1 to 3 times by the following: 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 It can be 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 its pharmaceutically acceptable salt; as well as One or more excipients selected from the group consisting of: (i) diluents or fillers, and (ii) Disintegrants.

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

3. The composition according to any one of claims 1 and 2, further comprising a flow aid, a lubricant, or a combination thereof.

4. The composition according to any one of claims 1 to 3, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (i) diluent or filler (ii) Disintegrants. (iii) Channel forming agents, (iv) Flow aids, and (v) Lubricant.

5. The composition according to any one of claims 1 to 3, further comprising an adhesive.

6. The composition according to any one of claims 1 to 4, wherein R 5' (C1-C6)-alkylene-S(O)2-R 6 .

7. The composition according to any one of claims 1 to 6, wherein the compound of formula (I) has a structure selected from the group consisting of formulas (II), (III) or (IV) or a pharmaceutically acceptable salt thereof: 。 8. The composition according to any one of claims 1 to 7, wherein the compound of formula (I) has a structure selected from the group consisting of formulas (II) or (III) or a pharmaceutically acceptable salt thereof: 。 9. The composition according to any one of claims 1 to 8, wherein the compound of formula (I) has the structure of formula (II) or a pharmaceutically acceptable salt thereof: 。 10. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of the 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 the 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 the compound of formula (I), wherein the pharmaceutically acceptable salt is a potassium salt.

13. The composition according to any one of claims 1 to 9, comprising a compound of formula (II) in the form of potassium ethoxide hydrate: 。 14. The composition according to any one of claims 1 to 9, comprising a pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is a zinc salt.

15. The composition according to any one of claims 1 to 14, wherein the composition comprises a compound of formula (I) having the structure of formula (II) or a pharmaceutically acceptable salt thereof, and (i) diluent or filler (ii) Disintegrants. (iii) Optionally, a channel forming agent. (iv) Flow aids, and (v) Lubricant.

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

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

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

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

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

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

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

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

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

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

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

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

33. The composition according to any one of claims 1 to 31, wherein the diluent or the filler is selected from the group consisting of: sugars, glucose dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, starch, cellulose and modified cellulose or combinations thereof.

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

35. The composition of claim 33, wherein the diluent or the 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 the filler comprises less than about 97% by weight of the total composition.

37. The composition according to any one of claims 1 to 36, wherein the amount of the diluent or the filler is from 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 the filler comprises 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 the filler comprises an amount of MCC 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 the filler comprises an amount of MCC 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 the filler comprises 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 the filler comprises 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 the filler comprises mannitol in an amount of about 10% to about 20% by weight of the total composition.

44. The composition according to any one of claims 1 to 43, wherein the diluent or the 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 channel forming agent is selected from the group consisting of sodium chloride and polyethylene glycol (PEG) or combinations thereof.

46. ​​The composition according to any one of claims 1 to 45, wherein the channel forming 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 channel forming agent is PEG.

48. The composition of claim 47, wherein the channel forming agent is PEG 1500.

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

50. The composition according to any one of claims 1 to 48, wherein the channel forming agent is present 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 channel forming agent is present 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, croscarmellose, starch and sodium starch glycolate or combinations thereof.

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

54. The composition according to any one of claims 1 to 53, wherein the amount of the disintegrant is from 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 amount of the disintegrant is 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 aid is selected from the group consisting of: silica, magnesium stearate, talc, and corn starch or combinations thereof.

57. The composition according to any one of claims 1 to 56, wherein the flow aid comprises silica.

58. The composition according to any one of claims 1 to 57, wherein the amount of the gliding agent 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 amount of the gliding agent is 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 stearoyl fumarate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil or combinations 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 said 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 amount of said lubricant is 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, wherein the composition further comprises an adhesive selected from the group consisting of: polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch and modified cellulose or combinations thereof.

65. The composition according to any one of claims 1 to 64, wherein the composition comprises 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) Optionally, a channel forming agent. (iii) Disintegrants (iv) Flow aids, and (v) Lubricant, When the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

66. The composition according to any one of claims 1 to 64, wherein the composition comprises 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) Optionally, a channel forming agent. (iii) Disintegrants (iv) Flow aids, and (v) Lubricant, When the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

67. The composition according to any one of claims 1 to 66, wherein the composition comprises 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) Optionally, a channel forming agent. (iii) Disintegrants (iv) Flow aids, and (v) Lubricant, When the channel forming agent is absent, the amount of the diluent or the filler is about 70% to about 90% by weight of the total composition, or when the channel forming agent is present, the amount of the diluent or the combination of the filler and the channel forming agent is about 70% to about 90% by weight of the total composition.

68. The composition according to any one of claims 1 to 66, wherein the composition comprises about 5% to about 20% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, said diluent or filler comprising about 65% to about 85% by weight of the total composition. (ii) a channel forming agent, said channel forming agent comprising about 10% to about 20% by weight of the total composition. (iii) Disintegrants (iv) Flow aids, and (v) Lubricant.

69. The composition according to any one of claims 1 to 66, wherein the composition comprises about 5% to about 10% by weight of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and (i) a diluent or filler, said diluent or filler comprising about 65% to about 75% by weight of the total composition. (ii) a channel forming agent, said channel forming agent comprising about 10% to about 20% by weight of the total composition. (iii) Disintegrants (iv) Flow aids, and (v) Lubricant.

70. The composition according to any one of claims 1 to 69, wherein the composition comprises: A disintegrant, wherein the amount of the disintegrant is about 5% to about 10% by weight of the total composition. A flow aid, wherein the amount of the flow aid is from about 0.5% to about 2% by weight of the total composition, and A lubricant, wherein the amount of the lubricant is from about 0.5% by weight to about 2% by weight of the total composition.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

89. The composition according to any one of claims 1 to 88, comprising at least one additional active ingredient, wherein the at least one additional active ingredient is selected from the group comprising one or more of the following substances: antidiabetic drugs, hypoglycemic 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, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein(a) antagonists, HM74A receptor agonists, lipase inhibitors, insulin, sulfonylureas, biguanides, meglitinide, thiazolidinediones, α-glucosidase inhibitors, ATP-dependent potassium permanganate acting on β cells. The active ingredients of this product include: glycogen phosphorylation enzyme inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose-1,6-bisphosphatase inhibitors, glucose transporter 4 regulators, glutamine-fructose-6-phosphatamidotransferase inhibitors, dipeptidyl peptidase IV inhibitors, 11-β-hydroxysteroid dehydrogenase 1 inhibitors, protein tyrosine phosphatase 1B inhibitors, sodium-dependent glucose transporter 1 or 2 regulators, GPR40 regulators, and hormones. Inhibitors of sensitive lipases, 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, CRFBP antagonists, urocorticin agonists, β3 agonists, CB 1. Receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, serotonin agonists, glycopyridine antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 regulators, diphenylazacyclobutanone derivatives, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase / amylase inhibitors, PPAR regulators, RXR regulators, or TR-β agonists or amphetamines.

90. The composition according to any one of claims 1 to 89, wherein the composition is in solid dosage form.

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

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

94. The composition according to any one of claims 1 to 93, wherein the composition is stable for at least 3 months.

95. The composition according to any one of claims 1 to 93, wherein the composition is stable for at least 4 months.

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

97. A method of treating cholestatic liver disease in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96.

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

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

100. The method according to any one of claims 97 to 99, wherein the cholestatic liver disease is 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, paraneoplastic cholestasis, or Stauffer syndrome. This includes various liver diseases such as cholestasis of pregnancy (ICP), contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, Alagille syndrome (ALGS), biliary atresia (BA), post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant related liver disease, intestinal failure related liver disease, 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 has elevated total serum bile acids (sBA) prior to the 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) as an inhibitor of ileal bile acid transporter (IBAT).

109. A method of treating hyperlipidemia in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96.

110. A method for lowering serum cholesterol levels in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96.

111. A method for treating arteriosclerosis in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96.

112. A method of treating syndrome X in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 96.

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

114. A method for producing a pharmaceutical composition according to any one of claims 1 to 96, the method comprising the step of: combining a therapeutically effective amount of the compound of formula (I) with one or more excipients selected from the group consisting of: (i) diluent or filler (ii) Disintegrants. (iii) Channel forming agents, (iv) Flow aids, and (v) Lubricant, To form an admixture; to mix the admixture; and to fill or compact the admixture in a capsule shell to form the pharmaceutical composition.

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

116. The kit according to claim 115, wherein the cholestatic liver disease is 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-related cholestasis, paraneoplastic cholestasis, Stoffel syndrome, intrahepatic cholestasis of pregnancy (ICP), contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, Durbin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Arageo syndrome (ALGS), biliary atresia (BA), post-catapulting biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant liver disease, intestinal failure-related liver disease, 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 cholestatic liver disease is PBC.

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

121. A kit for treating hyperlipidemia in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96.

122. A kit for lowering serum cholesterol levels in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96.

123. A kit for treating arteriosclerosis in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96.

124. A kit for treating syndrome X in a subject in need, wherein the kit comprises a therapeutically effective amount of the composition according to any one of claims 1 to 96.

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