Religlitazone polymorphic forms and formulations

Abstract

This disclosure provides a crystalline form of religlitazone, a pharmaceutical composition or formulation containing a crystalline form of religlitazone, and a method for treating a patient's disease, condition, or disorder, comprising administering a composition containing a crystalline form of religlitazone to the patient. In one embodiment, this disclosure provides a crystalline polymorph of religlitazone. In another embodiment, this disclosure provides a method for producing a crystalline polymorph of religlitazone. In yet another embodiment, this disclosure provides a pharmaceutical composition comprising a crystalline polymorph of religlitazone and one or more pharmaceutically acceptable carriers, diluents, or excipients.

Description

[Technical Field]

[0001] This disclosure provides a crystalline form of religlitazone, a pharmaceutical composition or formulation containing a crystalline form of religlitazone, and a method for treating a patient's disease, condition, or disorder, comprising administering a composition containing a crystalline form of religlitazone to the patient. [Background technology]

[0002] 5-[[4-[2-[5-(1-hydroxyethyl)pyridine-2-yl]ethoxy]phenyl]methyl]1,3-thiazolidined-2,4-dione (referred herein to as “religlitazone”) is a metabolite of pioglitazone (see, e.g., Sohda et al., Chem. Pharm. Bull. 43(12):2168-2172 (1995), Maeshiba et al., Arzneim.-Forsch / Drug Res. 47(I):29-35 (1997)) and possesses selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity. WO2015 / 150476A1 discloses religlitazone for use in the treatment of central nervous system disorders. WO2018 / 100557 discloses religlitazone for the treatment of non-alcoholic fatty liver disease ("NAFLD"), non-alcoholic steatohepatitis ("NASH"), and other diseases and disorders. WO2018 / 116281 discloses a method for preparing religlitazone. WO2019 / 234689 discloses an algorithm-based method for administering religlitazone based on steady-state plasma levels of religlitazone and associated pharmacokinetic parameters in a patient. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2015 / 150476 [Patent Document 2] International Publication No. 2018 / 100557 [Patent Document 3] International Publication No. 2018 / 116281 [Patent Document 4] International Publication No. 234689, 2019 [Non-patent literature]

[0004] [Non-Patent Document 1] Sohda et al.,Chem.Pharm.Bull.43(12):2168-2172(1995) [Non-Patent Document 2] Maeshiba et al.,Arzneim.-Forsch / Drug Res.47(I):29-35(1997) [Overview of the Initiative] [Means for solving the problem]

[0005] There is a need for religlitazone in solid form and formulation for use in the treatment of patients, such as those with central nervous system disorders, non-alcoholic fatty liver disease ("NAFLD"), non-alcoholic steatohepatitis ("NASH"), and other diseases, disorders, and conditions. In one embodiment, the present disclosure provides crystalline polymorphs of religlitazone. In another aspect, the present disclosure provides a method for producing crystalline polymorphs of religlitazone.

[0006] In another embodiment, the disclosure provides a crystalline polymorph of religlitazone and a pharmaceutically acceptable composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0007] In another embodiment, the present disclosure provides a pharmaceutical composition or formulation comprising crystalline polymorphs of religlitazone and water.

[0008] In another aspect, the disclosure provides a method for treating a disease, disorder, or condition in question using a crystalline polymorph or formulation of religlitazone.

[0009] In another aspect, the present disclosure provides a crystalline polymorphic form of reagliptin or a formulation thereof for use in treating a disease, disorder, or condition, which comprises administering to a subject, including a human, in need thereof, the crystalline polymorphic form of reagliptin or the formulation defined herein, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0010] In another aspect, the present disclosure provides a composition comprising reagliptin, reagliptin hydrochloride, or reagliptin hydrate, and (i) (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione, or a hydrochloride salt thereof, (ii) 2,2'-disulfanediyldi(3-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)propanoic acid), or a hydrochloride salt thereof, (iii) 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)phenyl)propanoic acid, or a hydrochloride salt thereof, and / or (iv) 5-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidin-2-one, or a hydrochloride salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] [Figure 1] XRPD diffractogram of reagliptin hydrochloride Form A. [Figure 2] Raman spectrum of reagliptin hydrochloride Form A. [Figure 3] Diagram showing the crystal structure of reagliptin hydrochloride Form A including disorder. [Figure 4A] Diagram showing the crystal structures of different stereoisomers of reagliptin hydrochloride Form A. [Figure 4B] Diagram showing the crystal structures of different stereoisomers of reagliptin hydrochloride Form A. [Figure 4C] This figure shows the crystal structures of different stereoisomers of religlitazone hydrochloride form A. [Figure 4D] This figure shows the crystal structures of different stereoisomers of religlitazone hydrochloride form A. [Figure 5] This is a DSC thermogram of religlitazone hydrochloride form A. [Figure 6] This is an XRPD diffraction pattern of religlitazone morphology B. [Figure 7] This is a DSC thermogram of Religlitazone morphology B. [Figure 8] This is the XRPD diffraction pattern of religlitazone hydrate morph C. [Figure 9] This is the Raman spectrum of religlitazone hydrate form C. [Figure 10] This is a DSC thermogram of religlitazone hydrate form C. [Figure 11] These are two XRPD diffraction patterns comparing religlitazon morphology B (upper diffraction pattern) and religlitazon morphology C (lower diffraction pattern). [Figure 12] This figure shows steps 1-7 of the manufacturing process flowchart used to prepare a pharmaceutical formulation containing religlitazone hydrate form C. [Figure 13] This figure shows steps 8-14 of the manufacturing process flowchart used to prepare a pharmaceutical formulation containing religlitazone hydrate form C. "MIN-102" refers to form A. [Figure 14] This figure shows steps 15-20 of a manufacturing process flowchart used to prepare a pharmaceutical formulation containing religlitazone hydrate form C. [Figure 15] These are two HPLC chromatograms of religlitazone oral suspensions at pH 4 (top) and pH 5.5 (bottom). [Modes for carrying out the invention]

[0012] In one embodiment, the present disclosure provides crystalline polymorphs of religlitazone hydrochloride, crystalline polymorphs of religlitazone, or crystalline polymorphs of religlitazone hydrate, which are collectively referred to as "religlitazone polymorphs" or individually as "religlitazone polymorphs."

[0013] In another embodiment, the religlitazone polymorph is the crystalline hydrochloride of religlitazone, i.e., religlitazone hydrochloride represented by the formula religlitazone·HCl. This polymorph is called "religlitazone hydrochloride form A" or simply "form A".

[0014] In another embodiment, the religlitazone polymorph is a crystalline, non-solvated free base of religlitazone. This polymorph is referred to as "religlitazone form B" or simply "form B".

[0015] In another embodiment, the religlitazone polymorph is a crystalline religlitazone hydrate represented by the formula religlitazone·xH2O (where x is 0.5 to 3). This polymorph is called "religlitazone hydrate form C" or simply "form C".

[0016] I. Crystalline religlitazone hydrochloride Form A In one embodiment, form A is characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation, having peaks at 10.8, 12.4, 20.5, 21.7, and 26.1 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0017] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least three peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0018] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least four peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0019] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least five peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0020] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least six peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0021] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least seven peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0022] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least eight peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0023] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least nine peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0024] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7, 29. It is characterized by having an XRPD pattern with at least 10 peaks at 9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0025] In another embodiment, form A uses CuKα radiation, with values ​​of 8.8, 9.2, 10.8, 12.4, 12.7, 15.5, 16.5, 17.0, 17.4, 17.7, 18.5, 19.7, 20.0, 20.5, 20.8, 21.7, 22.4, 22.7, 23.0, 24.3, 24.9, 25.2, 25.5, 26.1, 26.7, 27.0, 27.8, 28.3, 28.7, 29.3, 29.7 It is characterized by having an XRPD pattern with peaks at 29.9, 30.1, 31.2, 31.7, 31.9, 32.3, 32.7, 33.2, 33.5, 33.8, 34.1, 34.3, 35.0, 35.2, 35.6, 35.9, 36.4, 37.1, 37.5, 37.9, 38.2, 38.7, 39.0, 39.7, and / or 40.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0026] In another embodiment, form A is characterized by having essentially the same XRPD diffraction pattern as that shown in Figure 1.

[0027] In another embodiment, form A is 3307, 2925, 1748, 1642, 1612, 870, 638, 605, 116 cm -1 It is characterized by having an FT-Raman spectrum with a peak at cm -1 The value is ±4cm -1 That is the case.

[0028] In another embodiment, form A is 3307, 3096, 3065, 2970, 2925, 2871, 1748, 1685, 1642, 1612, 1585, 1436, 1327, 1310, 1244, 1207, 1184, 1153, 1088, 1070, 1034, 936, 908, 870, 854, 789, 737, 707, 646, 638, 605, 497, 469, 437, 380, 333, 309, 221, and 116 cm -1 It is characterized by having an FT-Raman spectrum with a peak at cm -1 The value is ±4cm -1 That is the case.

[0029] In another embodiment, form A is characterized by having essentially the same FT-Raman spectrum as that shown in Figure 2.

[0030] In another embodiment, form A is characterized by having a melting point with an onset temperature of approximately 203.98°C and a peak temperature of approximately 211.87°C, based on differential scanning calorimetry.

[0031] In another embodiment, form A is characterized by having essentially the same DSC thermogram as the one shown in Figure 5.

[0032] II. Crystalline religlitazone (non-solvated free base) Form B In one embodiment, form B is characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation, with peaks at 9.0, 16.6, and 18.8 degrees 2θ, and 2θ values ​​of ±0.2 degrees 2θ.

[0033] In another embodiment, form B is characterized by a powder X-ray diffraction (XRPD) pattern using CuKα radiation, with peaks at 9.0, 16.6, 18.8, 21.1, 23.8, and 24.7 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0034] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 18.8, 21.1, and 23.8 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0035] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 16.6, 21.8, and 24.7 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0036] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 15.2, 25.4, and 28.0 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0037] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 9.0, 19.8, and 30.8 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0038] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 10.5, 20.1, and 26.9 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0039] In another embodiment, form B features an XRPD pattern using CuKα radiation, with peaks at 12.4, 23.5, and 29.1 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0040] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least three peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0041] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least four peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0042] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least five peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0043] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least six peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0044] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least seven peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0045] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least eight peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0046] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28 It is characterized by having an XRPD pattern with at least nine peaks at 0.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0047] In another embodiment, form B uses CuKα radiation, with values ​​of 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28.0, 28. It is characterized by having an XRPD pattern with at least 10 peaks at 9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0048] In another embodiment, form B uses CuKα radiation at 7.6, 9.0, 10.5, 12.4, 15.2, 16.1, 16.6, 18.5, 18.8, 19.3, 19.8, 20.1, 20.5, 21.1, 21.8, 22.9, 23.2, 23.5, 23.8, 24.7, 25.4, 26.0, 26.5, 26.9, 27.4, 28. It is characterized by having an XRPD pattern with peaks at 0, 28.9, 29.1, 29.5, 29.9, 30.8, 31.2, 31.5, 32.1, 32.6, 32.9, 33.7, 34.4, 35.4, 35.8, 36.3, 36.9, 37.1, 38.0, 38.4 and / or 39.3 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0049] In another embodiment, form B is characterized by having essentially the same XRPD diffraction pattern as that shown in Figure 6.

[0050] In another embodiment, form B is characterized by having a melting point with an onset temperature of approximately 149.34°C and a peak temperature of approximately 153.56°C, based on differential scanning calorimetry.

[0051] In another embodiment, form B is characterized by having essentially the same DSC thermogram as the one shown in Figure 7.

[0052] In another embodiment, form B is characterized by having essentially the same TGA plot as that shown in Figure 7.

[0053] In another embodiment, form B is characterized by having a TGA that includes a mass loss of less than 1% of the total mass of the sample, for example, about 0.9%, or for example, about 0.05%, when heated to about 25°C to about 200°C.

[0054] In another embodiment, form B contains virtually no water or other solvent in the crystal lattice. In a particular embodiment, form B is non-solvated. In a particular embodiment, form B is anhydrous.

[0055] In another embodiment, form B is characterized by its stability profile. In another embodiment, the material of form B is stable, for example, its XRPD pattern remains substantially unchanged when exposed to high temperatures, high humidity, one or more solvents, and / or compression.

[0056] In another embodiment, the disclosure provides a pharmaceutical composition comprising a suspension in water of a religlitazone polymorph, for example, religlitazone (non-solvated free base) form B, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0057] III. Crystalline Religlitazone Hydrate Form C In one embodiment, form C is characterized by an XRPD pattern using CuKα radiation, with peaks at 19.1, 21.0, and 23.8 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0058] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 12.7, 15.4, 19.1, 21.0, 23.8, and 25.9 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0059] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 12.7, 15.4, and 16.9 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0060] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 16.9, 21.3, and 21.6 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0061] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 7.7, 24.6, and 28.0 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0062] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 9.2, 19.8, 24.6, and 24.9 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0063] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 10.6, 24.9, and 27.3 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0064] In another embodiment, form C features an XRPD pattern using CuKα radiation, with peaks at 9.2, 19.8, and 29.6 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0065] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least three peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, where the 2θ values ​​are ±0.2 degrees 2θ.

[0066] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least four peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0067] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least five peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0068] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least six peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0069] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least seven peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0070] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least eight peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0071] In another embodiment, form C uses CuKα radiation, with values ​​of 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29 It is characterized by having an XRPD pattern with at least nine peaks at 0.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0072] In another embodiment, form C uses CuKα radiation at 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, and 29. It is characterized by having an XRPD pattern with at least 10 peaks at 6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ, with 2θ values ​​of ±0.2 degrees 2θ.

[0073] In another embodiment, Form C is characterized by having an XRPD pattern with peaks at 4.0, 6.2, 7.7, 8.9, 9.2, 9.9, 10.6, 12.7, 15.4, 16.5, 16.9, 18.4, 19.1, 19.4, 19.8, 20.4, 21.0, 21.3, 21.6, 22.1, 23.0, 23.3, 23.8, 24.6, 24.9, 25.4, 25.6, 25.9, 26.4, 27.3, 28.0, 28.8, 29.6, 30.1, 30.7, 30.9, 31.2, 31.5, 31.9, 32.6, 33.0, 33.5, 33.8, 34.2, 34.5, 34.8, 35.3, 35.6, 36.1, 36.4, 37.1, 37.7, 38.2, 38.7, 38.9, 39.3, and / or 39.8 degrees 2θ using CuKα radiation, and the 2θ values are ±0.2 degrees 2θ.

[0074] In another embodiment, Form C is characterized by having an XRPD diffraction pattern that is essentially the same as that shown in FIG. 8.

[0075] In another embodiment, Form C is characterized by having an FT-Raman spectrum with peaks at 3056, 2960, 2992, 1735, 1608, 1205, 824, 656, 170 cm -1 and the cm -1 values are ±4 cm -1 .

[0076] In another embodiment, Form C is characterized by having an FT-Raman spectrum with peaks at 3056, 3017, 2992, 2960, 2921, 1735, 1608, 1582, 1472, 1437, 1388, 1333, 1314, 1295, 1246, 1205, 1184, 1147, 1072, 1014, 928, 901, 842, 824, 772, 736, 719, 656, 646, 636, 601, 531, 511, 467, 440, 397, 329, 274, and 170 cm -1 and the cm -1 values are ±4 cm -1 .

[0077] In another embodiment, form C is characterized by having essentially the same FT-Raman spectrum as that shown in Figure 9.

[0078] In another embodiment, form C is characterized by having a melting point with an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, based on differential scanning calorimetry.

[0079] In another embodiment, based on differential scanning calorimetry, form C is characterized by having a first broad endothermic phase with an onset temperature of approximately 32.74°C and a peak temperature of approximately 66.50°C, and a second sharp endothermic phase with an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C.

[0080] In another embodiment, form C is characterized by having essentially the same DSC thermogram as the one shown in Figure 10.

[0081] In another embodiment, form C is characterized by having essentially the same TGA plot as that shown in Figure 10.

[0082] In another embodiment, form C is characterized by having a TGA including a mass loss of about 5.0% of the total mass of the sample, e.g., about 4.8%, e.g., about 4.6%, e.g., about 4.3%, e.g., about 4.0%, e.g., about 3.80%, e.g., about 3.80%, e.g., about 40% of the total mass of the sample when heated to about 40°C to about 160°C. In another embodiment, form C contains water in the crystal lattice or contains water mixed with other organic solvents in the crystal lattice. In a particular embodiment, form C is a hydrate represented by the formula religlitazone·xH2O (where x is 0.5 to 3). In a particular embodiment, form C is a monohydrate, e.g., x is about 1.

[0083] In another embodiment, form C is characterized by its stability profile. In another embodiment, the material of form C is stable, and for example, its XRPD pattern remains substantially unchanged when exposed to high humidity, when exposed to one or more solvents, and / or when compressed.

[0084] In another embodiment, the disclosure provides a pharmaceutical composition comprising a suspension in water of a religlitazone polymorph, for example, religlitazone hydrate form C, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0085] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an aqueous suspension of religlitazone hydrate form C and optionally one or more pharmaceutically acceptable excipients.

[0086] IV. Method for preparing crystalline polymorphs of religlitazone In another embodiment, the present invention provides a method for producing crystalline form A of religlitazone as defined above, comprising the following steps:

[0087] (a) Providing a solution or suspension by providing religlitazone hydrochloride in an organic solvent or a mixture of organic solvents,

[0088] (b) Optionally, heat the mixture from step (a) to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 75°C.

[0089] (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and

[0090] (d) A step to isolate crystalline form A of religlitazone hydrochloride.

[0091] In another embodiment, the present invention provides a method for producing crystalline form B of religlitazone as defined above, comprising the following steps:

[0092] (a) A step of providing a solution or suspension by providing religlitazone hydrochloride in water or a mixture of water and an alcohol solvent,

[0093] (b) Optionally, heat the mixture from step (a) to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C.

[0094] (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and

[0095] (d) The step of isolating and drying the solid obtained in step (c) to provide religlitazone form B.

[0096] In one embodiment, the drying in step (d) may be carried out under atmospheric pressure or reduced pressure, at room temperature or at a temperature of 50°C to 130°C, preferably 80°C to 110°C.

[0097] In another embodiment, form B may be prepared by drying religlitazone hydrate form C under reduced pressure at a temperature of 50°C to 130°C.

[0098] In another embodiment, the present invention provides a method for producing crystalline religlitazone hydrate form C as defined above, comprising the following steps:

[0099] (a) A step of providing a solution or suspension by providing religlitazone hydrochloride in water or a mixture of water and an alcohol solvent,

[0100] (b) Optionally, heat the mixture from step (a) to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C.

[0101] (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and

[0102] (d) A step of isolating the solid obtained in step (c) to provide morphology C of religlitazone.

[0103] The religlitazone hydrochloride used in (a) may be in solvate, hydrate, anhydrous, crystalline, or amorphous form. Preferably, the preparation of either crystalline form B or hydrate form C begins in step (a) with religlitazone hydrochloride form A.

[0104] V. Pharmaceutical Compositions The pharmaceutical compositions disclosed herein contain conventional excipients known in the art and can be prepared by conventional methods. Oral dosage forms can be prepared according to conventional pharmaceutical formulation techniques by combining religlitazone, or a pharmaceutically acceptable salt thereof, e.g., form A, in a close mixture with at least one excipient, e.g., water.

[0105] For example, religlitazone, or a pharmaceutically acceptable salt or hydrate thereof, may be suspended in a pharmaceutically acceptable liquid carrier such as water. The liquid carrier may contain other suitable pharmaceutical additives, including but not limited to solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, pH modifiers, or osmotic pressure modifiers. A preferred example of a liquid carrier for oral administration is water optionally containing such additives, for example, a cellulose derivative such as a sodium carboxymethylcellulose solution. In one embodiment, the disclosure provides a pharmaceutical formulation comprising religlitazone in an amount of 0.01% w / v to 5% w / v, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a suitable amount of (QS) water until the total volume reaches 100%.

[0106] In another embodiment, the disclosure provides a pharmaceutical formulation comprising 0.01% w / v to 5% w / v of religlitazone hydrate form C and an appropriate amount of water until the total volume reaches 100%, for example, about 1.43 g of form C in 100 mL of water.

[0107] Pharmaceutical compositions comprising religlitazone, or a pharmaceutically acceptable salt or hydrate thereof, may be provided as a kit, with primary packaging in suitable containers, such as multi-dose Type III brown glass vials, and secondary packaging in carton boxes, with labels optionally provided. For administration purposes, graduated oral syringes of 5 mL, 10 mL, 12 mL, or 15 mL may also be provided.

[0108] This disclosure provides the following specific embodiments with respect to pharmaceutical compositions.

[0109] Embodiment 1F. A pharmaceutical preparation comprising (a) 0.01% w / v to 5% w / v of religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof, (b) 0.01% w / v to 2% w / v of one or more cellulose derivatives, and (c) an appropriate amount of water until the total volume reaches 100%.

[0110] Embodiment 2F. The pharmaceutical preparation according to Embodiment 1F, wherein the religlitazone, the pharmaceutically acceptable salt thereof, or the hydrate thereof is religlitazone hydrate form C.

[0111] Embodiment 3F. The pharmaceutical formulation according to Embodiment 1F or 2F, wherein the one or more cellulose derivatives comprises microcrystalline cellulose, sodium carboxymethylcellulose, or a mixture thereof.

[0112] Embodiment 4F. A pharmaceutical preparation according to any one of Embodiments 1F to 3F, further comprising one or more pH adjusting agents.

[0113] Embodiment 5F. The pharmaceutical preparation according to Embodiment 4F, wherein the one or more pH adjusting agents include sodium citrate, citric acid monohydrate, or a mixture thereof.

[0114] Embodiment 6F. A pharmaceutical preparation according to any one of Embodiments 1F to 5F, further comprising one or more preservatives in an amount of 0.001% w / v to 1.0% w / v.

[0115] Embodiment 7F. The pharmaceutical preparation according to Embodiment 6F, wherein the one or more preservatives include sodium benzoate.

[0116] Embodiment 8F. A pharmaceutical preparation according to any one of Embodiments 1F to 7F, further comprising one or more flavoring agents in an amount of 0.001% w / v to 3% w / v.

[0117] Embodiment 9F. The pharmaceutical preparation according to Embodiment 6F, wherein the one or more flavoring agents include strawberry flavoring.

[0118] Embodiment 10F. A pharmaceutical preparation according to any one of Embodiments 1F to 9F, further comprising one or more sweeteners in an amount of 0.01% w / v to 15% w / v.

[0119] Embodiment 11F. The pharmaceutical preparation according to Embodiment 10, wherein the sweetener is sorbitol, sodium saccharin, or a mixture thereof.

[0120] Embodiment 12F. The pharmaceutical preparation according to any one of Embodiments 1F to 11F, wherein the pH of the preparation is 3.5 to 4.5.

[0121] Embodiment 13F. The pharmaceutical formulation according to Embodiment 12F, wherein the pH of the formulation is approximately 4.

[0122] Embodiment 14F. The pharmaceutical formulation according to any one of Embodiments 1F to 13F, wherein the viscosity of the formulation is greater than 50 mPa*s and less than 5000 mPa*s, for example less than 4500 mPa*s or less than 4000 mPa*s, as measured according to the standard method described in Ph.Eur.2.2.8.

[0123] Embodiment 15F. A pharmaceutical preparation comprising (a) religlitazone hydrochloride form A and (b) religlitazone hydrate form C, which is prepared by mixing water.

[0124] Embodiment 16F. A pharmaceutical preparation of Embodiment 15F, prepared by mixing (a) about 1.5% w / v religlitazone hydrochloride form A, (b) about 8% w / v sorbitol powder, (c) about 1% w / v microcrystalline cellulose, (d) about 0.5% w / v sodium carboxymethylcellulose, (e) about 0.05% w / v sodium saccharin, (f) about 0.1% w / v sodium benzoate, (g) about 0.5% w / v sodium citrate, (h) about 0.1% w / v citric acid monohydrate, (i) about 0.015% w / v strawberry flavor, (j) about 1% w / v 0.2 M citric acid monohydrate aqueous solution, and (k) an appropriate amount of water until the total volume reaches 100%.

[0125] Embodiment 17F. A pharmaceutical preparation comprising (a) 1.0% to 2.0% w / v of religlitazone, a pharmaceutically acceptable salt or hydrate thereof, preferably hydrate form C, (b) about 1% w / v of microcrystalline cellulose, (c) about 0.5% w / v of sodium carboxymethylcellulose, (d) an appropriate amount of water until the total volume reaches 100%, and optionally (e) about 8% w / v of sorbitol powder, (f) about 0.05% w / v of sodium saccharin, (g) about 0.1% w / v of sodium benzoate, (h) about 0.5% w / v of sodium citrate, (i) about 0.1% w / v of citric acid monohydrate, (j) about 0.015% w / v of strawberry flavor, and (k) about 1% w / v of an aqueous solution of 0.2 M citric acid monohydrate.

[0126] Embodiment 18F. A pharmaceutical preparation comprising (a) about 1.43% w / v religlitazone hydrate, e.g., form C, (b) about 8% w / v sorbitol powder, (c) about 1% w / v microcrystalline cellulose, (d) about 0.5% w / v sodium carboxymethylcellulose, (e) about 0.05% w / v sodium saccharin, (f) about 0.1% w / v sodium benzoate, (g) about 0.5% w / v sodium citrate, (h) about 0.1% w / v citric acid monohydrate, (i) about 0.015% w / v strawberry flavor, (j) about 1% w / v 0.2 M citric acid monohydrate aqueous solution, and (k) an appropriate amount of water until the total volume reaches 100%.

[0127] Embodiment 19F. A pharmaceutical composition according to any one of Embodiments 1F to 14F, wherein the cellulose derivative has a viscosity of 1500 to 4500 mPa*s, for example 1500 to 3500 mPa*s, or for example 1500 to 3000 mPa*s, as measured by the Brookfield viscosity method.

[0128] Advantageously, the pharmaceutical formulations described in any one of Embodiments 1F to 19F allow for variable and patient-adapted doses of religlitazone. Furthermore, the religlitazone suspension formulations of this disclosure have a thixotropic polymer gel structure when at rest, in other words, their viscosity can only be observed when fluidized by gentle manual shaking immediately before administration. The viscosity is broken by agitation during shaking but then reformed after aging. Thus, the apparent viscosity of a thixotropic suspension depends on their previous shear history, including the duration of shearing. This property is useful for suspensions because the structure formed after standing prevents precipitation. Therefore, since the religlitazone suspension formulations of this disclosure are thixotropic and no precipitate is observed at rest, the need for redispersibility is avoided.

[0129] VI. Methods of treating a disease, disorder, or condition In another embodiment, the Disclosure provides religlitazone polymorphs, or a pharmaceutical composition or formulation comprising religlitazone polymorphs, for use in the treatment of a patient in need of treatment for a disease or disorder, the disease or disorder being a central nervous system disorder or disorder, a mitochondrial disorder, a liver disorder or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

[0130] In another embodiment, the disease or disorder is a central nervous system disorder or disorder.

[0131] In another embodiment, the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0132] In another embodiment, the central nervous system disease or disorder is a neurodegenerative disease.

[0133] In another embodiment, neurodegenerative diseases are selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative disorders and brain iron storage disorders (NBIA), neuromuscular disorders, and motor neuron diseases.

[0134] In another embodiment, the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0135] In another embodiment, the leukodystrophy is cerebral adrenoleukodystrophy.

[0136] In another embodiment, the degenerative ataxia is Friedreich's ataxia.

[0137] In another embodiment, motor neuron diseases are selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0138] In another embodiment, the cerebrovascular disease is selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0139] In another embodiment, the viral disease is selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, polio, herpes simplex, and varicella-zoster.

[0140] In another embodiment, the central nervous system disorder or disorder is a rare metabolic disorder selected from the group consisting of organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0141] In another embodiment, the disease or disorder is a mitochondrial disease.

[0142] In another embodiment, mitochondrial diseases include Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, Leigh-like syndrome, maternal Leigh syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, and 3-methyl Unresolved genetic defects, including luglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lie-like syndrome (MEGDEL), SURF1 (COX deficiency Lie syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. This includes isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, and carnitine palmitoyltransferase (CPT I or CPTII) Primary mitochondrial disorders selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutaric aciduria type II.

[0143] In another embodiment, mitochondrial disorders are selected from the group consisting of Rett syndrome, autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

[0144] In another embodiment, mitochondrial diseases include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorders, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorders of purine and / or pyrimidine synthesis, and facial disorders. Secondary mitochondrial disorders are selected from the group consisting of scapulohumeral muscular dystrophy (FSHD), congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus types), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0145] In another embodiment, the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lungs, or interstitial lung disease.

[0146] In another embodiment, the present disclosure provides a method for treating an inflammatory lung condition or disease caused by a viral infection in a patient who requires treatment for such condition.

[0147] In another embodiment, the viral infection is a human coronavirus infection, an influenza virus infection, or an HIV virus infection.

[0148] In another embodiment, the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant thereof.

[0149] In another embodiment, the human coronavirus is SARS-CoV-2.

[0150] In another embodiment, the human coronavirus is a mutant strain of SARS-CoV-2.

[0151] In another embodiment, the inflammatory lung condition or disease caused by a viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0152] In another embodiment, the inflammatory lung condition or disease caused by a viral infection is acute respiratory distress syndrome.

[0153] In another embodiment, the present disclosure provides religlitazone polymorphs for treating acute pulmonary inflammation in patients requiring treatment for it.

[0154] In another embodiment, acute inflammation of the lungs is caused by a bacterial infection.

[0155] In another embodiment, acute inflammation of the lungs is pneumonia or acute respiratory distress syndrome.

[0156] In another embodiment, the present disclosure provides religlitazone polymorphs for treating interstitial lung disease in patients requiring treatment for the disease.

[0157] In another embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis.

[0158] In another embodiment, the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0159] In another embodiment, the present disclosure provides a method for treating a patient in need of treatment for a disease or disorder, the method comprising administering to the patient a therapeutically effective amount of religlitazone polymorphism or a pharmaceutical composition of religlitazone polymorphism, the disease or disorder being a central nervous system disorder or disorder, a mitochondrial disorder, a liver disorder or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disorder, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disorder or disorder.

[0160] In another embodiment, the disease or disorder is a central nervous system disorder or disorder.

[0161] In another embodiment, the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0162] In another embodiment, the central nervous system disease or disorder is a neurodegenerative disease.

[0163] In another embodiment, neurodegenerative diseases are selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, ALS, degenerative ataxia, multiple system atrophy, NBIA (neurodegenerative disorders and cerebral iron storage disorders), neuromuscular disorders, and motor neuron diseases.

[0164] In another embodiment, the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0165] In another embodiment, the leukodystrophy is cerebral adrenoleukodystrophy.

[0166] In another embodiment, the degenerative ataxia is Friedreich's ataxia.

[0167] In another embodiment, motor neuron diseases are selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0168] In another embodiment, the central nervous system disorder is a cerebrovascular disease selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0169] In another embodiment, the central nervous system disorder is a viral disease selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, polio, herpes simplex, and varicella-zoster.

[0170] In another embodiment, the central nervous system disorder or disorder is a rare metabolic disorder selected from the group consisting of organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0171] In another embodiment, the disease or disorder is a mitochondrial disease.

[0172] In another embodiment, mitochondrial diseases include Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, Leigh-like syndrome, maternal Leigh syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, and 3-methyl Unresolved genetic defects, including luglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lie-like syndrome (MEGDEL), SURF1 (COX deficiency Lie syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. This includes isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, and carnitine palmitoyltransferase (CPT I or CPTII) Primary mitochondrial disorders selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutaric aciduria type II.

[0173] In another embodiment, mitochondrial disorders are selected from the group consisting of Rett syndrome, autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

[0174] In another embodiment, mitochondrial diseases include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorders, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorders of purine and / or pyrimidine synthesis, and facial disorders. Secondary mitochondrial disorders are selected from the group consisting of scapulohumeral muscular dystrophy (FSHD), congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus types), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0175] In another embodiment, the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lungs, or interstitial lung disease.

[0176] In another embodiment, the present disclosure provides religlitazone polymorphs for treating inflammatory lung conditions or diseases caused by viral infections in patients requiring treatment for such conditions.

[0177] In another embodiment, the viral infection is a human coronavirus infection, an influenza virus infection, or an HIV virus infection.

[0178] In another embodiment, the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant thereof.

[0179] In another embodiment, the human coronavirus is SARS-CoV-2.

[0180] In another embodiment, the human coronavirus is a mutant strain of SARS-CoV-2.

[0181] In another embodiment, the inflammatory lung condition or disease caused by a viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0182] In another embodiment, the inflammatory lung condition or disease caused by a viral infection is acute respiratory distress syndrome.

[0183] In another embodiment, the present disclosure provides religlitazone polymorphs for treating acute pulmonary inflammation in patients requiring treatment for it.

[0184] In another embodiment, acute inflammation of the lungs is caused by a bacterial infection.

[0185] In another embodiment, acute inflammation of the lungs is pneumonia or acute respiratory distress syndrome.

[0186] In another embodiment, the present disclosure provides religlitazone polymorphs for treating interstitial lung disease in patients requiring treatment for the disease.

[0187] In another embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis.

[0188] In another embodiment, the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0189] VII. Compounds and Compositions In another embodiment, the Disclosure relates to religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, e.g., form A, form B, or form C, as well as (i)(Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidined-2,4-dione, or their hydrochlorides, as impurities unexpectedly generated during the religlitazone manufacturing process, and (ii)2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)propane The present invention provides a composition comprising (iii) 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or a hydrochloride thereof, and / or (iv) 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxyl)benzyl)thiazolidined-2-one, or a hydrochloride thereof.

[0190] In another embodiment, the Disclosure provides 99.0 to 99.9 wt / wt% religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, e.g., form A, form B, or form C, and (i) 0.0001 to 0.2 wt / wt% (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione, or their hydrochlorides, and (ii) 0.0001 to 0.2 wt / wt% 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)propanoic acid, or the same. The present invention provides compositions comprising (iii) 0.0001 to 0.2 wt / wt% of the hydrochlorides of these, 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or their hydrochlorides, and / or (iv) 0.0001 to 0.15 wt / wt% of 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxyl)benzyl)thiazolidined-2-one, or their hydrochlorides.

[0191] In another embodiment, the disclosure provides (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidined-2,4-dione, or a pharmaceutically acceptable salt thereof.

[0192] In another embodiment, the disclosure provides 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0193] In another embodiment, the disclosure provides 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0194] In another embodiment, the disclosure provides 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidined-2-one, or a pharmaceutically acceptable salt thereof.

[0195] VIII.Definitions As used herein, the term "religlitazone" refers to a compound having formula I. [ka] Each stereocenter is either R or S configuration. Religlitazone is a mixture of four possible stereoisomers. The IUPAC name for religlitazone is 5-[[4-[2-[5-(1-hydroxyethyl)pyridine-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidined-2,4-dione.

[0196] Religlitazone can form a crystalline solid by incorporating water into its crystal lattice without chemically altering the religlitazone molecule, for example, religlitazone hydrate, or form C.

[0197] As used herein, the term “hydrate” refers to a crystalline form of a molecule that further contains water incorporated within its crystalline structure. The water molecules in a hydrate may exist in regular and / or irregular arrangements. A hydrate may contain stoichiometric or non-stoichiometric amounts of water molecules.

[0198] As used herein, the term “solvate” refers to a crystalline form of a molecule that further includes solvent molecules (or more) incorporated into its crystalline structure. When the solvent incorporated into the crystal is water, it is called a hydrate. The solvent molecules in a solvate may exist in regular and / or irregular arrangements. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. A solvate may exhibit polymorphism.

[0199] As used herein, the term “organic solvent” refers to an organic molecule capable of at least partially dissolving another substance (i.e., a solute). The solvent may be a liquid at room temperature. Preferred solvents are, but are not limited to, (C6-C6). 14 ) Aromatic hydrocarbon solvents, such as toluene, o-xylene, m-xylene, and p-xylene, halogenated (C1-C 12 ) hydrocarbon solvents, e.g., 1,2-dichloroethane, dichloromethane, chloroform, (C1-C 12 ) ether solvents, e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, (C1-C 12 ) Ester solvents, for example ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, (C3-C 12 ) Ketone solvents, such as acetone, methyl ethyl ketone, or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, (C1-C 12) Alcohol solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or acetonitrile. In another embodiment, the solvent is formed by a combination of two or more organic solvents.

[0200] As used herein, the term “alcohol” solvent refers to a hydrocarbon derivative in which one or more hydrogen atoms are substituted by an –OH group known as a hydroxyl group. Preferred alcohols include linear, cyclic, or branched C1-C6 alkyl alcohols, and any mixture thereof. This also includes commercially available alcohols. In another embodiment, the alcohols are methanol, ethanol, isopropanol, 1-propanol, and 1-butanol, as well as mixtures thereof.

[0201] As used herein, the term "room temperature" in the context of the present invention refers to a temperature of 15°C to 30°C, for example, 20°C to 25°C.

[0202] As used herein, the term “substantially pure” means that the crystalline material contains any other crystalline or amorphous form(s) containing hydrates or other solvates in amounts of about 10% by weight or less, e.g., about 1% to about 10% by weight, e.g., about 9% by weight, about 8% by weight, about 7% by weight, about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2% by weight, or about 1% by weight. In another embodiment, the religlitazone hydrochloride polymorph is substantially pure form A. In another embodiment, the religlitazone polymorph is substantially pure form B. In another embodiment, the religlitazone polymorph is substantially pure form C.

[0203] As used herein, the term “essentially the same” with respect to XRPD peak position and / or relative intensity means that variations in peak position and / or intensity are taken into account when comparing XRPD diffraction patterns. Similarly, the term “essentially the same” with respect to Raman or IR peak position means that variations in peak position are taken into account when comparing Raman or IR spectra. For example, XRPD peak position may exhibit variability between instruments, e.g., up to 0.2°²θ, i.e., ±0.2°²θ, and Raman and IR peak position may exhibit variability between instruments, e.g., up to 4 cm -1 That is, ±4cm -1 This can be shown. Relative peak intensity can also show inter-instrument variability due to crystallinity, orientation, prepared sample surface, and other factors known to those skilled in the art, for example in an XRPD diffraction pattern, and should be considered only as a qualitative measure.

[0204] As used herein, the term “and / or” should be understood as a specific disclosure of each of two particular features or components, with or without the other. Accordingly, the term “and / or” as used in phrases such as “A and / or B” is intended to include A and B, A or B, A (alone), and B (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to include each of the following embodiments: A, B, and C, A, B, or C, A or C, A or B, B or C, A and C, A and B, B and C, A (alone), B (alone), and C (alone).

[0205] The articles “a,” “an,” and “the” are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements.

[0206] As used herein, the term “about” includes the enumerated numbers ± 10%. Thus, “about 10” means 9 to 11. In another embodiment, the enumerated numbers are within 5% of the indicated values. In yet another embodiment, the enumerated numbers are within 1% of the indicated values. In yet another embodiment, the enumerated numbers are within 0.5% of the indicated values.

[0207] The word “includes” is used to reflect its non-restrictive meaning, that is, to mean that a given product or process may, at its discretion, have additional features or elements beyond those expressly described. Where an embodiment is described in the language of “includes,” it is understood that other similar embodiments described in the terms “consist of” and / or “essentially consist of” are also contemplated and within the scope of this disclosure.

[0208] In the context of this disclosure, the term “improve” is understood to mean any improvement in the condition of the patient being treated.

[0209] The “effective” or “therapeutic effective” dose of a drug or pharmacologically active agent refers to a quantity of the drug or agent that is non-toxic but sufficient to produce the desired effect. The “effective” dose will vary from patient to patient, depending on the individual’s age and overall health, the specific active agent(s), etc. Therefore, it is not always possible to specify an exact “effective dose.” However, an appropriate “effective” dose for any given individual may be determined by a person skilled in the art using routine experiments.

[0210] In the context of this specification, the terms “treatment” or “to treat” and similar terms mean improving or eliminating a disease or one or more symptoms associated with such disease. “Treatment” also includes improving or eliminating the physiological sequelae of a disease.

[0211] The term "primary mitochondrial disorder" or "PMD" refers to mitochondrial disorders that may result from germline mutations in mitochondrial DNA (mtDNA) and / or nuclear DNA (nDNA) genes that encode electron transport chain (ETC) proteins, and therefore the production of adenosine triphosphate (ATP), the major cellular energy carrier.

[0212] The term "secondary mitochondrial disorder" or "SMD" refers to mitochondrial disorders involving many pathological processes that do not involve oxidative phosphorylation (OXPHOS), including genetic disorders with germline mutations in non-OXPHOS genes. SMD can also be acquired secondary to certain harmful environmental influences that can cause oxidative stress.

[0213] The term "appropriate amount" or "QS" means adding the same amount of the ingredient to the formulation as is required to achieve the desired result, but not exceeding it.

[0214] The term “container” therefore means any receptacle and closure suitable for storing, shipping, dispensing, and / or handling the compositions of the formulations described herein. Non-limiting exemplary containers include vials, ampoules, bottles, and syringes.

[0215] The term "package insert" refers to the information accompanying a medicine that provides instructions on how to administer the product, along with necessary safety and efficacy data, enabling physicians, pharmacists, and consumers to make informed decisions regarding the use of the product. Package inserts are generally considered the "label" of a medicine.

[0216] The term "cellulose derivative" may include cellulose powder, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal microcrystalline cellulose (e.g., FMC RC-591), hydroxyethylcellulose (e.g., Natrosol 250 HX), hydroxypropylcellulose, hydroxypropyl methylcellulose (e.g., Benecel K250PH, Methocel K100 LV, Methocel E50 LV, Methocel E15 LV, and Pharmacoat 615), methylhydroxyethylcellulose, sodium carboxymethylcellulose (e.g., Blanose 9M31F, Blanose 9H4XF, Aqualon 9M31F PH), natural starches, such as corn starch and potato starch, pregelatinized starch, and mixtures thereof. In some embodiments, the "cellulose derivative" is colloidal microcrystalline cellulose (e.g., FMC RC-591), hydroxyethyl cellulose (e.g., Natrosol 250 HX), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose (e.g., Blanose 9M31F, Blanose 9H4XF), and mixtures thereof.

[0217] In some embodiments, the cellulose derivative has a viscosity of 1500–4500 mPa*s, e.g., 1500–3500 mPa*s, e.g., 1500–3000 mPa*s, as measured by the Brookfield viscosity method. In particular, the viscosity is any value between 1500 and 4500, e.g., 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900. , 2950, ​​3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, 3600, 3650, 3700, 3750, 3800, 3850, 3900, 3950, 4000, 4050, 4100, 4150, 4200, 4250, 4300, 4350, 4400, 4450, 4500 mPa*s, and any combination thereof.

[0218] IX. Specific Embodiments This disclosure provides the following specific embodiments.

[0219] Embodiment 1.

[0220] (i) X-ray powder diffraction (XRPD) patterns using CuKα radiation, having peaks at 19.1, 21.0, and 23.8 degrees 2θ, where the 2θ value is ±0.2 degrees 2θ, or

[0221] (ii) X-ray powder diffraction patterns using CuKα radiation with d-spacing of 4.65, 4.23, and 3.73 Å, or

[0222] (iii) 3056, 2960, 2992, 1735, 1608, 1205, 824, 656, 170cm -1 An FT-Raman spectrum having a peak at cm -1 The value is ±4cm-1 This is the FT-Raman spectrum, or

[0223] (iv) A melting point having an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, based on differential scanning calorimetry, or

[0224] (v) A crystalline religlitazone hydrate form C characterized by having a combination of (i), (ii), (iii), and / or (iv).

[0225] Embodiment 2. The crystalline religlitazone hydrate form C according to Embodiment 1, characterized by having an XRPD pattern using CuKα radiation, having peaks at 19.1, 21.0, and 23.8 degrees 2θ, and having a 2θ value of ±0.2 degrees 2θ.

[0226] Embodiment 3. A crystalline religlitazone hydrate form C according to any one of Embodiments 1 or 2, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 12.7, 15.4, and 25.9 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0227] Embodiment 4. A crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 3, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 16.9, 21.3, and 21.6 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0228] Embodiment 5. A crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 4, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 7.7, 24.6, and 28.0 degrees 2θ, and having a 2θ value of ±0.2 degrees 2θ.

[0229] Embodiment 6. A crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 5, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 10.6, 24.9, and 27.3 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0230] Embodiment 7. A crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 6, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 9.2, 19.8, and 29.6 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0231] Embodiment 8. Crystalline religlitazone hydrate form C according to Embodiment 1, characterized by having d intervals of 4.65, 4.23, and 3.73 Å using CuKα radiation.

[0232] Embodiment 9. A crystalline religlitazone hydrate according to any one of Embodiments 1 or 8, further characterized by having d intervals of 6.99, 5.74, and 3.44 Å, using CuKα radiation.

[0233] Embodiment 10. Crystalline religlitazone hydrate form C according to any one of Embodiments 1, 8, or 9, further characterized by having d intervals of 5.24, 4.17, and 4.11 Å using CuKα radiation.

[0234] Embodiment 11. Crystalline religlitazone hydrate form C according to any one of Embodiments 1 or 8-10, further characterized by having d intervals of 11.41, 3.62, and 3.18 Å using CuKα radiation.

[0235] Embodiment 12. Crystalline religlitazone hydrate form C according to any one of Embodiments 1 or 8-11, further characterized by having d intervals of 8.32, 3.57, and 3.26 Å using CuKα radiation.

[0236] Embodiment 13. Crystalline religlitazone hydrate form C according to any one of Embodiments 1 or 8-12, further characterized by having d intervals of 9.60, 4.48, and 3.02 Å using CuKα radiation.

[0237] Embodiment 14.3056, 2960, 2992, 1735, 1608, 1205, 824, 656, 170cm -1 An FT-Raman spectrum having a peak at cm -1 The value is ±4cm -1 The crystalline religlitazone hydrate form C according to Embodiment 1, characterized by having an FT-Raman spectrum.

[0238] Embodiment 15. Crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 14, characterized by having a mass loss of approximately 4.3% between 40°C and 160°C, based on thermogravimetric analysis.

[0239] Embodiment 16. Crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 15, characterized by having a melting point with an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, based on differential scanning calorimetry.

[0240] Embodiment 17. A pharmaceutical composition comprising an aqueous suspension of crystalline religlitazone hydrate form C as described in any one of Embodiments 1 to 16, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0241] Embodiment 18.

[0242] (i) X-ray powder diffraction (XRPD) patterns using CuKα radiation, having peaks at 18.8, 21.1, and 23.8 degrees 2θ, where the 2θ value is ±0.2 degrees 2θ, or

[0243] (ii) X-ray powder diffraction patterns with d-spacing of 4.73, 4.21, and 3.73 Å using CuKα radiation, or

[0244] (iii) A melting point having an onset temperature of approximately 149.34°C and a peak temperature of approximately 153.56°C, based on differential scanning calorimetry, or

[0245] (iv) A crystalline religlitazone (non-solvated free base) form B characterized by having a combination of (i), (ii), and / or (iii).

[0246] Embodiment 19. The crystalline religlitazone morph B according to Embodiment 18, characterized by having an XRPD pattern using CuKα radiation, having peaks at 18.8, 21.1, and 23.8 degrees 2θ, and having a 2θ value of ±0.2 degrees 2θ.

[0247] Embodiment 20. A crystalline religlitazone form B according to any one of Embodiments 18 or 19, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 16.6, 21.8, and 24.7 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0248] Embodiment 21. A crystalline religlitazone form B according to any one of Embodiments 18 to 20, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 15.2, 25.4, and 28.0 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0249] Embodiment 22. A crystalline religlitazone form B according to any one of Embodiments 18 to 21, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 9.0, 19.8, and 30.8 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0250] Embodiment 23. A crystalline religlitazone form B according to any one of Embodiments 21 to 22, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 10.5, 20.1, and 26.9 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0251] Embodiment 24. A crystalline religlitazone form B according to any one of Embodiments 21 to 23, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 12.4, 23.5, and 29.1 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

[0252] Embodiment 25. Crystalline religlitazone form B according to Embodiment 18, characterized by having d intervals of 4.73, 4.21, and 3.73 Å, using CuKα radiation.

[0253] Embodiment 26. Crystalline religlitazone form B according to any one of Embodiments 18 or 25, further characterized by having d intervals of 5.33, 4.07, and 3.60 Å, using CuKα radiation.

[0254] Embodiment 27. Crystalline religlitazone form B according to any one of Embodiments 18, 25, or 26, further characterized by having d intervals of 5.84, 3.50, and 3.18 Å using CuKα radiation.

[0255] Embodiment 28. Crystalline religlitazone form B according to any one of Embodiments 18 or 25-27, further characterized by having d intervals of 9.78, 4.48, and 2.90 Å using CuKα radiation.

[0256] Embodiment 29. Crystalline religlitazone form B according to any one of Embodiments 18 or 25-28, further characterized by having d intervals of 8.43, 4.41, and 3.31 Å using CuKα radiation.

[0257] Embodiment 30. Crystalline rosiglitazone Form B according to any one of Embodiments 18 or 25 - 29, further characterized by having d - spacings of 7.11, 3.79, and 3.06 Å using CuKα radiation.

[0258] Embodiment 31. Crystalline rosiglitazone Form B according to any one of Embodiments 18 - 30, characterized by having a melting point with an onset temperature of about 149.34 °C and a peak temperature of about 153.56 °C based on differential scanning calorimetry.

[0259] Embodiment 32. Crystalline rosiglitazone Form B according to any one of Embodiments 18 - 31, characterized by having a mass loss of about 0.9% between 40 °C and 100 °C based on thermogravimetric analysis.

[0260] Embodiment 33. A pharmaceutical composition comprising an aqueous suspension of crystalline rosiglitazone Form B according to any one of Embodiments 18 - 32 and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0261] Embodiment 34.

[0262] (a) Rosiglitazone, its pharmaceutically acceptable salt, or its hydrate in an amount of 0.01% w / v - 5% w / v,

[0263] (b) One or more cellulose derivatives in an amount of 0.01% w / v - 2% w / v, having a viscosity of 1500 - 4500 mPa·s, preferably 1500 - 3500 mPa·s, more preferably 1500 - 3000 mPa·s, measured by the Brookfield viscometry method, and

[0264] (c) An appropriate amount of water up to 100% of the total amount, a pharmaceutical preparation.

[0265] Embodiment 35. The pharmaceutical formulation according to Embodiment 34, wherein the religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is religlitazone form B, characterized by (i) an XRPD pattern using CuKα radiation having peaks at 18.8, 21.1, and 23.8 degrees 2θ, with a 2θ value of ±0.2 degrees 2θ, or (ii) having a mass loss of about 0.9% between 40°C and about 100°C, based on thermogravimetric analysis.

[0266] Embodiment 36. The pharmaceutical formulation according to Embodiment 34, wherein the religlitazone, a pharmaceutically acceptable salt thereof, or its hydrate is (i) an XRPD pattern using CuKα radiation having peaks at 19.1, 21.0, and 23.8 degrees 2θ, with a 2θ value of ±0.2 degrees 2θ, or (ii) a religlitazone hydrate form C having a mass loss of about 4.3% between 40°C and about 160°C, based on thermogravimetric analysis.

[0267] Embodiment 37. The pharmaceutical preparation according to Embodiment 34, wherein religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is present in an amount of 1% w / v to 2% w / v.

[0268] Embodiment 38. The pharmaceutical preparation according to Embodiment 35, wherein the religlitazone form B is present in an amount of 1% w / v to 2% w / v.

[0269] Embodiment 39. The pharmaceutical preparation according to Embodiment 36, wherein the religlitazone hydrate form C is present in an amount of 1% w / v to 2% w / v.

[0270] Embodiment 40. The pharmaceutical preparation according to any one of Embodiments 34 to 39, wherein the one or more cellulose derivatives comprises microcrystalline cellulose, sodium carboxymethylcellulose, or a mixture thereof.

[0271] Embodiment 41. A pharmaceutical preparation according to any one of Embodiments 34 to 40, further comprising one or more pH adjusting agents.

[0272] Embodiment 42. The pharmaceutical preparation according to Embodiment 41, wherein the one or more pH adjusting agents include sodium citrate, citric acid monohydrate, or a mixture thereof.

[0273] Embodiment 43.0.001% w / v to 1.0% w / v. A pharmaceutical preparation according to any one of Embodiments 34 to 42, further comprising one or more preservatives in an amount of 1% w / v to 1.0% w / v.

[0274] Embodiment 44. The pharmaceutical preparation according to Embodiment 43, wherein the one or more preservatives include sodium benzoate.

[0275] Embodiment 45.0.00 A pharmaceutical preparation according to any one of Embodiments 34 to 44, further comprising one or more flavoring agents in an amount of 1% w / v to 3% w / v.

[0276] Embodiment 46. The pharmaceutical preparation according to Embodiment 45, wherein one or more flavoring agents include strawberry flavoring.

[0277] Embodiment 47.0. A pharmaceutical preparation according to any one of Embodiments 34 to 46, further comprising one or more sweeteners in an amount of 0.01% w / v to 15% w / v.

[0278] Embodiment 48. The pharmaceutical preparation according to Embodiment 47, wherein the sweetener is sorbitol, sodium saccharin, or a mixture thereof.

[0279] Embodiment 49. The pharmaceutical preparation according to any one of Embodiments 34 to 48, wherein the pH of the preparation is 3.5 to 4.5.

[0280] Embodiment 50. The pharmaceutical preparation according to Embodiment 49, wherein the pH of the preparation is approximately 4.

[0281] Embodiment 51. The pharmaceutical formulation according to any one of Embodiments 34 to 50, wherein the viscosity of the formulation is greater than 50 mPa*s and less than 5000 mPa*s, preferably less than 4,500 mPa*s.

[0282] Embodiment 52.

[0283] (a) Religlitazone, its pharmaceutically acceptable salt or hydrate, preferably hydrate form C, in an amount of 1.0% - 2.0% w / v, (b) approximately 1% w / v of microcrystalline cellulose, (c) approximately 0.5% w / v of sodium carboxymethylcellulose, (d) an appropriate amount of water up to a total of 100%, and optionally (e) approximately 8% w / v of sorbitol powder, (f) approximately 0.05% w / v of sodium saccharin, (g) approximately 0.1% w / v of sodium benzoate, (h) approximately 0.5% w / v of sodium citrate, (i) approximately 0.1% w / v of citric acid monohydrate, (j) approximately 0.015% w / v of strawberry flavor, (k) approximately 1% w / v of an aqueous solution of 0.2M citric acid monohydrate, a pharmaceutical preparation according to Embodiment 34.

[0284] Embodiment 53. A pharmaceutical preparation prepared by mixing (a) approximately 1.5% w / v of reloglitazone hydrochloride, such as form A, (b) approximately 8% w / v of sorbitol powder, (c) approximately 1% w / v of microcrystalline cellulose, (d) approximately 0.5% w / v of sodium carboxymethylcellulose, (e) approximately 0.05% w / v of sodium saccharin, (f) approximately 0.1% w / v of sodium benzoate, (g) approximately 0.5% w / v of sodium citrate, (h) approximately 0.1% w / v of citric acid monohydrate, (i) approximately 0.015% w / v of strawberry flavor, (j) approximately 1% w / v of an aqueous solution of 0.2M citric acid monohydrate, and (k) an appropriate amount of water up to a total of 100%.

[0285] Embodiment 54. A crystalline religlitazone hydrate form C described in any one of Embodiments 1 to 16, or the pharmaceutical composition described in Embodiment 17, or the crystalline religlitazone form B described in any one of Embodiments 18 to 32, or the pharmaceutical composition described in Embodiment 33, or the pharmaceutical preparation described in any one of Embodiments 34 to 53, for use in the treatment of a patient requiring treatment for a disease or disorder, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, or a chronic meat disease. Crystalline religlitazone hydrate form C as described in any one of Embodiments 1 to 16, or the pharmaceutical composition as described in Embodiment 17, or crystalline religlitazone form B as described in any one of Embodiments 18 to 32, or the pharmaceutical composition as described in Embodiment 33, or the pharmaceutical preparation as described in any one of Embodiments 34 to 53.

[0286] Embodiment 55. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 54, wherein the disease or disorder is a central nervous system disease or disorder.

[0287] Embodiment 56. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 55, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0288] Embodiment 57. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 56, wherein the central nervous system disease or disorder is a neurodegenerative disease.

[0289] Embodiment 58. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 57, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative disorders and cerebral iron storage disorders (NBIA), neuromuscular disorders, and motor neuron diseases.

[0290] Embodiment 59. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 58, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0291] Embodiment 60. The crystalline religlitazone form or pharmaceutical composition or preparation according to Embodiment 59, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

[0292] Embodiment 61. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 58, wherein the degenerative ataxia is Friedreich's ataxia.

[0293] Embodiment 62. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 58, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0294] Embodiment 63. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 56, wherein the cerebrovascular disease is selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0295] Embodiment 64. The crystalline religlitazone form or pharmaceutical composition or preparation according to Embodiment 56, wherein the viral disease is selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, poliovirus infection, herpes simplex, and varicella-zoster.

[0296] Embodiment 65. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 55, wherein the central nervous system disease or disorder is a rare metabolic disease selected from the group consisting of organic acidosis, fatty acid disorders, and genetic mitochondrial disorders.

[0297] Embodiment 66. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 54, wherein the disease or disorder is a mitochondrial disease.

[0298] Embodiment 67. The mitochondrial disease is Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Lie syndrome, Lie-like syndrome, maternal Lie syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and mitochondrial encephalomyopathy with red rag fibers. Myoclonus epilepsy (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal inherited diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, 3-methyl Unresolved genetic defects, including luglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lie-like syndrome (MEGDEL), SURF1 (COX deficiency Lie syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. This includes isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, and carnitine palmitoyltransferase (CPT I or CPTII) A crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 66, which is a primary mitochondrial disorder selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutariculosis type II.

[0299] Embodiment 68. The crystalline relitazone form or pharmaceutical composition or formulation according to Embodiment 67, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome, dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

[0300] Embodiment 69. The mitochondrial disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorder, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorder or purine and / or pyrimidine synthesis, facioscapulohumeral muscular dystrophy (FSHD), The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 66 is a secondary mitochondrial disorder selected from the group consisting of congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus type), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0301] Embodiment 70. The crystalline religlitazone form or pharmaceutical composition according to Embodiment 54, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or interstitial lung disease.

[0302] Embodiment 71. A crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 70 for treating a patient who requires treatment for an inflammatory lung condition or disease caused by a viral infection.

[0303] Embodiment 72. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 71, wherein the viral infection is human coronavirus infection, influenza virus infection, or HIV virus infection.

[0304] Embodiment 73. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 72, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant thereof.

[0305] Embodiment 74. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 73, wherein the human coronavirus is SARS-CoV-2.

[0306] Embodiment 75. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 74, wherein the human coronavirus is a mutant strain of SARS-CoV-2.

[0307] Embodiment 76. The crystalline religlitazone form or pharmaceutical composition or formulation according to any one of Embodiments 71 to 75, wherein the inflammatory lung condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0308] Embodiment 77. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 76, wherein the inflammatory lung condition or disease caused by the viral infection is acute respiratory distress syndrome.

[0309] Embodiment 78. A crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 70 for treating acute pulmonary inflammation in a patient requiring treatment for the same condition.

[0310] Embodiment 79. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 78, wherein the acute inflammation of the lung is caused by a bacterial infection.

[0311] Embodiment 80. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 78, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

[0312] Embodiment 81. The crystalline religlitazone form or pharmaceutical composition or preparation according to Embodiment 70 for treating interstitial lung disease in patients requiring treatment for interstitial lung disease.

[0313] Embodiment 82. The crystalline religlitazone form or pharmaceutical composition or preparation according to Embodiment 70, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

[0314] Embodiment 83. The crystalline religlitazone form or pharmaceutical composition or formulation according to Embodiment 54, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0315] Embodiment 84. A method for producing crystalline religlitazone hydrate form C as described in Embodiment 1,

[0316] (a) A step of providing a solution or suspension by providing religlitazone hydrochloride, preferably form A, in water or a mixture of water and an alcohol solvent.

[0317] (b) Optionally, heat the mixture from step (a) to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C.

[0318] (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and

[0319] (d) A method comprising the step of isolating the solid obtained in step (c) to provide morphology C of religlitazone.

[0320] Embodiment 85. A method for producing crystalline religlitazone form B as described in Embodiment 18,

[0321] (a) A step of providing a solution or suspension by providing religlitazone hydrochloride, for example form A, in water or a mixture of water and an alcohol solvent.

[0322] (b) Optionally, heat the mixture from step (a) to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C.

[0323] (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and

[0324] (d) A method comprising the step of isolating and drying the solid obtained in step (c) to provide religlitazone form B.

[0325] Embodiment 86. The kit comprising (ii) a pharmaceutical composition according to any one of Embodiments 34 to 53 in a container, and a label including instructions on how to use the kit.

[0326] Embodiment 87. The kit according to Embodiment 86, wherein the label is approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health, Labour and Welfare (MHLW).

[0327] Embodiment 88. The kit according to Embodiment 86 or 87, further comprising a graduated oral syringe of 8.5 mL, 10 mL, 12 mL, or 15 mL.

[0328] Embodiment 89. A method for treating a patient in need of treatment for a disease or disorder, comprising administering to the patient a therapeutically effective amount of religlitazone hydrate form C described in any one of Embodiments 1 to 16, or the pharmaceutical composition described in Embodiment 17, or crystalline religlitazone form B described in any one of Embodiments 18 to 32, or the pharmaceutical composition described in Embodiment 33, or the pharmaceutical preparation described in any one of Embodiments 34 to 53, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

[0329] Embodiment 90. The method according to Embodiment 89, wherein the disease or disorder is a central nervous system disease or disorder.

[0330] Embodiment 91. The method according to Embodiment 90, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0331] Embodiment 92. The method according to Embodiment 91, wherein the central nervous system disease or disorder is a neurodegenerative disease.

[0332] Embodiment 93. The method according to Embodiment 92, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, ALS, degenerative ataxia, multiple system atrophy, NBIA (neurodegenerative disorders and cerebral iron storage disorders), neuromuscular disorders, and motor neuron diseases.

[0333] Embodiment 94. The method according to Embodiment 93, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0334] Embodiment 95. The method according to Embodiment 94, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

[0335] Embodiment 96. The method according to Embodiment 93, wherein the degenerative ataxia is Friedreich's ataxia.

[0336] Embodiment 97. The method according to Embodiment 93, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0337] Embodiment 98. The method according to Embodiment 91, wherein the central nervous system disorder is a cerebrovascular disease selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0338] Embodiment 99. The method according to Embodiment 91, wherein the central nervous system disorder is a viral disease selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, polio, herpes simplex, and varicella-zoster.

[0339] Embodiment 100. The method according to Embodiment 91, wherein the central nervous system disease or disorder is a rare metabolic disorder selected from the group consisting of organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0340] Embodiment 101. The method according to Embodiment 89, wherein the disease or disorder is a mitochondrial disease.

[0341] Embodiment 102. The mitochondrial disease is Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Lie syndrome, Lie-like syndrome, maternal Lie syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and red rag fibers. Myoclonus epilepsy (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal inherited diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, 3-Me Unresolved genetic defects, including cylglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lee-like syndrome (MEGDEL), SURF1 (COX deficiency Lee syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. Isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, carnitine palmitoyltransferase (CPT I or CPTII) The method according to Embodiment 101, wherein the primary mitochondrial disorder is selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutaric aciduria type II.

[0342] Embodiment 103. The method according to Embodiment 102, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome, dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

[0343] Embodiment 104. The mitochondrial disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorder, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorder or purine and / or pyrimidine synthesis, facioscapulohumeral muscular dystrophy The method according to Embodiment 101, wherein the secondary mitochondrial disorder is selected from the group consisting of muscular dystrophy (FSHD), congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus type), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0344] Embodiment 105. The method according to Embodiment 89, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or interstitial lung disease.

[0345] Embodiment 106. The method according to Embodiment 105 for treating a patient who requires treatment for an inflammatory lung condition or disease caused by a viral infection.

[0346] Embodiment 107. The method according to Embodiment 106, wherein the viral infection is human coronavirus infection, influenza virus infection, or HIV virus infection.

[0347] Embodiment 108. The method according to Embodiment 107, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant strain thereof.

[0348] Embodiment 109. The method according to Embodiment 108, wherein the human coronavirus is SARS-CoV-2.

[0349] Embodiment 110. The method according to Embodiment 109, wherein the human coronavirus is a mutant strain of SARS-CoV-2.

[0350] Embodiment 111. The method according to any one of Embodiments 106 to 110, wherein the inflammatory lung condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0351] Embodiment 112. The method according to Embodiment 111, wherein the inflammatory lung condition or disease caused by the viral infection is acute respiratory distress syndrome.

[0352] Embodiment 113. The method according to Embodiment 105 for treating acute pulmonary inflammation in a patient requiring treatment.

[0353] Embodiment 114. The method according to Embodiment 113, wherein the acute inflammation of the lung is caused by a bacterial infection.

[0354] Embodiment 115. The method according to Embodiment 114, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

[0355] Embodiment 116. The method according to Embodiment 105 for treating interstitial lung disease in a patient requiring treatment for interstitial lung disease.

[0356] Embodiment 117. The method according to Embodiment 116, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

[0357] Embodiment 118. The method according to Embodiment 89, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0358] Embodiment 119. A method for preparing crystalline religlitazone form B, comprising the steps of (a) providing religlitazone hydrochloride in water or a mixture of water and an alcohol solvent to provide a solution or suspension; (b) optionally heating the mixture from step (a) at a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C; (c) optionally cooling the solution or suspension obtained from step (b) to room temperature; and (d) isolating and drying the solid obtained from step (c) to provide religlitazone form B.

[0359] Embodiment 120. A method for preparing crystalline religlitazone hydrate form C, comprising the steps of (a) providing religlitazone hydrochloride in water or a mixture of water and an alcohol solvent to provide a solution or suspension; (b) optionally heating the mixture from step (a) at a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C; (c) optionally cooling the solution or suspension obtained from step (b) to room temperature; and (d) isolating the solid obtained from step (c) to provide religlitazone hydrate form C.

[0360] Embodiment 121. Use of crystalline religlitazone hydrate form C according to any one of Embodiments 1 to 16, or the pharmaceutical composition according to Embodiment 17, or crystalline religlitazone form B according to any one of Embodiments 18 to 32, or the pharmaceutical composition according to Embodiment 33, or the pharmaceutical preparation according to any one of Embodiments 34 to 53, in the manufacture of a pharmaceutical for the treatment of a patient who requires treatment for a disease or disorder, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

[0361] Embodiment 122. The use according to Embodiment 121, wherein the disease or disorder is a central nervous system disease or disorder.

[0362] Embodiment 123. The use according to Embodiment 122, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0363] Embodiment 124. The use according to Embodiment 123, wherein the central nervous system disease or disorder is a neurodegenerative disease.

[0364] Embodiment 125. The use according to Embodiment 124, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative disorders and brain iron storage disorders (NBIA), neuromuscular disorders, and motor neuron diseases.

[0365] Embodiment 126. The use according to Embodiment 125, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0366] Embodiment 127. The use according to Embodiment 126, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

[0367] Embodiment 128. The use according to Embodiment 125, wherein the degenerative ataxia is Friedreich's ataxia.

[0368] Embodiment 129. The use according to Embodiment 58125, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0369] Embodiment 130. The use according to Embodiment 123, wherein the cerebrovascular disease is selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0370] Embodiment 131. The use according to Embodiment 123, wherein the viral disease is selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, polio, herpes simplex, and varicella-zoster.

[0371] Embodiment 132. The use according to Embodiment 122, wherein the central nervous system disease or disorder is a rare metabolic disorder selected from the group consisting of organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0372] Embodiment 133. The use according to Embodiment 121, wherein the disease or disorder is a mitochondrial disease.

[0373] Embodiment 134. The mitochondrial disease is Rett syndrome, Alper's disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Lie syndrome, Lie-like syndrome, maternal Lie syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and red rag fibers. Myoclonus epilepsy (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal inherited diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, 3-Me Unresolved genetic defects, including cylglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lee-like syndrome (MEGDEL), SURF1 (COX deficiency Lee syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. Isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, carnitine palmitoyltransferase (CPT I or CPTII) The use according to Embodiment 133, which is a primary mitochondrial disorder selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutaric aciduria type II.

[0374] Embodiment 135. The use according to Embodiment 134, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome, dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

[0375] Embodiment 136. The mitochondrial disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorder, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorder or purine and / or pyrimidine synthesis, facioscapulohumeral muscular dystrophy The use according to Embodiment 133 is a secondary mitochondrial disorder selected from the group consisting of muscular dystrophy (FSHD), congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus type), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0376] Embodiment 137. The use according to Embodiment 121, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or interstitial lung disease.

[0377] Embodiment 138. The use of Embodiment 137 for treating an inflammatory lung condition or disease caused by a viral infection in a patient who requires treatment for it.

[0378] Embodiment 139. The use according to Embodiment 138, wherein the viral infection is human coronavirus infection, influenza virus infection, or HIV virus infection.

[0379] Embodiment 140. The use according to Embodiment 139, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant thereof.

[0380] Embodiment 141. The use according to Embodiment 140, wherein the human coronavirus is SARS-CoV-2.

[0381] Embodiment 142. The use according to Embodiment 141, wherein the human coronavirus is a mutant strain of SARS-CoV-2.

[0382] Embodiment 143. The use according to any one of Embodiments 138 to 142, wherein the inflammatory lung condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0383] Embodiment 144. The use according to Embodiment 143, wherein the inflammatory lung condition or disease caused by the viral infection is acute respiratory distress syndrome.

[0384] Embodiment 145. The use of Embodiment 137 for treating acute pulmonary inflammation in a patient requiring treatment.

[0385] Embodiment 146. The use according to Embodiment 145, wherein the acute inflammation of the lung is caused by a bacterial infection.

[0386] Embodiment 147. The use according to Embodiment 145, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

[0387] Embodiment 148. The use of Embodiment 137 for treating interstitial lung disease in patients who require treatment for it.

[0388] Embodiment 149. The use according to Embodiment 137, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

[0389] Embodiment 150. The use according to Embodiment 121, wherein the liver disease or disorder is NASH or NAFLD.

[0390] Embodiment 151. A compound that is (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidined-2,4-dione, or a pharmaceutically acceptable salt thereof.

[0391] Embodiment 152. A compound that is 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0392] Embodiment 153. A compound which is 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 154. A compound that is 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidined-2-one, or a pharmaceutically acceptable salt thereof.

[0394] Embodiment 155. The compound according to any one of Embodiments 151 to 154, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

[0395] Embodiment 156.99.0 to 99.9 wt / wt% religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and

[0396] (i) 0.0001 to 0.2 wt / wt% of (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione, or its hydrochloride salt,

[0397] (ii) 0.0001 to 0.2 wt / wt% of 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride salt,

[0398] (iii) 0.0001 to 0.2 wt / wt% of 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride salt, and / or

[0399] (iv) A composition comprising 0.0001 to 0.15 wt / wt% of 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidined-2-one or its hydrochloride salt.

[0400] Embodiment 157. A composition of Embodiment 156 comprising 99.0 to 99.9 wt / wt% religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and 0.0001 to 0.15 wt / wt% (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione, or its hydrochloride.

[0401] Embodiment 158. A composition according to Embodiment 156 or 157, comprising 99.0 to 99.9 wt / wt% religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and 0.0001 to 0.15 wt / wt% 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride.

[0402] Embodiment 159.99.0 to 99.9 by weight / weight % religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and 0.0001 to 0.15 by weight / weight % 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride, the composition according to any one of Embodiments 156 to 158.

[0403] Embodiment 160.99.0 to 99.9 by weight / weight % religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and 0.0001 to 0.15 by weight / weight % 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidined-2-one, or its hydrochloride, according to any one of Embodiments 156 to 159.

[0404] Embodiment 161. A composition according to any one of Embodiments 156 to 160, further comprising water and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0405] Embodiment 162.

[0406] (a) A composition according to any one of embodiments 156 to 160 in an amount of 0.01% w / v to 5% w / v,

[0407] (b) One or more cellulose derivatives in an amount of 0.01% w / v to 2% w / v, having a viscosity of 1500 to 4500 mPa*s, preferably 1500 to 3500 mPa*s, more preferably 1500 to 3000 mPa*s, as measured by the Brookfield viscosity method, and

[0408] (c) A pharmaceutical preparation containing an appropriate amount of water until the total volume reaches 100%.

[0409] Embodiment 163. The pharmaceutical preparation according to Embodiment 162, wherein the composition is present in an amount of 1% w / v to 2% w / v.

[0410] Embodiment 164. The pharmaceutical formulation according to Embodiment 162 or 163, wherein the one or more cellulose derivatives comprises microcrystalline cellulose, sodium carboxymethylcellulose, or a mixture thereof.

[0411] Embodiment 165. A pharmaceutical preparation according to any one of Embodiments 162 to 164, further comprising one or more pH adjusting agents, for example, sodium citrate, citric acid monohydrate, or a mixture thereof.

[0412] Embodiment 166.0.001% w / v to 1.0% w / v. A pharmaceutical preparation according to any one of Embodiments 162 to 165, further comprising one or more preservatives in an amount of 1.001% w / v to 1.0% w / v.

[0413] Embodiment 167. The pharmaceutical preparation according to Embodiment 16, wherein the one or more preservatives include sodium benzoate.

[0414] Embodiment 168.0.001% w / v to 3% w / v of one or more flavoring agents, further comprising the pharmaceutical preparation according to any one of Embodiments 12 to 17.

[0415] Embodiment 169. The pharmaceutical preparation according to Embodiment 168, wherein one or more flavoring agents include strawberry flavoring.

[0416] Embodiment 170.0.0.A pharmaceutical preparation according to any one of Embodiments 162 to 169, further comprising one or more sweeteners in an amount of 1.01% w / v to 15% w / v.

[0417] Embodiment 171. The pharmaceutical preparation according to Embodiment 170, wherein the sweetener is sorbitol, sodium saccharin, or a mixture thereof.

[0418] Embodiment 172. The pharmaceutical preparation according to any one of Embodiments 162 to 171, wherein the pH of the preparation is 3.5 to 4.5.

[0419] Embodiment 173. The pharmaceutical formulation according to Embodiment 172, wherein the pH of the formulation is approximately 4.

[0420] Embodiment 174. The pharmaceutical formulation according to any one of Embodiments 162 to 173, wherein the viscosity of the formulation is greater than 50 mPa*s and less than 5000 mPa*s, preferably less than 4,500 mPa*s.

[0421] Embodiment 175.

[0422] (a) A composition in an amount of 1.0% to 2.0% w / v,

[0423] (b) Microcrystalline cellulose of approximately 1% w / v,

[0424] (c) Approximately 0.5% w / v sodium carboxymethylcellulose,

[0425] (d) an appropriate amount of water until the total volume reaches 100%,

[0426] And, optionally,

[0427] (e) Sorbitol powder with approximately 8% w / v

[0428] (f) Sodium saccharin at approximately 0.05% w / v

[0429] (g) Approximately 0.1% w / v sodium benzoate,

[0430] (h) Approximately 0.5% w / v sodium citrate,

[0431] (i) Citric acid monohydrate at approximately 0.1% w / v,

[0432] (j) Approximately 0.015% w / v strawberry flavoring,

[0433] (k) A pharmaceutical preparation according to Embodiment 162, comprising an aqueous solution of 0.2 M citric acid monohydrate at approximately 1% w / v.

[0434] Embodiment 176.

[0435] (a) About 1.5% w / v of any one of the compositions of Embodiments 156 to 160,

[0436] (b) Sorbitol powder with approximately 8% w / v

[0437] (c) Approximately 1% w / v microcrystalline cellulose,

[0438] (d) Approximately 0.5% w / v sodium carboxymethylcellulose,

[0439] (e) Sodium saccharin at approximately 0.05% w / v

[0440] (f) Sodium benzoate at approximately 0.1% w / v

[0441] (g) Approximately 0.5% w / v sodium citrate,

[0442] (h) Approximately 0.1% w / v citric acid monohydrate,

[0443] (i) Approximately 0.015% w / v strawberry flavoring,

[0444] (j) an aqueous solution of 0.2 M citric acid monohydrate with a concentration of approximately 1% w / v, and

[0445] (k) A pharmaceutical preparation prepared by mixing an appropriate amount of water until the total volume reaches 100%.

[0446] Embodiment 177. A pharmaceutical formulation according to any one of Embodiments 162 to 176 for use in the treatment of a patient in need of treatment for a disease or disorder, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

[0447] Embodiment 178. The pharmaceutical preparation according to Embodiment 177, wherein the disease or disorder is a central nervous system disease or disorder.

[0448] Embodiment 179. The pharmaceutical formulation according to Embodiment 178, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0449] Embodiment 180. The pharmaceutical preparation according to Embodiment 179, wherein the central nervous system disease or disorder is a neurodegenerative disease.

[0450] Embodiment 181. The pharmaceutical formulation according to Embodiment 180, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative disorders and cerebral iron storage disorders (NBIA), neuromuscular disorders, and motor neuron diseases.

[0451] Embodiment 182. The pharmaceutical preparation according to Embodiment 181, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

[0452] Embodiment 183. The pharmaceutical preparation according to Embodiment 182, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

[0453] Embodiment 184. The pharmaceutical preparation according to Embodiment 181, wherein the degenerative ataxia is Friedreich's ataxia.

[0454] Embodiment 185. The pharmaceutical formulation according to Embodiment 181, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

[0455] Embodiment 186. The pharmaceutical preparation according to Embodiment 179, wherein the cerebrovascular disease is selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

[0456] Embodiment 187. The pharmaceutical preparation according to Embodiment 179, wherein the viral disease is selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, polio, herpes simplex, and varicella-zoster.

[0457] Embodiment 188. The pharmaceutical preparation according to Embodiment 178, wherein the central nervous system disease or disorder is a rare metabolic disease selected from the group consisting of organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

[0458] Embodiment 189. The pharmaceutical preparation according to Embodiment 177, wherein the disease or disorder is a mitochondrial disease.

[0459] Embodiment 190. The mitochondrial disease is Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Lie syndrome, Lie-like syndrome, maternal Lie syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and mitochondrial encephalomyopathy with red rag fibers. Myoclonus epilepsy (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal inherited diabetes and hearing impairment (MIDD), ataxic neuropathy spectrum, 3-Me Unresolved genetic defects, including cylglutaconic aciduria, sensorineural hearing loss, neuroradiological findings of Lee-like syndrome (MEGDEL), SURF1 (COX deficiency Lee syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. Isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactate with brainstem and spinal cord involvement (LBSL), Luft's disease, carnitine palmitoyltransferase (CPT I or CPTII) A pharmaceutical formulation according to Embodiment 189, which is a primary mitochondrial disorder selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutaric aciduria type II.

[0460] Embodiment 191. The pharmaceutical formulation according to Embodiment 190, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome, dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red rag fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular muscle palsy (CPEO).

[0461] Embodiment 192. The mitochondrial disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorder, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorder or purine and / or pyrimidine synthesis, facioscapulohumeral muscular dystrophy The pharmaceutical formulation according to Embodiment 189, which is a secondary mitochondrial disorder selected from the group consisting of Loffy (FSHD), congenital muscular dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus type), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

[0462] Embodiment 193. The pharmaceutical formulation according to Embodiment 177, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or interstitial lung disease.

[0463] Embodiment 194. A pharmaceutical formulation according to Embodiment 193 for treating a patient who requires treatment for an inflammatory lung condition or disease caused by a viral infection.

[0464] Embodiment 195. The pharmaceutical preparation according to Embodiment 194, wherein the viral infection is human coronavirus infection, influenza virus infection, or HIV virus infection.

[0465] Embodiment 196. The pharmaceutical preparation according to Embodiment 195, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant strain thereof.

[0466] Embodiment 197. The pharmaceutical preparation according to Embodiment 196, wherein the human coronavirus is SARS-CoV-2.

[0467] Embodiment 198. The pharmaceutical preparation according to Embodiment 197, wherein the human coronavirus is a mutant strain of SARS-CoV-2.

[0468] Embodiment 199. The pharmaceutical preparation according to any one of Embodiments 194 to 198, wherein the inflammatory lung condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

[0469] Embodiment 200. The pharmaceutical preparation according to Embodiment 199, wherein the inflammatory lung condition or disease caused by the viral infection is acute respiratory distress syndrome.

[0470] Embodiment 201. A pharmaceutical formulation according to Embodiment 193 for treating acute pulmonary inflammation in a patient requiring treatment.

[0471] Embodiment 202. The pharmaceutical preparation according to Embodiment 201, wherein the acute inflammation of the lung is caused by a bacterial infection.

[0472] Embodiment 203. The pharmaceutical preparation according to Embodiment 201, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

[0473] Embodiment 204. A pharmaceutical preparation according to Embodiment 203 for treating interstitial lung disease in patients requiring treatment for interstitial lung disease.

[0474] Embodiment 205. The pharmaceutical preparation according to Embodiment 203, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

[0475] Embodiment 206. The pharmaceutical preparation according to Embodiment 177, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0476] Embodiment 207. A composition according to any one of Embodiments 156 to 161, comprising religlitazone hydrochloride form A.

[0477] Embodiment 208. A composition according to any one of Embodiments 156 to 161, comprising religlitazone form B.

[0478] Embodiment 209. A composition according to any one of Embodiments 156 to 161, comprising religlitazone hydrate form C.

[0479] Embodiment 210. A pharmaceutical preparation according to any one of Embodiments 162 to 206, comprising religlitazone hydrochloride form A.

[0480] Embodiment 211. A pharmaceutical preparation according to any one of Embodiments 162 to 206, comprising religlitazone form B.

[0481] Embodiment 212. A pharmaceutical preparation according to any one of Embodiments 162 to 206, comprising religlitazone hydrate form C.

[0482] Embodiment 213. The kit comprising (ii) a pharmaceutical preparation according to any one of Embodiments 162-206 or 210-212 in a container, and a label including instructions on how to use the kit.

[0483] Embodiment 214. The kit according to Embodiment 213, wherein the label is approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health, Labour and Welfare (MHLW).

[0484] Embodiment 213 or Embodiment 214 further comprises a graduated oral syringe of 5.5 mL, 10 mL, 12 mL, or 15 mL. [Examples]

[0485] instrumentation X-ray powder diffraction (XRPD) Sample Preparation: To obtain the powder diffraction pattern of the obtained solid, approximately 20 mg of unprocessed sample was prepared in a standard sample holder using two polyacetate foils.

[0486] Data Acquisition: Powder diffraction patterns were acquired using a Bruker D8 Advance Series 2Theta / Theta powder diffraction system with CuKα1 emission (1.54060 Å) in transmission configuration. This system is equipped with a VANTEC-1 single-photon count PSD, germanium monochromator, 90-position autochanger sample stage, fixed divergent slit, and radial solar. Data acquisition and evaluation were performed using the DIFFRAC plus XRD Commander V.2.4.1 program and EVA V.12.0 program.

[0487] Differential Scanning Calorimetry (DSC) DSC analysis was recorded using a Mettler Toledo DSC822e. 1–3 mg of sample was weighed into a 40 μL aluminum crucible with a pinhole lid (using a microscale MX5, Mettler) and heated under a nitrogen stream (50 mL / min) at a heating rate of 10 °C / min from 30–300 °C. Data acquisition and evaluation were performed using STARe software.

[0488] Thermogravimetric analysis (TGA) Thermogravimetric analysis was recorded using a Mettler Toledo SDTA851e. 1–3 mg of sample was weighed into a 40 μL aluminum crucible with a pinhole lid (using a microscale MX5, Mettler) and heated under a nitrogen stream (50 mL / min) at 30–300°C at a rate of 10°C / min. Data acquisition and evaluation were performed using STARe software.

[0489] FT-Raman spectroscopy Data acquisition: FT-Raman measurements were performed on the Raman module of a Thermo Nicolet iS50 spectrometer equipped with an InGaAs detector, a CaF2 beam splitter, and a laser operating at 1064 nm.

[0490] Sample preparation: Approximately 5 mL of syrup was centrifuged in a Genevac, and the solid at the bottom was then scooped out with a spatula and analyzed.

[0491] Single crystal structure determination Data acquisition: The measured crystals were prepared under inert conditions, immersed in perfluoropolyether as a protective oil for the operation. Crystal structure determination was performed using an APPEX 2 4K CCD area detector, MoK α The analysis was performed using an Apex DUO Kappa 4-axis goniometer equipped with a Microfocus Source E025 IuS (0.71073 Å) using radiation, a Quazar MX multilayer optics system as a monochromator, and an Oxford Cryosystems Cryostream 700 plus cryogenic device (T=-173°C). Global data acquisition was used with ω and φ scans.

[0492] Programs used: Data acquisition APEX-2, data processing Bruker Saint, and absorption correction SADABS.

[0493] Structural Derivation and Fine-Tuning: The crystal structure was determined using the computer program SHELXT. Visualization was performed using the program SHELXle. Missing atoms were then identified from difference Fourier synthesis and added to the atom list. All measured intensities were used for F 2 The least-squares fine-tuning was performed using the SHELXL2015 program. All non-hydrogen atoms were fine-tuned, including the anisotropy displacement parameter.

[0494] Example 1 Characterization of Morphology A Religlitazone hydrochloride form A was prepared by suspending religlitazone hydrochloride in ethanol at room temperature for 10 days, decanting the mother liquor, and recovering the resulting solid.

[0495] The X-ray powder diffraction (XRPD) diffraction pattern for morphology A is shown in Figure 1. The XRPD peak list (±0.2 degrees 2θ) is shown in Table 1. [Table 1-1] [Table 1-2]

[0496] The Raman spectrum of morphology A is shown in Figure 2. Raman peak list (±4cm) -1 ) are shown in Table 2. [Table 2]

[0497] The structure of morphology A was elucidated by single-crystal X-ray diffraction. Selected crystals of morphology A were examined using an optical microscope with polarized light. Suitable single crystals obtained by crystallization in 90% ethanol were prepared by coating them in perfluoropolyether oil and mounted using a magnetic Kapton loop for SCXRD measurement. The measurement was performed at 100K.

[0498] After elucidating the structure from the collected data, we were able to fine-tune the structure to achieve excellent quality (R1 4.83%). The asymmetric unit contains one molecule of a partially disordered cationic organic compound and one chloride anion, supporting the compound's identity as a hydrochloride salt.

[0499] The disorder observed in cationic organic compounds supports the presence of combinations / mixtures of different enantiomers and diastereomers within a single crystal. Pure enantiomers should always crystallize in chiral space groups. A mixture formed by four molecules, including two diastereomers and their corresponding enantiomers, crystallizes exceptionally in a central symmetric space group where all four molecules are disordered and share the same positions within the crystal packing. See Figures 3 and 4a-4d. The four stereoisomers, due to their very similar molecular volumes, mix and crystallize together in a single crystal form. The occupancy ratio of chiral centers with alcohol groups is 0.72:0.28, and the occupancy ratio of chiral centers bonded to sulfur atoms is 0.52:0.48. Since it is not clear which ratio of the first chiral groups corresponds to the second chiral groups, it is not possible to assign the exact ratio of stereoisomers, but it should be approximately 70:30. Furthermore, please note that the obtained ratios are representative of the measured crystal and may vary depending on the structure determination of other crystals.

[0500] Form A melts at an onset temperature of approximately 203.98°C and a peak temperature of approximately 211.87°C, according to DSC analysis. See Figure 5.

[0501] Example 2 Characterization of Morphology B Religlitazone hydrochloride form A was suspended in water at 80°C, then cooled to room temperature and stirred overnight to prepare religlitazone form B, i.e., a non-solvated free base. The resulting white solid was then filtered and dried at 100°C under a vacuum of 2 mbar for 15 hours.

[0502] The X-ray powder diffraction (XRPD) diffraction pattern for morphology B is shown in Figure 6. The XRPD peak list (±0.2 degrees 2θ) is shown in Table 3. [Table 3-1] [Table 3-2]

[0503] Form B dissolves at an onset temperature of approximately 149.34°C and a peak temperature of approximately 153.56°C, according to DSC analysis. Thermogravimetric analysis shows a mass loss of 0.9% between 40°C and 100°C, suggesting desolvation. See Figure 7.

[0504] Example 3 Characterization of Morphology C Religlitazone hydrate form C was prepared by suspending religlitazone hydrochloride form A in water at room temperature for 10 days, decanting the mother liquor, and recovering the resulting solid.

[0505] The X-ray powder diffraction (XRPD) diffraction pattern for morphology C is shown in Figure 8. The XRPD peak list (±0.2 degrees 2θ) is shown in Table 4. [Table 4-1] [Table 4-2]

[0506] The Raman spectrum of morphology C is shown in Figure 9. Raman peak list (±4cm) -1 ) are shown in Table 5. [Table 5]

[0507] Form C melts at an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, according to DSC analysis. Thermogravimetric analysis shows a mass loss of 4.3% between 40°C and 160°C (1 molecule of water = 4.2%, religlitazone xH2O, where x=1), followed by a mass loss due to decomposition beginning at 190°C. See Figure 10.

[0508] Example 4 Oral suspension formulation development testing and manufacturing process Formulation development focused on evaluating and determining the quality characteristics of the religlitazone drug product for the desired dosage design, and included viscosity tests, pH tests, optimization of sensory properties, efficacy tests of preservatives (loading tests), uniformity tests, syringe dosage tests, and solubility tests. Surprisingly, during these tests, it was discovered that when religlitazone HCl, for example form A, was mixed with water, religlitazone hydrate form C was formed.

[0509] Viscosity test Several formulations P7-P11, P16, and P17 with varying viscosities were prepared by incorporating microcrystalline cellulose (FMC RC-591), sodium carboxymethylcellulose (BLANOSE 9H4XF and BLANOSE 9M31F, where BLANOSE 9M31F has a lower viscosity than BLANOSE 9H4XF), and hydroxyethylcellulose (Natrosol® 250HX) at different concentrations, and are shown in Table 6. [Table 6]

[0510] Pure vehicle compositions and formulations were tested. Formulations P7, P8, and P9 had high or very high viscosity. Formulations P10, P11, P16, and P17 showed better flow than formulations P7-P9. The use of acetic acid produced an unpleasant odor; therefore, formulations containing sodium citrate / citric acid were used for further testing. In these tests, the selection and type of excipients (colloidal microcrystalline cellulose and sodium carboxymethylcellulose) were also tested.

[0511] pH test Formulations P19-P21, P24, and P26 (Table 7) were evaluated at different pH values ​​to investigate their physicochemical and microbiological stability. A preservative matching the pH of each formulation was selected.

[0512] The initial trial was conducted at a pH of 5.0 (P19, P20, and P21). This pH was adjusted with sodium citrate and 0.1 M citric acid, and methylparaben and propylparaben were added as preservatives. Simultaneously, pH 4.0 was investigated (P24 and P26), and sodium benzoate was selected as the preservative. One impurity was detected in the suspension at pH=5.0. No impurities were present at pH=4.0, so development of the formulation at pH=4.0 continued. Sodium citrate / citric acid buffer was added to ensure pH stability (P26). [Table 7]

[0513] Optimization of sensory characteristics The functional properties (sensory and viscosity) of formulation P26 (formulation P32) improved by the addition of strawberry flavoring. The manufacturer's recommended standard strawberry flavoring concentration (0.015 g / 100 mL) was selected. The formulations are shown in Table 8. [Table 8]

[0514] The resulting suspension (P32) exhibited a uniform white appearance, was free of particulate aggregates (occasional small particles visible on the glass container walls), and had appropriate fluidity after gentle stirring. The viscosity of this suspension was tested using a Brookfield viscometer, and the results are shown in Table 9. Based on the positive results of this formulation (P32), development proceeded with its use. [Table 9]

[0515] The amount of preservative in formulation P32 was evaluated. A set of bench-scale formulations, inspired by suspension P32 and with different preservative (sodium benzoate) concentrations, were prepared under engineering conditions and their efficacy was preliminaryly evaluated. The formulations and results are shown in Table 10. [Table 10]

[0516] All three batches met the European Pharmacopoeia (Ph.Eur.) and United States Pharmacopeia (USP) requirements for total aerobic microorganisms (TAMC) and total yeast and mold (TYMC) for this type of formulation, specifically <100 CFU / mL TAMC and <10 CFU / mL TYMC.

[0517] Next, the effectiveness of antimicrobial preservation in a 13.66 mg / mL oral suspension of religlitazone was investigated using one GMP pilot batch (22 L scale). This batch, codenamed 160001, contained 1.0 mg / mL of a preservative (sodium benzoate). The test results are shown in Table 11. [Table 11]

[0518] The diluents used in the plate counting method and antimicrobial preservation efficacy tests were effective in restoring microbial growth in the proposed formulations. Batch 160001 complied with the criteria for antimicrobial preservation efficacy for oral formulations according to the USP and Ph.Eur standards. A lower concentration of preservative (1.0 mg / mL sodium benzoate) in batch 160001 demonstrated efficacy, which was the preservative concentration selected for the oral suspension of religlitazone 13.66 mg / mL.

[0519] Religritazone 13.66 mg / mL oral suspension batch 160001 (sodium benzoate 0.1% w / v) was subjected to the ICH long-term stability program. Microbiological testing was performed to evaluate the efficacy of sodium benzoate over time. The loading test was repeated at the end of the stability test while the sample was stored under long-term conditions.

[0520] To prepare for the possibility of increased microbial concentration during stability testing, batch 170001 CON (scale 22L) containing a higher concentration of preservative, 1.5 mg / mL (0.15% w / v), and "Religlitazone 13.66 mg / mL oral suspension 100mL CON" was tested to evaluate the range of preservative efficacy of a similar formulation and target concentration of preservative (Religlitazone 13.66 mg / mL oral suspension 100mL, batch 160001). This also demonstrated preservative efficacy against microorganisms.

[0521] The same batch was tested again after a 36-month period, and compliance was demonstrated. The results are shown in Table 12. [Table 12]

[0522] Uniformity test Homogeneity of the suspension is an important attribute, stemming from the properties of the religlitazone active ingredient and its concentration in the formulation. Insufficient homogeneity of the suspension can negatively impact the reliability of the dosage.

[0523] The homogeneity of the selected formulations was investigated in representative batch samples of religlitazone 13.66 mg / mL oral suspension (batch 160001) after shaking the bottles by hand for 30 seconds (this is a recommended procedure before extracting clinical doses). Ten bottles were analyzed in duplicate. These bottles were randomly sampled at time intervals during the bottle filling process for this batch. These results are shown in Table 13. All data obtained were within the range of 100 ± 5% for the religlitazone assay and 100 ± 10% for the sodium benzoate assay. [Table 13]

[0524] The results indicate that this bulk test formulation (13.66 mg / mL religlitazone, 1.0 mg / mL sodium benzoate) exhibits the appropriate homogeneity as tested in clinical-style dispensing bottles.

[0525] The results support the homogeneity of the religlitazone oral suspension in a multi-dose container after initial resting. These are in complete agreement with the thixotropic nature of this formulation. Religlitazone content was measured in upright and inverted samples from the same batch and aging, and was 101.4% and 99.8%, respectively, after 30 seconds of shaking.

[0526] Furthermore, uniformity was checked for each batch bulk, and sampled samples taken at different points in the manufacturing process were tested.

[0527] The attribute of the absence of sediment is considered unnecessary to include in stability testing, as the presence of sediment would indicate heterogeneity. Homogeneity is always ensured by shaking for 30 seconds before administration, which is included in the instructions accordingly.

[0528] Syringe Dosage Test A syringe dispensing test was conducted to determine the accuracy of dispensing religlitazone oral suspension within the range of 0.5 to 10 mL using a 10 mL syringe. For the test, 10 syringes (n=10) were filled to the selected nominal volume and injected in a single dose. The dispensing test was an in-house method that faithfully reproduced the procedure performed by a patient.

[0529] Considering the density of the specific religlitazone oral suspension batch used in this study (GMP batch 170001 ESC, density 1.04 g / mL used in the Phase 2 / 3 clinical trial), the volume of religlitazone oral suspension dispensed was directly weighed, and the results were converted to volume. This provided a mean range as a measure of accuracy and precision in use. The study results presented in Table 14 show a mean syringe dose delivery range (precision / accuracy) of ±0.03 mL at 0.5% RSD under the tested conditions. This is within the manufacturer's tolerance range of ±0.59 mL for a 10 mL syringe. [Table 14]

[0530] The selected 10 mL syringe was shown to be suitable for administering 13.66 mg / mL of religlitazone oral suspension along the full dosing range of 0.5–10 mL.

[0531] Other properties of oral suspension Dissolved fraction: Based on the inherent physicochemical properties of religlitazone HCl, the fraction dissolved at the oral suspension pH should be negligible. This formulation contains a viscous matrix that provides elasticity to the suspension, which hinders reliable direct measurement of religlitazone in the aqueous phase of the oral suspension. Therefore, a dummy determination was performed during formulation development to simulate a worst-case scenario. The dissolved religlitazone was measured in a composition that mimics a 13.66 mg / mL oral suspension of religlitazone but lacks a viscous system (i.e., aqueous solution), thus allowing for centrifugation. Even under these conditions, the dissolved religlitazone did not exceed 0.5% of the total dose.

[0532] Particle Size Distribution / Dissolution: As part of the dissolution method development, the effect of DS particle size on the dissolution rate of religlitazone oral suspension was evaluated. Based on the results, dissolution was determined to meet the specification acceptance criteria with DS PSD of D90 = 132 μm. Furthermore, the release and stability results of religlitazone oral suspension under both accelerated and long-term conditions were in accordance with the proposed specification of 80% (Q) or higher in 30 minutes.

[0533] Manufacturing process The pharmaceutical formulations described herein may be prepared according to the manufacturing process flowcharts shown in Figures 12-14.

[0534] Example 5 [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] Synthesis of impurity B [ka] Compound 1 (see WO2018 / 116281) was dissolved in THF, and 1M TBAF solution in THF was added. The mixture was stirred overnight at room temperature (rt) and concentrated under vacuum. The resulting crude solid was then dissolved in DCM, and the reaction mixture was filtered over a silica plug (AcOEt / Tol 8 / 2). The filtrate was concentrated under vacuum to obtain impurity B as a yellow oily substance. The structure of impurity B is as follows: 1 This was confirmed by NMR and HPLC-MS.

[0535] Synthesis of impurity C [ka] Compound 1 was dissolved in acetonitrile under a nitrogen atmosphere at 50°C. 30% aqueous NaOH solution was added, and the solution was stirred at 50°C for 5 hours. The reaction mixture was quenched by adding aqueous KHSO4 solution, the organic phase was diluted with diethyl ether, separated, and dried to obtain a solution of Compound 2.

[0536] Iodine was added in small amounts to a solution of compound 2 under a nitrogen atmosphere, and the solution was stirred overnight at room temperature. The reaction mixture was quenched with a thiosulfate solution, the phases were separated, dried, and concentrated to obtain crude compound 3.

[0537] Crude compound 3 was dissolved in THF and deprotected with HCl to produce compound 4 (impurity C), which was further purified by reverse-phase chromatography. The structure of impurity C is as follows: 1 This was confirmed by NMR and HPLC-MS. See Figure 15.

[0538] Synthesis of impurity D [ka] Compound 1 was dissolved in acetonitrile under a nitrogen atmosphere at 50°C. 30% aqueous NaOH solution was added, and the solution was stirred at 50°C for 4 hours. The reaction mixture was quenched by adding aqueous KHSO4 solution, the organic phase was diluted with iPrOAc, separated, dried, and concentrated to obtain crude compound 2.

[0539] Half of crude compound 2 was dissolved in THF and cooled to 2–5°C. The solution of the borane THF complex was then added dropwise while maintaining the temperature. The solution was then stirred at 5°C for 2 hours and at room temperature for 2 hours. Methanol was slowly added to quench the reaction, and the mixture was stirred at room temperature over the weekend. The mixture was concentrated to obtain compound 3 as the crude product.

[0540] To a solution of compound 2 in THF, compound 3 and iodine were added in small amounts. The mixture was stirred overnight at room temperature. The reaction was quenched by adding an aqueous solution of thiosulfate, then water and sorbitol were added, and the phases were separated. The organic phase was dried and concentrated to obtain compound 4 as the crude product.

[0541] A crude mixture of compound 4 was dissolved in THF, and an aqueous HCl solution was slowly added. The solution was stirred at room temperature for 3 hours. A saturated aqueous bicarbonate solution was added, and the mixture was concentrated under vacuum.

[0542] The residue was incorporated into methanol and filtered, and the crude product was purified by reverse-phase chromatography. A second purification was performed via preparative chromatography (SFC) to obtain pure compound 5 (impurity D). The structure of impurity D is as follows: 1 This was confirmed by NMR and HPLC-MS.

[0543] Synthesis of impurity H [ka] Compound 1 was first treated with NaNO2 and HCl in a mixture of acetone and water at 10°C, and then with AcONa, acrylonitrile, and CuCl 2. 2H2O was added, and the reaction mixture was heated at 40°C for 4 hours to obtain compound 2.

[0544] Compound 2 was treated with AcSK in a THF / DMF mixture at room temperature for 12 hours to obtain compound 3.

[0545] BH3.THF was added to a solution of compound 3 in THF at 0°C, and the reaction mixture was heated to room temperature for 12 hours to obtain compound 4.

[0546] Compound 4 was coupled with CDI in acetonitrile using K2CO3 as a base. The reaction mixture was heated at 70°C for 18 hours to obtain compound 5.

[0547] Compound 5 was demethylated using BBr3 in DCM at room temperature for 3 hours to obtain compound 6.

[0548] Compound 8 was obtained by the Mitsunobu reaction (see IRP2-1, WO2018 / 116281) between compound 6 and compound 7 using DIAD and PPh3 in THF over 12 hours from 0°C to room temperature.

[0549] Impurity H was obtained by deprotecting compound 8 under acidic conditions (using HCl).

[0550] The structure of impurity H is, 1 This was confirmed by NMR and HPLC-MS.

[0551] Although the disclosure has been fully described here, it will be understood by those skilled in the art that the same can be done within a broad and equivalent range of conditions, formulations, and other parameters without affecting the scope of the present invention or any embodiment thereof.

[0552] Other embodiments of this disclosure will be apparent to those skilled in the art in consideration of the specification and practice of the invention disclosed herein. This specification and examples are for illustrative purposes only, and the true scope and spirit of the invention are intended to be shown by the following claims.

[0553] All patents, patent applications, and publications cited herein are incorporated herein in their entirety by reference.

Claims

1. (i) X-ray powder diffraction (XRPD) patterns using CuKα radiation, having peaks at 19.1, 21.0, and 23.8 degrees 2θ, and having a 2θ value of ±0.2 degrees 2θ, or (ii) X-ray powder diffraction patterns with d-spacing of 4.65, 4.23, and 3.73 Å using CuKα radiation, or (iii) 3056, 2960, 2992, 1735, 1608, 1205, 824, 656, and 170 cm －１ An FT-Raman spectrum having a peak at cm －１ The value is ±4 cm －１ This is the FT-Raman spectrum, or (iv) A melting point having an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, based on differential scanning calorimetry, or A crystalline religlitazone hydrate form C characterized by having a combination of (i), (ii), (iii), and / or (iv).

2. The crystalline religlitazone hydrate form C according to claim 1, characterized by having an XRPD pattern using CuKα radiation, having peaks at 19.1, 21.0, and 23.8 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

3. The crystalline religlitazone hydrate form C according to claim 1 or 2, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 12.7, 15.4, and 25.9 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

4. The crystalline religlitazone hydrate form C according to any one of claims 1 to 3, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 16.9, 21.3, and 21.6 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

5. The crystalline religlitazone hydrate form C according to any one of claims 1 to 4, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 7.7, 24.6, and 28.0 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

6. The crystalline religlitazone hydrate form C according to any one of claims 1 to 5, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 10.6, 24.9, and 27.3 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

7. The crystalline religlitazone hydrate form C according to any one of claims 1 to 6, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 9.2, 19.8, and 29.6 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

8. The crystalline religlitazone hydrate form C according to claim 1, characterized by having d intervals of 4.65, 4.23, and 3.73 Å, using CuKα radiation.

9. Crystalline religlitazone hydrate form C according to any one of claims 1 or 8, further characterized by having d intervals of 6.99, 5.74, and 3.44 Å using CuKα radiation.

10. Crystalline religlitazone hydrate form C according to any one of claims 1, 8, or 9, further characterized by having d intervals of 5.24, 4.17, and 4.11 Å using CuKα radiation.

11. Crystalline religlitazone hydrate form C according to any one of claims 1 or 8 to 10, further characterized by having d intervals of 11.41, 3.62, and 3.18 Å using CuKα radiation.

12. Crystalline religlitazone hydrate form C according to any one of claims 1 or 8 to 11, further characterized by having d intervals of 8.32, 3.57, and 3.26 Å using CuKα radiation.

13. Crystalline religlitazone hydrate form C according to any one of claims 1 or 8 to 12, further characterized by having d intervals of 9.60, 4.48, and 3.02 Å using CuKα radiation.

14. 3056, 2960, 2992, 1735, 1608, 1205, 824, 656, and 170 cm －１ An FT-Raman spectrum having a peak at cm －１ The value is ±4 cm －１ The crystalline religlitazone hydrate form C according to claim 1, characterized by having an FT-Raman spectrum.

15. Crystalline religlitazone hydrate form C according to any one of claims 1 to 14, characterized by having a mass loss of approximately 4.3% between 40°C and 160°C, based on thermogravimetric analysis.

16. Crystalline religlitazone hydrate form C according to any one of claims 1 to 15, characterized in that it has a melting point having an onset temperature of approximately 149.45°C and a peak temperature of approximately 153.50°C, based on differential scanning calorimetry.

17. A pharmaceutical composition comprising an aqueous suspension of crystalline religlitazone hydrate form C according to any one of claims 1 to 16, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

18. (i) X-ray powder diffraction (XRPD) patterns using CuKα radiation, having peaks at 18.8, 21.1, and 23.8 degrees 2θ, and having a 2θ value of ±0.2 degrees 2θ, or (ii) X-ray powder diffraction patterns with d-spacing of 4.73, 4.21, and 3.73 Å using CuKα radiation, or (iii) A melting point having an onset temperature of approximately 149.34°C and a peak temperature of approximately 153.56°C, based on differential scanning calorimetry, or Crystalline religlitazone form B, characterized by having a combination of (i), (ii), and / or (iii).

19. Crystalline religlitazone morph B according to claim 18, characterized in that it has an XRPD pattern using CuKα radiation, having peaks at 18.8, 21.1, and 23.8 degrees 2θ, and the 2θ value is ±0.2 degrees 2θ.

20. Crystalline religlitazone morph B according to claim 18 or 19, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 16.6, 21.8, and 24.7 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

21. Crystalline religlitazone form B according to any one of claims 18 to 20, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 15.2, 25.4 and 28.0 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

22. Crystalline religlitazone morph B according to any one of claims 18 to 21, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 9.0, 19.8, and 30.8 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

23. Crystalline religlitazone morph B according to any one of claims 21 to 22, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 10.5, 20.1, and 26.9 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

24. Crystalline religlitazone morph B according to any one of claims 21 to 23, further characterized by having an XRPD pattern using CuKα radiation, having peaks at 12.4, 23.5, and 29.1 degrees 2θ, wherein the 2θ value is ±0.2 degrees 2θ.

25. Crystalline religlitazone form B according to claim 18, characterized by having d intervals of 4.73, 4.21, and 3.73 Å, using CuKα radiation.

26. Crystalline religlitazone form B according to any one of claim 18 or 25, further characterized by having d intervals of 5.33, 4.07, and 3.60 Å using CuKα radiation.

27. Crystalline religlitazone form B according to any one of claims 18, 25, or 26, further characterized by having d intervals of 5.84, 3.50, and 3.18 Å using CuKα radiation.

28. Crystalline religlitazone form B according to any one of claims 18 or 25-27, further characterized by having d intervals of 9.78, 4.48, and 2.90 Å using CuKα radiation.

29. Crystalline religlitazone form B according to any one of claims 18 or 25-28, further characterized by having d intervals of 8.43, 4.41, and 3.31 Å using CuKα radiation.

30. Crystalline religlitazone form B according to any one of claims 18 or 25-29, further characterized by having d intervals of 7.11, 3.79, and 3.06 Å using CuKα radiation.

31. Crystalline religlitazone form B according to any one of claims 18 to 30, characterized in that it has a melting point having an onset temperature of approximately 149.34°C and a peak temperature of approximately 153.56°C, based on differential scanning calorimetry.

32. Crystalline religlitazone form B according to any one of claims 18 to 31, characterized by having a mass loss of approximately 0.9% between 40°C and 100°C, based on thermogravimetric analysis.

33. A pharmaceutical composition comprising an aqueous suspension of crystalline religlitazone form B according to any one of claims 18 to 32, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

34. (a) Religlitazone in an amount of 0.01% w / v to 5% w / v, a pharmaceutically acceptable salt thereof, or a hydrate thereof, (b) One or more cellulose derivatives in an amount of 0.01% w / v to 2% w / v, having a viscosity of 1500 to 4500 mPa*s, preferably 1500 to 3500 mPa*s, more preferably 1500 to 3000 mPa*s, as measured by the Brookfield viscosity method, (c) A pharmaceutical preparation containing an appropriate amount of water until the total volume reaches 100%.

35. The pharmaceutical formulation according to claim 34, wherein the religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is (i) an XRPD pattern using CuKα radiation having peaks at 18.8, 21.1, and 23.8 degrees 2θ, with a 2θ value of ±0.2 degrees 2θ, or (ii) a religlitazone form B having a mass loss of about 0.9% between 40°C and about 100°C based on thermogravimetric analysis.

36. The pharmaceutical formulation according to claim 34, wherein the religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is (i) an XRPD pattern using CuKα radiation having peaks at 19.1, 21.0, and 23.8 degrees 2θ, with a 2θ value of ±0.2 degrees 2θ, or (ii) a religlitazone hydrate form C having a mass loss of about 4.3% between 40°C and about 160°C, based on thermogravimetric analysis.

37. The pharmaceutical preparation according to claim 34, wherein religlitazone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is present in an amount of 1% w / v to 2% w / v.

38. The pharmaceutical preparation according to claim 35, wherein the religlitazone form B is present in an amount of 1% w / v to 2% w / v.

39. The pharmaceutical preparation according to claim 36, wherein the religlitazone hydrate form C is present in an amount of 1% w / v to 2% w / v.

40. The pharmaceutical preparation according to any one of claims 34 to 39, wherein the one or more cellulose derivatives comprises microcrystalline cellulose, sodium carboxymethylcellulose, or a mixture thereof.

41. A pharmaceutical preparation according to any one of claims 34 to 40, further comprising one or more pH adjusting agents.

42. The pharmaceutical preparation according to claim 41, wherein the one or more pH adjusting agents include sodium citrate, citric acid monohydrate, or a mixture thereof.

43. A pharmaceutical preparation according to any one of claims 34 to 42, further comprising one or more preservatives in an amount of 0.001% w / v to 1.0% w / v.

44. The pharmaceutical preparation according to claim 43, wherein the one or more preservatives include sodium benzoate.

45. A pharmaceutical preparation according to any one of claims 34 to 44, further comprising one or more flavoring agents in an amount of 0.001% w / v to 3% w / v.

46. The pharmaceutical preparation according to claim 45, wherein the one or more flavoring agents include strawberry flavoring.

47. A pharmaceutical preparation according to any one of claims 34 to 46, further comprising one or more sweeteners in an amount of 0.01% w / v to 15% w / v.

48. The pharmaceutical preparation according to claim 47, wherein the sweetener is sorbitol, sodium saccharin, or a mixture thereof.

49. The pharmaceutical preparation according to any one of claims 34 to 48, wherein the pH of the preparation is 3.5 to 4.

5.

50. The pharmaceutical preparation according to claim 49, wherein the pH of the preparation is approximately 4.

51. The pharmaceutical formulation according to any one of claims 34 to 50, wherein the viscosity of the formulation is greater than 50 mPa*s and less than 5000 mPa*s, preferably less than 4,500 mPa*s.

52. (a) Religlitazone in an amount of 1.0% to 2.0% w / v, a pharmaceutically acceptable salt or hydrate thereof, preferably in hydrate form C, (b) Microcrystalline cellulose of about 1% w / v, (c) Approximately 0.5% w / v sodium carboxymethylcellulose, (d) an appropriate amount of water until the total volume reaches 100%, And, optionally, (e) Sorbitol powder with approximately 8% w / v (f) Approximately 0.05% w / v sodium saccharin, (g) Approximately 0.1% w / v sodium benzoate, (h) Approximately 0.5% w / v sodium citrate, (i) Approximately 0.1% w / v citric acid monohydrate, (j) Approximately 0.015% w / v strawberry flavoring, (k) The pharmaceutical preparation according to claim 34, comprising an aqueous solution of 0.2 M citric acid monohydrate at approximately 1% w / v.

53. (a) Approximately 1.5% w / v religlitazone hydrochloride, preferably form A. (b) Sorbitol powder with approximately 8% w / v (c) Microcrystalline cellulose of approximately 1% w / v, (d) Approximately 0.5% w / v sodium carboxymethylcellulose, (e) Approximately 0.05% w / v sodium saccharin, (f) Approximately 0.1% w / v sodium benzoate, (g) Approximately 0.5% w / v sodium citrate, (h) Approximately 0.1% w / v citric acid monohydrate, (i) Approximately 0.015% w / v strawberry flavoring, (j) an aqueous solution of 0.2 M citric acid monohydrate at approximately 1% w / v, and (k) A pharmaceutical preparation prepared by mixing an appropriate amount of water until the total volume reaches 100%.

54. For use in the treatment of a patient in need of treatment for a disease or disorder which is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disease, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disease, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder, a crystalline religlitazone hydrate form C according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17, or a crystalline religlitazone form B according to any one of claims 18 to 32, or a pharmaceutical composition according to claim 33, or a pharmaceutical preparation according to any one of claims 34 to 53.

55. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 54, wherein the disease or disorder is a central nervous system disease or disorder.

56. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 55, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, seizures, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemia, fatty acid disorders, and genetic mitochondrial disorders.

57. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 56, wherein the central nervous system disease or disorder is a neurodegenerative disease.

58. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 57, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative disorders and cerebral iron storage disorders (NBIA), neuromuscular disorders, and motor neuron diseases.

59. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 58, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenal spinal neuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

60. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 59, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

61. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 58, wherein the degenerative ataxia is Friedreich's ataxia.

62. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 58, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS) - Marie-Tooth disease, Guillain-Barré syndrome, and adrenal spinal neuropathy (AMN).

63. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 56, wherein the cerebrovascular disease is selected from the group consisting of whole-cerebral ischemia or local ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

64. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 56, wherein the viral disease is selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, poliovirus infection, herpes simplex, and varicella-zoster.

65. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 55, wherein the central nervous system disease or disorder is a rare metabolic disease selected from the group consisting of organic acidosis, fatty acid disorders, and genetic mitochondrial disorders.

66. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 54, wherein the disease or disorder is a mitochondrial disease.

67. The aforementioned mitochondrial diseases include Rett syndrome, Alpers disease, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, Lie-like syndrome, maternal Leigh syndrome (MILS), mitochondrial depletion syndrome (MDS), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and myoclosis with red rag fibers. Nusal epilepsy (MERRF), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, chronic progressive extraocular muscle palsy (CPEO), autosomal dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), mitochondrial myopathy, cardiomyopathy, mitochondrial encephalopathy, myoclonus epilepsy, maternal inherited diabetes mellitus and hearing impairment (MIDD), ataxic neuropathy spectrum, 3-methylglucan Unresolved genetic defects include taconic aciduria, sensorineural hearing loss, neuroradiological findings of Lee-like syndrome (MEGDEL), SURF1 (COX deficiency Lee syndrome due to complex IV surfactant protein deficiency), oxidative phosphorylation disorders, Barth syndrome, lethal infant cardiomyopathy (LIC), pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, and disturbances in pyruvate oxidation and ATP+PCr production rates. Isolated or combined OXPHOS deficiency, POLG2 mutation, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatinine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, lactic acidosis, leukoencephalopathy and elevated lactic acid (LBSL) with brainstem and spinal cord involvement, Luft's disease, carnitine palmitoyltransferase (CPT I or CPTII) A crystalline religlitazone form or pharmaceutical composition or pharmaceutical preparation according to claim 66, which is a primary mitochondrial disorder selected from the group consisting of deficiencies, short-chain acyl-CoA dehydrogenase deficiency (SCAD), short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), multiple acyl-CoA dehydrogenase deficiency (MADD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), trifunctional protein (TFP) deficiency, and glutariculosis type II.

68. The crystalline relitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 67, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome, dominant optic atrophy (DOA), autosomal dominant optic atrophy (ADOA), complex I deficiency, Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with red ragged fibers (MERRF), mitochondrial neurogastroenterological encephalopathy syndrome (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), Pearson syndrome, and chronic progressive extraocular palsy (CPEO).

69. The aforementioned mitochondrial diseases include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (BMD), congenital myopathy, glycogen storage disorders, spinal and bulbar muscular atrophy (SBMA), arginosuccinic aciduria, autism spectrum disorder (ASD), autoimmune diseases of the skin (such as pemphigus vulgaris and lupus), methylmalonic aciduria and propionic aciduria, disorders or purine and / or pyrimidine synthesis, facioscapulohumeral muscular dystrophy (FSHD), and congenital muscle The crystalline religlitazone form or pharmaceutical composition or pharmaceutical preparation according to claim 66, which is a secondary mitochondrial disorder selected from the group consisting of dystrophy, collagen VI muscular dystrophy (e.g., Ulrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal and Emery-Dreyfus type), DiGeorge syndrome, and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathy, Charcot-Marie-Tooth (CMT) neuropathy, and drug-induced peripheral neuropathy).

70. The crystalline religlitazone form or pharmaceutical composition according to claim 54, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or interstitial lung disease.

71. A crystalline religlitazone form or pharmaceutical composition or pharmaceutical preparation according to claim 70, for treating a patient who requires treatment for an inflammatory lung condition or disease caused by a viral infection.

72. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 71, wherein the viral infection is human coronavirus infection, influenza virus infection, or HIV virus infection.

73. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 72, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant strain thereof.

74. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 73, wherein the human coronavirus is SARS-CoV-2.

75. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 74, wherein the human coronavirus is a mutant strain of SARS-CoV-2.

76. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to any one of claims 71 to 75, wherein the inflammatory lung condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

77. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 76, wherein the inflammatory lung condition or disease caused by the viral infection is acute respiratory distress syndrome.

78. A crystalline religlitazone form or pharmaceutical composition or pharmaceutical preparation according to claim 70 for treating acute pulmonary inflammation in a patient requiring treatment for the same.

79. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 78, wherein the acute inflammation of the lung is caused by a bacterial infection.

80. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 78, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

81. A crystalline religlitazone form or pharmaceutical composition or pharmaceutical preparation according to claim 70 for treating interstitial lung disease in patients requiring treatment for interstitial lung disease.

82. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 70, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

83. The crystalline religlitazone form, pharmaceutical composition, or pharmaceutical preparation according to claim 54, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

84. A method for producing crystalline religlitazone hydrate form C as described in claim 1, (a) A step of providing a solution or suspension by providing religlitazone hydrochloride, preferably form A, in water or a mixture of water and an alcohol solvent. (b) Optionally, the mixture from step (a) is heated to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C. (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and (d) A method comprising the step of isolating the solid obtained in step (c) to provide form C of religlitazone.

85. A method for producing crystalline religlitazone form B as described in claim 18, (a) A step of providing a solution or suspension by providing religlitazone hydrochloride, preferably form A, in water or a mixture of water and an alcohol solvent. (b) Optionally, the mixture from step (a) is heated to a suitable temperature, preferably 40°C to 100°C, more preferably 50°C to 85°C. (c) Optionally, a step of cooling the solution or suspension obtained from step (b) to room temperature, and (d) A method comprising the step of isolating and drying the solid obtained in step (c) to provide religlitazone form B.

86. (ii) The kit comprising a pharmaceutical preparation according to any one of claims 34 to 53 in a container, and a label including instructions on how to use the kit.

87. The kit according to claim 86, wherein the label is approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health, Labour and Welfare (MHLW).

88. The kit according to claim 86 or 87, further comprising a graduated oral syringe with markings of 5 mL, 10 mL, 12 mL, or 15 mL.

89. 99.0–99.9 wt / wt% religlitazone (free base), religlitazone hydrochloride, or religlitazone hydrate, and (i) 0.0001 to 0.2 wt / wt% of (Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione, or its hydrochloride salt, (ii) 0.0001 to 0.2 wt / wt% of 2,2'-disulfanediylbis(3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride salt, (iii) 0.0001 to 0.2 wt / wt% of 2-((1-hydroxy-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propan-2-yl)disulfanyl)-3-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)phenyl)propanoic acid, or its hydrochloride salt, and / or (iv) A composition comprising 0.0001 to 0.15 wt / wt% of 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidined-2-one or its hydrochloride salt.

90. The composition according to claim 89, comprising religlitazone hydrochloride form A.

91. The composition according to claim 89, comprising religlitazone form B.

92. The composition religlitazone hydrate form C according to claim 89.

93. (a) The composition according to any one of claims 89 to 92 in an amount of 0.01% w / v to 5% w / v, (b) One or more cellulose derivatives in an amount of 0.01% w / v to 2% w / v, having a viscosity of 1500 to 4500 mPa*s, preferably 1500 to 3500 mPa*s, more preferably 1500 to 3000 mPa*s, as measured by the Brookfield viscosity method, and (c) A pharmaceutical preparation containing an appropriate amount of water until the total volume reaches 100%.

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