Granules for suspension

Abstract

The present disclosure provides granules for suspension. Specifically, the present disclosure is a pharmaceutical composition comprising: a compound represented by formula 1 or a pharmaceutically acceptable salt or solvate thereof; a binder; and a dispersant. The binder includes a binder selected from the group consisting of a cellulose-based binder, a povidone-based binder, a vinyl alcohol-based binder, and a polysaccharide thickener-based binder. The dispersant is selected from the group consisting of an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose-based dispersant, and a fatty acid ester salt dispersant.

Description

Granules for suspension

[0001] The present disclosure provides pharmaceutical compositions. The pharmaceutical compositions may include granules for suspension.

[0002] WO 2009 / 061744 discloses methods for treating or inhibiting mitochondrial diseases such as Friedreich's ataxia (FRDA), Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Kearns-Sayre syndrome (KSS), and other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and pervasive developmental disorders such as autism, and describes compounds useful in the methods, such as 4-(p-quinolyl)-2-hydroxybutanamide derivatives. Also described is the synthesis of racemic 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide from racemic Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).

[0003] WO 2016 / 100579 describes anhydrate, hydrate, and solvate polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide and methods of using such compositions for the treatment or prevention of oxidative stress disorders, including mitochondrial disorders, disorders of reduced energy processing, neurodegenerative diseases, and diseases of aging, and methods of making such polymorphic and amorphous forms.

[0004] WO 2021 / 167095 describes an optically resolved Trolox intermediate and a method for its preparation.

[0005] International Publication No. 2009 / 061744 International Publication No. 2016 / 100579 International Publication No. 2021 / 167095

[0006] As a result of extensive research, the present inventors have discovered a granule for suspension which contains a compound represented by formula 1 or a pharmaceutically acceptable salt or solvate thereof and which has good dispersibility and inhibits hydrate formation and crystal growth.

[0007] For example, the present disclosure provides the following: (Term 1) Equation 1: or a pharmaceutically acceptable salt or solvate thereof; a binder; and a dispersing agent. (Item 2) The pharmaceutical composition of Item 1, wherein the binder is selected from the group consisting of a cellulose-based binder, a povidone-based binder, a vinyl alcohol-based binder, and a thickening polysaccharide binder. (Item 3) The pharmaceutical composition of Item 2, wherein the cellulose-based binder is selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose. (Item 4) The pharmaceutical composition of Item 2, wherein the povidone-based binder is selected from the group consisting of povidone and copovidone. (Item 5) The pharmaceutical composition of Item 2, wherein the vinyl alcohol-based binder is selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer. (Item 6) The pharmaceutical composition of Item 2, wherein the thickening polysaccharide binder is xanthan gum. (Item 7) The pharmaceutical composition according to any one of Items 1 to 6, wherein the dispersant is selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants. (Item 8) The pharmaceutical composition according to Item 7, wherein the inorganic salt dispersant comprises a dispersant selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate. (Item 9) The pharmaceutical composition according to Item 7, wherein the ether dispersant comprises polyethylene glycol 6000. (Item 10) The pharmaceutical composition according to Item 7, wherein the starch dispersant comprises corn starch. (Item 11) The pharmaceutical composition according to Item 7, wherein the cellulose-based dispersant comprises a dispersant selected from the group consisting of microcrystalline cellulose-carmellose sodium, carmellose, and carmellose calcium. (Item 12) The pharmaceutical composition according to Item 7, wherein the fatty acid ester salt dispersant comprises sodium stearyl fumarate. (Item 13) The pharmaceutical composition according to Item 1, wherein the binder comprises a cellulose-based binder, and the dispersant comprises a dispersant selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants. (Item 14) The pharmaceutical composition according to Item 1, wherein the binder comprises:Item 15. The pharmaceutical composition of Item 1, wherein the binder is selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersing agent is selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carmellose, crystalline cellulose-carmellose sodium, magnesium aluminum metasilicate, sodium stearyl fumarate, and carmellose calcium. Item 16. The pharmaceutical composition of Item 1, wherein the binder is selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersing agent is selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, and carmellose. (Item 17) The pharmaceutical composition of Item 1, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises a dispersing agent selected from the group consisting of light anhydrous silicic acid, corn starch, carmellose, polyethylene glycol 6000, microcrystalline cellulose-carmellose sodium, magnesium aluminometasilicate, sodium stearyl fumarate, and carmellose calcium. (Item 18) The pharmaceutical composition of Item 1, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises a dispersing agent selected from the group consisting of light anhydrous silicic acid, corn starch, and carmellose. (Item 19) The pharmaceutical composition of Item 1, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises light anhydrous silicic acid. (Item 20) The pharmaceutical composition of Item 1, wherein the binder comprises hypromellose, and the dispersing agent comprises a dispersing agent selected from the group consisting of light anhydrous silicic acid and polyethylene glycol 6000. (Item 21) The pharmaceutical composition according to Item 1, wherein the binder comprises hypromellose, and the dispersing agent comprises light anhydrous silicic acid. (Item 22) The pharmaceutical composition according to Item 1, wherein the binder comprises methylcellulose,Item 1: The pharmaceutical composition according to Item 1, wherein the dispersing agent comprises light anhydrous silicic acid. (Item 23) The pharmaceutical composition according to Item 1, wherein the binder comprises a povidone-based binder, and wherein the dispersing agent comprises a dispersing agent selected from the group consisting of inorganic salt dispersing agents, ether dispersing agents, starch dispersing agents, cellulose-based dispersing agents, and fatty acid ester salt dispersing agents. (Item 24) The pharmaceutical composition according to Item 1, wherein the binder comprises a povidone-based binder, and wherein the dispersing agent comprises a dispersing agent selected from the group consisting of inorganic salt dispersing agents and cellulose-based dispersing agents. (Item 25) The pharmaceutical composition according to Item 1, wherein the binder comprises copovidone, and wherein the dispersing agent comprises a dispersing agent selected from the group consisting of light anhydrous silicic acid and crystalline cellulose-carmellose sodium. (Item 26) The pharmaceutical composition according to Item 1, wherein the binder comprises a cellulose-based binder, and wherein the dispersing agent comprises an inorganic salt dispersing agent. (Item 27) The pharmaceutical composition of Item 26, wherein the binder comprises a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersing agent comprises a dispersing agent selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate. (Item 28) The pharmaceutical composition of Item 27, wherein the binder comprises a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersing agent comprises light anhydrous silicic acid. (Item 29) The pharmaceutical composition of Item 28, wherein the binder comprises a binder selected from the group consisting of hydroxypropyl cellulose and hypromellose, and the dispersing agent comprises light anhydrous silicic acid. (Item 30) The pharmaceutical composition of Item 1, wherein the binder comprises a cellulose-based binder, and the dispersing agent comprises an ether dispersing agent. (Item 31) The pharmaceutical composition of Item 30, wherein the binder comprises a binder selected from the group consisting of hydroxypropyl cellulose and hypromellose, and the dispersing agent comprises polyethylene glycol 6000. (Item 32) The pharmaceutical composition of Item 31, wherein the binder comprises hypromellose, and the dispersing agent comprises polyethylene glycol 6000. (Item 33) The pharmaceutical composition of Item 31, wherein the binder comprises a cellulose-based binder, and the dispersing agent comprisesThe pharmaceutical composition of Item 1, comprising a starch-based dispersing agent. (Item 34) The pharmaceutical composition of Item 33, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises corn starch. (Item 35) The pharmaceutical composition of Item 1, wherein the binder comprises a cellulose-based binder, and the dispersing agent comprises a cellulose-based dispersing agent. (Item 36) The pharmaceutical composition of Item 35, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises a dispersing agent selected from carmellose, microcrystalline cellulose-carmellose sodium, and carmellose calcium. (Item 37) The pharmaceutical composition of Item 36, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises a dispersing agent selected from microcrystalline cellulose-carmellose sodium, and carmellose calcium. (Item 38) The pharmaceutical composition of Item 36, wherein the binder comprises hydroxypropyl cellulose, and the dispersing agent comprises a dispersing agent selected from microcrystalline cellulose-carmellose sodium, and carmellose calcium. (Item 39) The pharmaceutical composition of Item 1, wherein the binder comprises a cellulose-based binder, and the dispersant comprises a fatty acid ester salt dispersant. (Item 40) The pharmaceutical composition of Item 39, wherein the binder comprises hydroxypropyl cellulose, and the dispersant comprises sodium stearyl fumarate. (Item 41) The pharmaceutical composition of Item 1, wherein the binder comprises a povidone-based binder, and the dispersant comprises a cellulose-based dispersant. (Item 42) The pharmaceutical composition of Item 41, wherein the binder comprises copovidone, and the dispersant comprises microcrystalline cellulose-carmellose sodium. (Item 43) The pharmaceutical composition of Item 1, wherein the binder comprises a povidone-based binder, and the dispersant comprises an inorganic salt dispersant. (Item 44) The pharmaceutical composition according to Item 43, wherein the binder comprises a binder selected from the group consisting of copovidone, povidone (designated K value: 29-32), and povidone (designated K value: 17), and the dispersing agent comprises light anhydrous silicic acid. (Item 45) The pharmaceutical composition according to Item 44, wherein the binder comprises a binder selected from the group consisting of copovidone and povidone (designated K value: 29-32), and the dispersing agent comprises light anhydrous silicic acid. (Item 46) The pharmaceutical composition according to Item 44, wherein the binder comprises a vinyl alcohol-based binder,Item 1: The pharmaceutical composition according to Item 1, wherein the dispersing agent comprises an inorganic salt dispersing agent. (Item 47) The pharmaceutical composition according to Item 46, wherein the binder comprises a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer, and wherein the dispersing agent comprises light anhydrous silicic acid. (Item 48) The pharmaceutical composition according to Item 47, wherein the binder comprises a polyvinyl alcohol-polyethylene glycol graft copolymer, and wherein the dispersing agent comprises light anhydrous silicic acid. (Item 49) The pharmaceutical composition according to Item 1, wherein the binder comprises a vinyl alcohol-based binder, and wherein the dispersing agent comprises a cellulose-based dispersing agent. (Item 50) The pharmaceutical composition according to Item 49, wherein the binder comprises a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer, and wherein the dispersing agent comprises microcrystalline cellulose-carmellose sodium. (Item 51) The pharmaceutical composition of Item 1, wherein the binder comprises a thickening polysaccharide binder, and the dispersing agent comprises an inorganic salt dispersing agent. (Item 52) The pharmaceutical composition of Item 51, wherein the binder comprises xanthan gum, and the dispersing agent comprises light anhydrous silicic acid. (Item 53) The pharmaceutical composition of any one of Items 1 to 52, wherein the pharmaceutical composition comprises a suspending agent. (Item 54) The pharmaceutical composition of Item 53, wherein the suspending agent comprises a carboxyvinyl polymer. (Item 55) The pharmaceutical composition of any one of Items 1 to 54, wherein the pharmaceutical composition comprises a sweetener. (Item 56) The pharmaceutical composition of Item 55, wherein the sweetener comprises sucralose. (Item 57) The pharmaceutical composition of any one of Items 1 to 56, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of binder per 1000 mg of the compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof. (Item 58) The pharmaceutical composition according to any one of Items 1 to 57, wherein the pharmaceutical composition comprises 0.01 to 10% by weight of a dispersing agent relative to the total weight of the composition. (Item 59) The pharmaceutical composition comprises 1 mg to 1000 mg of a suspending agent per 1000 mg of the compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof.The pharmaceutical composition according to any one of Items 1 to 58. (Item 60) The pharmaceutical composition according to any one of Items 1 to 59, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a sweetener per 1000 mg of the compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof. (Item 61) Granules for suspension for use in the manufacture of a pharmaceutical composition, the granules comprising the pharmaceutical composition according to any one of Items 1 to 60. (Item 62) Granules for suspension according to Item 61, which are granules for use in the preparation of a suspension. (Item 63) Granules for suspension for use in the manufacture of a pharmaceutical composition, the pharmaceutical composition according to any one of Items 1 to 60. (Item 64) Granules for suspension according to Item 63, which are granules for use in the preparation of a suspension. (Item 65) The pharmaceutical composition according to any one of Items 1 to 60, which are granules for use in the preparation of a pharmaceutical composition. (Item 66) The pharmaceutical composition of Item 65, which is a granule for suspension for preparing a suspension. (Item 67) A suspension comprising the pharmaceutical composition of any one of Items 1 to 60, which is a granule for suspension for use in producing a pharmaceutical composition. (Item 68) The pharmaceutical composition of any one of Items 1 to 60, which is in a suspended state. (Item 69) A method for treating or preventing a disease in a subject in need thereof, comprising the step of administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of Items 1 to 60, 65 to 66, or 68, or the suspension of Item 67. (Item 70) A method for producing the pharmaceutical composition of any one of Items 1 to 60, 65 to 66, or 68, or the suspension of Item 67, which comprises the step of mixing the compound, or a pharmaceutically acceptable salt or solvate thereof, with the binder and the dispersant. (Item 71) A method for producing a pharmaceutical composition, comprising the step of mixing the granules for suspension according to any one of Items 61 or 62 with necessary additives and / or a suspension solvent (including, for example, an aqueous solvent such as purified water). (Item 72) A method for preparing a pharmaceutical composition in a medical setting for administration to a subject, comprising the step of mixing the granules for suspension according to any one of Items 63 or 64 with necessary additives and / or a suspension solvent (including, for example, an aqueous solvent such as purified water). (Item 73) A method for treating or suppressing oxidative stress disorders, orThe pharmaceutical composition according to any one of Items 1 to 60, 65, 66 or 68, the granules for suspension according to any one of Items 61 to 64, the suspension according to Item 67, or the method according to any one of Items 69 to 72, for adjusting one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers. (Item 74) Mitochondrial disorders; inherited mitochondrial diseases; Alpers' disease; Barth syndrome; beta-oxidation deficiency; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia (CPEO); CPT I deficiency; CPT II deficiency; Friedreich's ataxia (FA); glutaric aciduria type II; Kearns-Sayre syndrome (KSS); lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCAD); LCHAD; Leigh syndrome; Leigh-like syndrome; Leber's hereditary optic neuropathy (LHON); fatal infantile cardiomyopathy (LIC); Luft's disease; multiple acyl-CoA dehydrogenase deficiency (MAD); medium-chain acyl-CoA dehydrogenase deficiency (MCAD); mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS); myoclonic epilepsy with ragged-red fibers (MERRF); mitochondrial recessive ataxia syndrome (MIRAS); mitochondrial cytopathy,Mitochondrial DNA depletion; mitochondrial encephalopathy; mitochondrial myopathy; mitochondrial neurogastrointestinal encephalopathy (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutations; respiratory chain disorders; short-chain acyl-CoA dehydrogenase deficiency (SCAD); SCHAD; very long-chain acyl-CoA dehydrogenase deficiency (VLCAD); myopathy; cardiomyopathy; encephalomyopathies; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; muscle atrophy Alzheimer's disease (ALS); Motor neuron disease; Neurological disorders; Epilepsy; Age-related diseases; Macular degeneration; Diabetes; Metabolic syndrome; Cancer; Brain cancer; Genetic diseases; Huntington's disease; Mood disorders; Schizophrenia; Bipolar disorder; Pervasive developmental disorders; Autistic disorder; Asperger's syndrome; Childhood disintegrative disorder (CDD); Rett's syndrome; PDD not otherwise specified (PDD-NOS); Cerebrovascular accident; Stroke; Visual impairment; Optic neuropathy; Dominant juvenile optic atrophy; Toxic-induced optic neuropathy; Glaucoma; Stargardt macular dystrophy; Diabetic retinopathy; Diabetes Maculopathy; Retinopathy of Prematurity; Ischemia-Reperfusion-Related Retinal Damage; Oxygen Toxicity; Hemoglobinopathy; Thalassemia; Sickle Cell Anemia; Stroke; Ischemia; Renal Tubular Acidosis; Attention Deficit Hyperactivity Disorder (ADHD); Neurodegenerative Disorders Leading to Hearing Loss or Balance Disorders; Dominant Optic Atrophy (DOA); Maternally Inherited Diabetes Mellitus with Hearing Loss (MIDD); Chronic Fatigue; Contrast-Induced Renal Injury; Contrast-Induced Retinopathy; Abetalipoproteinemia; Retinitis Pigmentosa; Wolfram Disease; Tourette's Syndrome; Cobalamin C Deficiency; Methylmalonic Aciduria; Glioblastoma; Down's Syndrome; Acute Renal Cell Disease (Item 75) The pharmaceutical composition according to any one of Items 1 to 60, 65, 66, or 68, the granules for suspension according to any one of Items 61 to 64, the suspension according to Item 67, or the method according to any one of Items 69 to 72, for treating or suppressing an oxidative stress disorder selected from the group consisting of vascular necrosis, muscular dystrophy, leukodystrophy, progressive supranuclear palsy, spinal muscular atrophy, hearing loss, noise-induced hearing loss, traumatic brain injury, juvenile Huntington's disease, multiple sclerosis, NGLY1, multiple system atrophy, adrenoleukodystrophy, and adrenal myeloneuropathy. (Item 76) The pharmaceutical composition according to any one of Items 1 to 60, 65, 66, or 68, the granules for suspension according to any one of Items 61 to 64, the suspension according to Item 67, or the method according to any one of Items 69 to 72, for treating or preventing amyotrophic lateral sclerosis (ALS).The pharmaceutical composition according to any one of Items 66 or 68, the granules for suspension according to any one of Items 61 to 64, the suspension according to Item 67, or the method according to any one of Items 69 to 72.

[0008] The present disclosure provides granules for suspension that have good dispersibility, suppression of hydrate formation and crystal growth.

[0009] Figure 1 shows microscopic images at 100x (top) and 700x (bottom) of anhydrous crystals from Example 12 stored at 5°C for 3 days. Sizes may vary depending on printing and image magnification, so please refer to the dimensions within each image. The anhydrous crystals are very thin, rod-like, and not very yellow (light yellow). Figure 2 shows microscopic images at 100x (top) and 700x (bottom) of hydrate crystals from Example 16 stored at 5°C for 14 days. The hydrate crystals are plate-like or block-like crystals with a strong yellow color. Occasionally, crystals that appear to be two pairs of crystals combined can be seen. Figure 3 shows, from left to right, photographs of Examples 14, 4, 20, 15, and 16 stored at 5°C for 14 days. Visually, the anhydrous crystals are light yellow, while the hydrate crystals are yellow to orange. Visually visible yellow to orange crystals are rated as "hydrate present (◎)."

[0010] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will prevail.

[0011] The present disclosure will be described in further detail below.

[0012] Abbreviations used herein have their conventional meaning within the art unless otherwise specified.

[0013] References herein to "about" a value or parameter include the variation that is directed to the value or parameter itself. For example, "about X" includes "X" itself as well as values ​​that allow for ±10% of error, unless otherwise specified.

[0014] As used herein, "Trolox" refers to 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R-isomer is referred to as R-Trolox, and the S-isomer is referred to as S-Trolox. Trolox can be prepared by synthetic methods well known to those skilled in the art, for example, the methods described in U.S. Pat. Nos. 3,947,473, 4,003,919, and 4,026,907.

[0015] As used herein, the term "binder" refers to an additive used to impart binding strength to a powder mixture containing a drug substance and additives to form the mixture, and to fix the ratio of the drug substance and additives in the formulation to make the content uniform, or to increase the particle size of the solid formulation to improve flowability. Examples of binders include cellulose-based binders, povidone-based binders, vinyl alcohol-based binders, and thickening polysaccharide binders.

[0016] Cellulosic binders include hydroxypropyl cellulose, hypromellose, methylcellulose, hypromellose phthalate, hypromellose acetate succinate, carmellose, hydroxyethyl cellulose, and alginic acid.

[0017] Povidone-based binders include povidone and copovidone. Povidone is a linear polymer of 1-vinyl-2-pyrrolidone. Copovidone is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate. Povidone and copovidone can be distinguished by their viscosity characteristics (K value). The K value can be determined by the K value measurement method specified in the "Povidone" and "Copovidone" sections of the "Japanese Pharmacopoeia, 18th Edition" pharmaceutical articles. In the case of "povidone," specifically, the amount of the product corresponding to the dehydrated product shown in the table below, converted according to the product's "labeled K value," is precisely weighed, dissolved in water to make exactly 100 mL, and allowed to stand for 60 minutes to prepare the sample solution. The sample solution and water are tested at 25°C using Viscosity Measurement Method 1 described in the Japanese Pharmacopoeia, and the K value can be calculated using the following formula: In the case of "Copovidone," specifically, the amount corresponding to 1.00 g of the product converted into dry matter is precisely weighed out, dissolved in water to make exactly 100 mL, and left to stand for 60 minutes to obtain the sample solution. The sample solution and water are tested at 25°C according to Method 1 of the Viscosity Measurement Method described in the Japanese Pharmacopoeia, and the K value can be calculated using the following formula:

[0018] The "labeled K value" is the value listed on the product. This specification also uses the labeled K value listed on the raw material product. The povidone and copovidone usable in this disclosure are not limited to these values. The "labeled K value" is a representative value. For povidone, when actually measured using this method, the K value of povidone with a labeled K value of 15 or less falls within the range of 85.0% to 115.0% of the labeled K value. For povidone with a labeled K value greater than 15 falls within the range of 90.0% to 108.0% of the labeled K value. For copovidone, when actually measured using this method, the K value of copovidone falls within the range of 90.0% to 110.0% of the labeled K value. For example, if the labeled K value of a povidone raw material is "17," the K value calculated using this method is acceptable, ranging from 90.0% to 108.0% of that value (15.3 to 18.4).

[0019] The K value of povidone is, for example, 10 to 120. It is preferably 10 to 100, more preferably 10 to 80, even more preferably 15 to 35, and most preferably 25 to 35. Examples of povidone include Kollidon 17PF (BASF) (designated K value: 17) and Plasdone K29 / 32 (Ashland) (designated K value: 29 to 32).

[0020] The K value of copovidone is, for example, 10 to 120, preferably 10 to 80, and more preferably 15 to 35. Examples of copovidone include Kollidon VA64 (BASF) (designated K value: 28) and Plasdone S630 (Ashland) (designated K value: 28).

[0021] Examples of vinyl alcohol binders include polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0022] Thickening polysaccharide binders include xanthan gum, gellan gum, guar gum, carrageenan, gum arabic, pectin, and pullulan.

[0023] In the present disclosure, the content of the "binder" is not particularly limited, but may be, for example, 1 mg to 1000 mg per 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof, preferably 2 mg to 500 mg, more preferably 5 mg to 300 mg, and even more preferably 20 mg to 200 mg.

[0024] As used herein, the term "dispersant" refers to a substance that improves the fluidity or dispersion of particles in a solid state, prevents to a certain extent the aggregation of particles when the formulation comes into contact with water, improves the dispersion of the formulation in water when it comes into contact with water, or prevents strong re-aggregation of particles in the formulation in water. Examples of dispersants include inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants.

[0025] Examples of inorganic salt dispersants include light anhydrous silicic acid and magnesium aluminometasilicate.

[0026] Examples of ether dispersants include polyethylene glycols (polyethylene glycol 600, polyethylene glycol 4000, polyethylene glycol 6000, etc.) and propylene glycol.

[0027] Starch dispersants include corn starch, rice starch, sodium starch glycolate, and partially pregelatinized starch.

[0028] Examples of cellulose-based dispersants include crystalline cellulose, carmellose sodium, carmellose, and carmellose calcium.

[0029] Examples of fatty acid ester salt dispersants include sucrose fatty acid esters and sodium stearyl fumarate.

[0030] In the present disclosure, the content of the "dispersant" is not particularly limited, but may be, for example, 0.01 to 10 wt % relative to the weight of the entire composition, preferably 0.1 to 8 wt %, more preferably 0.5 to 5 wt %, even more preferably 1 to 5 wt %, and particularly preferably 2 to 5 wt %.

[0031] As used herein, the term "suspending agent" refers to a substance that is added when granules are dispersed or suspended in water to form a suspension, for the purposes of maintaining the dispersion of suspended particles and improving ease of administration. As a "suspending agent", a substance with thickening properties or viscosity can also be used.

[0032] Suspending agents include thickening polysaccharides such as xanthan gum, guar gum, locust bean gum, tragacanth gum, sodium alginate, and carrageenan; acrylic acid copolymers such as carboxyvinyl polymers; cellulose derivatives such as carboxymethylcellulose, hypromellose, hydroxypropylcellulose, and methylcellulose; polyvinyl alcohol, povidone (polyvinylpyrrolidone), and combinations thereof.

[0033] In the present disclosure, the content of the "suspending agent" is not particularly limited, but may be, for example, 0.1 to 600 mg per 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof, preferably 1.25 to 300 mg, more preferably 2.5 to 300 mg, and even more preferably 6.25 to 300 mg.

[0034] As used herein, the term "sweetener" refers to a taste-masking substance that adds sweetness to a preparation, improves the feeling of taking the preparation, or masks the unpleasant taste of ingredients contained in the preparation.

[0035] Examples of sweeteners include aspartame, neotame, advantame, sucralose, sodium saccharin, dipotassium glycyrrhizinate, acesulfame K, maltitols, erythritol, xylitol, trehalose, thaumatin, and stevia.

[0036] In the present disclosure, the content of the "sweetener" is not particularly limited, and it is desirable to incorporate an amount sufficient to impart an appropriate taste masking effect when the suspension is formed, for example, 0.125 to 900 mg per 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof, preferably 1.25 to 600 mg, more preferably 6.25 to 300 mg.

[0037] The pharmaceutical composition of the present disclosure may contain additives that can be used in conventional pharmaceutical preparations, as long as they do not interfere with the effects of the present invention. Examples of such additives include, but are not limited to, thickeners, preservatives, stabilizers, buffers, colorants, flavors, etc.

[0038] The present disclosure encompasses all forms (e.g., tautomers, amorphous forms, crystalline forms, various crystalline polymorphs, etc.) of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide (compound of Formula 1). It also encompasses its optical isomers and mixtures thereof. The proportion of the R isomer in the case of such a mixture is not particularly limited, but is preferably 60% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and most preferably 99% by weight or more.

[0039] The compounds of Formula 1 and pharmaceutically acceptable salts thereof may exist in the form of hydrates and / or solvates, and therefore these hydrates or solvates, such as ethanol solvates, are also included in the present disclosure.

[0040] Examples of "pharmaceutically acceptable salts" include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, amino acids, etc.; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc.; organic acid salts such as acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc.

[0041] The compound of formula 1 used in the present disclosure may be milled, if necessary.

[0042] In this disclosure, "healthcare setting" refers to any setting in which the pharmaceutical compositions of the present disclosure are used, including hospitals, clinics, nursing facilities, homes (e.g., home health care), and the like.

[0043] In this disclosure, "modulating" or "modulating" an energy biomarker means changing the level of the energy biomarker to a desired value or changing the level of the energy biomarker in a desired direction (e.g., increasing or decreasing). WO 2016 / 100579 is incorporated by reference. Modulation can include, but is not limited to, normalization and enhancement, as defined below.

[0044] "Normalizing" or "normalizing" an energy biomarker is defined as changing the level of the energy biomarker from a pathological value toward a normal value, where a normal value of the energy biomarker can be 1) the level of the energy biomarker in a healthy person or subject, or 2) a level of the energy biomarker that alleviates one or more undesirable symptoms in a person or subject. That is, normalizing an energy biomarker that is decreased in a disease state means increasing the level of the energy biomarker toward a normal (healthy) value or toward a value that alleviates the undesirable symptom; normalizing an energy biomarker that is elevated in a disease state means decreasing the level of the energy biomarker toward a normal (healthy) value or toward a value that alleviates the undesirable symptom.

[0045] "Enhancing" or "enhancing" an energy biomarker means intentionally changing the level of one or more energy biomarkers away from normal or pre-enhancement values ​​to achieve a beneficial or desired effect. For example, in situations where a subject has significant energy demands, it may be desirable to increase the ATP level in the subject to a level that exceeds the normal level of ATP in the subject. In that normalizing energy biomarkers may not achieve optimal results in a subject, enhancement may also be beneficial in subjects suffering from diseases or conditions such as mitochondrial disorders. In such cases, enhancing one or more energy biomarkers may be beneficial. For example, such subjects may benefit from higher than normal levels of ATP or lower than normal levels of lactate.

[0046] Modulating, normalizing, or enhancing the energy biomarker Coenzyme Q means modulating, normalizing, or enhancing one or more variants of the predominant Coenzyme Q in the species in question. For example, the predominant Coenzyme Q variant in humans is Coenzyme Q10. If a species or subject has more than one variant of Coenzyme Q present in significant amounts (i.e., present in an amount that, when modulated, normalized, or enhanced, can have a beneficial effect on the species or subject), modulating, normalizing, or enhancing Coenzyme Q can refer to modulating, normalizing, or enhancing any or all variants of Coenzyme Q present in the species or subject.

[0047] The term "respiratory chain disorder" refers to a disorder resulting from a defect or disorder in a protein or other component of the mitochondrial respiratory chain, resulting in reduced oxygen utilization by mitochondria, cells, tissues, or individuals. "Proteins or other components of the mitochondrial respiratory chain" refers to components comprising mitochondrial complexes I, II, III, IV, and / or V, including, but not limited to, proteins, tetrapyrroles, and cytochromes. "Respiratory chain proteins" refer to protein components of these complexes, and "respiratory chain protein disorder" refers to a disorder resulting from a defect or disorder in a protein of the mitochondrial respiratory chain, resulting in reduced oxygen utilization by mitochondria, cells, tissues, or individuals.

[0048] The term "Parkinson's disease" (also called "parkinsonism" and "parkinsonism syndrome") ("PD") is intended to include not only Parkinson's disease but also drug-induced parkinsonism and postencephalitic parkinsonism. Parkinson's disease is also known as paralysis agitans or shaking palsy. It is characterized by tremors, muscle rigidity, and loss of postural reflexes. The disease usually progresses slowly over the course of 10 to 20 years, after which these symptoms cause disabling symptoms. Parkinson's disease models have been created by treating animals with methamphetamine or MPTP to mimic the effects of Parkinson's disease. These animal models have been used to evaluate the effectiveness of various treatments for Parkinson's disease.

[0049] The term "Friedreich's ataxia" is intended to encompass other related ataxias, sometimes referred to as hereditary ataxias, familial ataxias, or Friedreich's tabes.

[0050] The term "ataxia" is a nonspecific clinical manifestation that refers to dysfunction of the parts of the nervous system (such as the cerebellum) that coordinate movement. People with ataxia have problems with coordination because the parts of the nervous system that control movement and balance are affected. Ataxia can affect the fingers, hands, arms, legs, trunk, speech, and eye movements. The term ataxia is often used to describe symptoms of incoordination that may be associated with infection, injury, other diseases, or degenerative changes in the central nervous system. Ataxia is also used to refer to a group of specific degenerative diseases of the nervous system called hereditary ataxia and sporadic ataxia. Ataxia is also often accompanied by hearing loss.

[0051] There are three types of ataxia: cerebellar ataxia (which includes vestibular-cerebellar, spino-cerebellar, and cerebro-cerebellar dysfunction); sensory ataxia; and vestibular ataxia. Examples of diseases that can be classified as spinocerebellar ataxia or multiple system atrophy include hereditary olivopontocerebellar atrophy, hereditary cerebellar cortical atrophy, Friedreich's ataxia, Machado-Joseph disease, Ramsay Hunt syndrome, hereditary dentatorubral-pallidoluysian atrophy, hereditary spastic paraplegia, Shy-Drager syndrome, corticocerebellar atrophy, striatonigral degeneration, Marinesco-Sjogren's syndrome, alcoholic corticocerebellar atrophy, paraneoplastic cerebellar atrophy associated with malignancy, toxic cerebellar atrophy caused by toxic substances, vitamin E deficiency due to mutations in alpha-tocopherol transfer protein (aTTP) or lipid absorption disorders such as abetalipoproteinemia, and cerebellar atrophy associated with endocrine disruption.

[0052] Examples of ataxic symptoms include ataxia, truncal ataxia, limb ataxia, autonomic nervous system disorders (orthostatic hypotension, urinary disorders, decreased sweating, sleep apnea, orthostatic syncope, etc.), lower limb stiffness, ocular nystagmus, oculomotor nerve disorders, pyramidal tract dysfunction, extrapyramidal symptoms (postural dysfunction, muscle rigidity, akinesia, tremor), dysphagia, tongue atrophy, posterior column symptoms, muscle atrophy, muscle weakness, increased deep reflexes, sensory impairment, scoliosis, kyphoscoliosis, foot deformities, dysarthria, dementia, manic states, and decreased motivation for rehabilitation.

[0053] Preferred Embodiments In one embodiment of the present disclosure, a compound of Formula 1: or a pharmaceutically acceptable salt or solvate thereof; a binder; and a dispersant.

[0054] In the present disclosure, the binder may include a binder selected from the group consisting of a cellulose-based binder, a povidone-based binder, a vinyl alcohol-based binder, and a thickening polysaccharide binder.

[0055] In the present disclosure, the cellulosic binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methyl cellulose.

[0056] In the present disclosure, the povidone-based binder may include a binder selected from the group consisting of povidone and copovidone.

[0057] In the present disclosure, the vinyl alcohol-based binder may include a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer.

[0058] In the present disclosure, the thickening polysaccharide binder may include xanthan gum.

[0059] In the present disclosure, the dispersant may be selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants.

[0060] In the present disclosure, the inorganic salt dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate.

[0061] In the present disclosure, the ether dispersant may include polyethylene glycol 6000.

[0062] In the present disclosure, the starch dispersant may include corn starch.

[0063] In the present disclosure, the cellulose-based dispersant may include a dispersant selected from the group consisting of microcrystalline cellulose carmellose sodium, carmellose, and carmellose calcium.

[0064] In the present disclosure, the fatty acid ester salt dispersant may include sodium stearyl fumarate.

[0065] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include a dispersant selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants.

[0066] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include a dispersant selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, and cellulose-based dispersants.

[0067] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carmellose, crystalline cellulose-carmellose sodium, magnesium aluminum metasilicate, sodium stearyl fumarate, and carmellose calcium.

[0068] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methylcellulose, and the dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, and carmellose.

[0069] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersing agent may include a dispersing agent selected from the group consisting of light anhydrous silicic acid, corn starch, carmellose, polyethylene glycol 6000, crystalline cellulose-carmellose sodium, magnesium aluminometasilicate, sodium stearyl fumarate, and carmellose calcium.

[0070] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid, corn starch, and carmellose.

[0071] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersant may include light anhydrous silicic acid.

[0072] In the present disclosure, the binder may include hypromellose, and the dispersant may include a dispersant selected from the group consisting of a light anhydrous silicic acid dispersant and polyethylene glycol 6000.

[0073] In the present disclosure, the binder may include hypromellose, and the dispersing agent may include light anhydrous silicic acid.

[0074] In the present disclosure, the binder may include methyl cellulose, and the dispersant may include light anhydrous silicic acid.

[0075] In the present disclosure, the binder may include a povidone-based binder, and the dispersant may include a dispersant selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants.

[0076] In the present disclosure, the binder may include a povidone-based binder, and the dispersant may include a dispersant selected from the group consisting of inorganic salt dispersants and cellulose-based dispersants.

[0077] In the present disclosure, the binder may include copovidone, and the dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid and crystalline cellulose carmellose sodium.

[0078] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include an inorganic salt dispersant.

[0079] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methyl cellulose, and the dispersant may include a dispersant selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate.

[0080] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methyl cellulose, and the dispersing agent may include light anhydrous silicic acid.

[0081] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose and hypromellose, and the dispersing agent may include light anhydrous silicic acid.

[0082] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include an ether-based dispersant.

[0083] In the present disclosure, the binder may include a binder selected from the group consisting of hydroxypropyl cellulose and hypromellose, and the dispersing agent may include polyethylene glycol 6000.

[0084] In the present disclosure, the binder may include hypromellose and the dispersing agent may include polyethylene glycol 6000.

[0085] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include a starch-based dispersant.

[0086] In the present disclosure, the binder may include hydroxypropyl cellulose and the dispersant may include corn starch.

[0087] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include a cellulose-based dispersant.

[0088] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersant may include a dispersant selected from carmellose, crystalline cellulose carmellose sodium, and carmellose calcium.

[0089] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersant may include a dispersant selected from microcrystalline cellulose carmellose sodium and carmellose calcium.

[0090] In the present disclosure, the binder may include hydroxypropyl cellulose, and the dispersant may include carmellose.

[0091] In the present disclosure, the binder may include a cellulose-based binder, and the dispersant may include a fatty acid ester salt dispersant.

[0092] In the present disclosure, the binder may include hydroxypropyl cellulose and the dispersant may include sodium stearyl fumarate.

[0093] In the present disclosure, the binder may include a povidone-based binder, and the dispersant may include a cellulose-based dispersant.

[0094] In the present disclosure, the binder may include copovidone, and the dispersant may include light anhydrous silicic acid.

[0095] In the present disclosure, the binder may include a povidone-based binder, and the dispersant may include an inorganic salt dispersant.

[0096] In the present disclosure, the binder may include a binder selected from the group consisting of copovidone, povidone (designated K value: 29 to 32), and povidone (designated K value: 17), and the dispersing agent may include light anhydrous silicic acid.

[0097] In the present disclosure, the binder may include a binder selected from the group consisting of copovidone and povidone (designated K value: 29 to 32), and the dispersing agent may include light anhydrous silicic acid.

[0098] In the present disclosure, the binder may include a vinyl alcohol binder, and the dispersant may include an inorganic salt dispersant.

[0099] In the present disclosure, the binder may include a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer, and the dispersant may include light anhydrous silicic acid.

[0100] In the present disclosure, the binder may include a polyvinyl alcohol-polyethylene glycol graft copolymer, and the dispersant may include light anhydrous silicic acid.

[0101] In the present disclosure, the binder may include a vinyl alcohol-based binder, and the dispersant may include a cellulose-based dispersant.

[0102] In the present disclosure, the binder may include a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer, and the dispersing agent may include microcrystalline cellulose-carmellose sodium.

[0103] In the present disclosure, the binder may include a thickening polysaccharide binder, and the dispersant may include an inorganic salt dispersant.

[0104] In the present disclosure, the binder may include xanthan gum, and the dispersant may include light anhydrous silicic acid.

[0105] In the present disclosure, the pharmaceutical composition may include a suspending agent.

[0106] In the present disclosure, the suspending agent may include a carboxyvinyl polymer.

[0107] In the present disclosure, the pharmaceutical composition may contain a sweetener.

[0108] In the present disclosure, the sweetener may include sucralose.

[0109] In the present disclosure, the pharmaceutical composition may contain 1 mg to 1000 mg of a binder per 1000 mg of the compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0110] In the present disclosure, the pharmaceutical composition may contain 0.01 to 10% by weight of a dispersant based on the total weight of the composition.

[0111] In the present disclosure, the pharmaceutical composition may contain 1 mg to 1000 mg of a suspending agent per 1000 mg of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0112] In the present disclosure, the pharmaceutical composition may contain 1 mg to 1000 mg of a sweetener per 1000 mg of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0113] In one embodiment of the present disclosure, there is provided a granule for suspension for use in producing a pharmaceutical composition, the granule for suspension comprising any of the pharmaceutical compositions described above.

[0114] In the present disclosure, it may be granules for suspension for preparing a suspension.

[0115] In one embodiment of the present disclosure, there is provided a granule for suspension for use in producing a pharmaceutical composition, the granule for suspension being the pharmaceutical composition described in any one of the above.

[0116] In the present disclosure, it may be granules for suspension for preparing a suspension.

[0117] In one embodiment of the present disclosure, there is provided a pharmaceutical composition according to any one of the above claims, which is a granule for suspension for use in preparing a pharmaceutical composition.

[0118] In the present disclosure, it may be granules for suspension for preparing a suspension.

[0119] In one embodiment of the present disclosure, there is provided a suspension comprising the pharmaceutical composition according to any one of the above, which is a granule for suspension for producing a pharmaceutical composition.

[0120] In the present disclosure, it may be in a suspended state.

[0121] In one embodiment of the present disclosure, there is provided a method for treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of any one of the pharmaceutical compositions or the suspension described above.

[0122] In one embodiment of the present disclosure, there is provided a method for producing the pharmaceutical composition described in any one of the above or the suspension described above, the method comprising the step of mixing the compound or a pharmaceutically acceptable salt or solvate thereof, the binder, and the dispersant.

[0123] In one embodiment of the present disclosure, there is provided a method for producing a pharmaceutical composition, the method comprising the step of mixing the suspension granules described in any one of the above with necessary additives and / or a suspension solvent (e.g., including an aqueous solvent such as purified water).

[0124] In one embodiment of the present disclosure, there is provided a method for preparing a pharmaceutical composition for administration to a subject at a medical site, the method comprising mixing the suspension granules described in any one of the above with necessary additives and / or a suspension solvent (e.g., including an aqueous solvent such as purified water).

[0125] In one embodiment of the present disclosure, there is provided a pharmaceutical composition according to any one of the above, a granule for suspension according to any one of the above, a suspension according to any one of the above, or a method according to any one of the above, for treating or suppressing a stress disorder, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers.

[0126] In one embodiment of the present disclosure, the present invention relates to mitochondrial disorders; inherited mitochondrial diseases; Alpers' disease; Barth's syndrome; beta-oxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia (CPEO); CPT I deficiency; CPT II deficiency; Friedreich's ataxia (FA); glutaric aciduria type II; Kearns-Sayre syndrome (KSS); lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCAD); LCHAD; Leigh syndrome; Leigh-like syndrome; Leber hereditary optic neuropathy (LHON); fatal infantile cardiomyopathy (LIC); Luft disease; multiple acyl-CoA dehydrogenase deficiency (MAD); medium-chain acyl-CoA dehydrogenase deficiency (MCAD); mitochondrial Mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS); myoclonic epilepsy with ragged-red fibers (MERRF); mitochondrial recessive ataxia syndrome (MIRAS); mitochondrial cytopathy, mitochondrial DNA depletion; mitochondrial encephalopathy; mitochondrial myopathy; mitochondrial neurogastrointestinal encephalopathy (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; pyruvate carboxylase deficiency; pyruvate Dehydrogenase deficiency; POLG mutations; respiratory chain disorders; short-chain acyl-CoA dehydrogenase deficiency (SCAD); SCHAD; very long-chain acyl-CoA dehydrogenase deficiency (VLCAD); muscle disorders; cardiomyopathy; encephalomyopathies; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); motor neuron disease; neurological disorders; epilepsy; age-related diseases; macular degeneration; diabetes; metabolic syndrome; cancer; brain cancer; genetic diseases; Huntington's disease; mood disorders ; Schizophrenia; Bipolar disorder; Pervasive developmental disorder; Autistic disorder; Asperger's syndrome; Childhood disintegrative disorder (CDD); Rett's disorder; PDD not otherwise specified (PDD-NOS); Cerebrovascular accident; Stroke; Visual impairment; Optic neuropathy; Dominant juvenile optic atrophy; Toxic-induced optic neuropathy; Glaucoma; Stargardt macular dystrophy; Diabetic retinopathy; Diabetic maculopathy; Retinopathy of prematurity; Ischemia-reperfusion-related retinal damage; Oxygen toxicity; Hemochromatosis; Thalassemia;Sickle cell anemia; stroke; ischemia; renal tubular acidosis; attention deficit hyperactivity disorder (ADHD); neurodegenerative disorders leading to hearing loss or balance problems; dominant optic atrophy (DOA); maternally inherited diabetes mellitus with hearing loss (MIDD); chronic fatigue; contrast-induced renal injury; contrast-induced retinopathy; abetalipoproteinemia; retinitis pigmentosa; Wolfram disease; Tourette's syndrome; cobalamin c deficiency; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; muscular dystrophy The present invention provides a pharmaceutical composition according to any one of the above, a granule for suspension according to any one of the above, or a method according to any one of the above, for treating or suppressing an oxidative stress disorder selected from the group consisting of: encephalopathy; leukodystrophy; progressive supranuclear palsy; spinal muscular atrophy; hearing loss; noise-induced hearing loss; traumatic brain injury; juvenile Huntington's disease; multiple sclerosis; NGLY1; multiple system atrophy; adrenoleukodystrophy; and adrenal myeloneuropathy.

[0127] In one embodiment of the present disclosure, there is provided a pharmaceutical composition described in any one of the above, a granule for suspension described in any one of the above, or a method described in any one of the above, for treating or preventing amyotrophic lateral sclerosis (ALS).

[0128] Diseases Amenable to Treatment or Suppression Using the Compositions and Methods of the Disclosure A variety of disorders / diseases (such as mitochondrial disorders, disorders of reduced energy processing, neurodegenerative diseases, and diseases of aging) are believed to be caused or exacerbated by oxidative stress that affects normal electron flow within cells and can be treated or suppressed using the compositions of the disclosure.

[0129] Non-limiting examples of oxidative stress disorders include, for example, mitochondrial disorders (including inherited mitochondrial diseases) (Alpers' disease, Barth's syndrome, beta-oxidation deficiency, carnitine-acyl-carnitine deficiency, carnitine deficiency, creatine deficiency syndrome, coenzyme Q10 deficiency, complex I deficiency, complex II deficiency, complex III deficiency, complex IV deficiency, complex V deficiency, COX deficiency, chronic progressive external ophthalmoplegia (CPEO), CPT I deficiency, CPT II deficiency, Friedreich's ataxia (FA), glutaric aciduria type II, Kearns-Sayre syndrome (KSS), lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency (LCAD), LCHAD, Leigh disease or Leigh syndrome, Leigh-like syndrome, Leber hereditary optic neuropathy (also called LHON, Leber disease, Leber optic atrophy (LOA), or Leber optic neuropathy (LON)), fatal infantile cardiomyopathy (LIC), Luft Disease, Multiple Acyl-CoA Dehydrogenase Deficiency (MAD), Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD), Mitochondrial Myopathy, Encephalopathy, Lactacidosis, and Stroke (MELAS), Myoclonic Epilepsy with Ragged-Red Fibers (MERRF), Mitochondrial Recessive Ataxia Syndrome (MIRAS), Mitochondrial Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy, Mitochondrial Myopathy, Mitochondrial Neurogastrointestinal encephalopathy (MNGIE), neuropathy, ataxia, and retinitis pigmentosa (NARP), Pearson syndrome, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, POLG mutations, respiratory chain disorders, short-chain acyl-CoA dehydrogenase deficiency (SCAD), SCHAD, very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), etc.); muscle disorders (cardiomyopathies and encephalomyopathies, etc.); neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc.); neurological diseases (such as epilepsy); age-related diseases, particularly those for which CoQ10 has been proposed to treat, such as macular degeneration, diabetes (e.g., type 2 diabetes mellitus), metabolic syndrome, and cancer (e.g., brain cancer); genetic diseases (such as Huntington's disease (which is also a neurological disease)); mood disorders (such as schizophrenia and bipolar disorder);Pervasive developmental disorders (such as autistic disorder, Asperger's syndrome, childhood disintegrative disorder (CDD), Rett's disorder, and PDD not otherwise specified (PDD-NOS)); cerebrovascular accidents (such as stroke); vision disorders (such as vision disorders caused by neurodegenerative diseases of the eye (optic neuropathy, Leber's hereditary optic neuropathy, dominantly inherited juvenile optic atrophy, toxic-induced optic neuropathy, glaucoma, age-related macular degeneration (both "dry" i.e., non-exudative and "wet" i.e., exudative macular degeneration), Stargardt's macular dystrophy, diabetic retinopathy, diabetic maculopathy, retinopathy of prematurity, or ischemia-reperfusion-related retinal damage); disorders caused by energy failure, including oxygen deficiency, intoxication, or toxicity, and diseases resulting from qualitative or quantitative disruption of oxygen transport (hemoglobinopathies (e.g., thalassemia or Other diseases involving mitochondrial dysfunction, such as excitotoxic neuronal damage (such as damage associated with seizures, stroke, and ischemia), and other disorders involving renal tubular acidosis; attention deficit hyperactivity disorder (ADHD); neurodegenerative disorders leading to hearing loss or balance disorders; dominant optic atrophy (DOA); maternally inherited diabetes with hearing loss (MIDD); chronic fatigue; contrast-induced renal injury; and contrast-induced retinopathy injury. ; abetalipoproteinemia; retinitis pigmentosa; Wolfram's disease; Tourette's syndrome; cobalamin c deficiency; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; muscular dystrophy; leukodystrophy; progressive supranuclear palsy; spinal muscular atrophy; hearing loss (e.g., noise-induced hearing loss); traumatic brain injury; juvenile Huntington's disease; multiple sclerosis; NGLY1; multiple system atrophy; adrenoleukodystrophy; and adrenomyeloneuropathy. It should be understood that certain specific diseases or disorders may fall into more than one category; for example, Huntington's disease is not only a neurological disease but also a genetic disease. Furthermore, certain oxidative stress diseases and disorders can also be considered mitochondrial disorders. International Publication No. WO 2016 / 100579 is incorporated by reference.

[0130] The compound represented by Formula 1 (Compound 1) has an unpleasant taste, which is masked with a sweetener in the formulation of the present disclosure. For ease of manufacture and handling during distribution, the particles are bound and granulated with a binder (to enlarge the particles), and fluidity is imparted with a dispersant. For the purpose of suspending in water, dispersibility is imparted with a dispersant. When a formulation with these characteristics is designed, it has been observed that the suspended particles become coarser and the drug becomes hydrated over time after suspension.

[0131] Such changes impair the properties of the formulation. Coarsening of suspended particles deteriorates dispersion stability and the resulting uniformity of the drug in the suspension, while hydration of the drug causes discoloration and a change in appearance, and the growth of hydrates coarsens the particles. Furthermore, coarsening of particles and drugs adversely affects the sensation of oral administration (e.g., foreign body sensation) and can cause blockages in tube-fed administration in patients with gastrostomy tubes.

[0132] The pharmaceutical composition of the present disclosure has good dispersibility, which is beneficial when preparing a suspension, and has the ability to inhibit hydrate formation and crystal growth, which is beneficial over time after suspension formation.

[0133] (Formulation method) Coarse crystals of Compound 1 are crushed as needed to obtain Compound 1 for formulation preparation. Generally, to design a homogeneous and uniform formulation, the drug substance / raw material is crushed as needed, but if this does not pose a problem in formulation design, the drug substance / raw material may be used as is. Compound 1 can be obtained, for example, by the method described in WO2021 / 167095.

[0134] Specific examples of formulation preparation methods are described below, but the formulation preparation method is not limited to these. Compound 1, a binder, a suspending agent, and a sweetener are mixed as formulation ingredients. This mixture is charged into a dispensing mixer, and purified water is gradually added as granulation water while repeatedly stirring and mixing the mixture and adding purified water, and then stirred and mixed to obtain a granulated product. This granulated product is wet-sized using a sieve and dried to obtain a dried granulated product. This dried granulated product is dry-sized using a sieve to obtain granules.

[0135] The granules and dispersant are mixed and the entire mixture is sieved. The sieved product is mixed to obtain the formulation.

[0136] In addition to the above preparation methods, formulations can also be prepared by, for example, the following method. Compound 1, a suspending agent, a sweetener, and, if necessary, a binder are mixed as formulation raw materials. This mixture is charged into a stirring granulator, and purified water or an aqueous binder solution is added and stirred to granulate, yielding a granulated product. This granulated product is wet-granulated if necessary, and dried in a fluidized bed granulation dryer or the like to yield a dried granulated product. This dried granulated product is dry-granulated if necessary to obtain granules. The granules and a dispersant are mixed to obtain a formulation.

[0137] The granulation method is preferably a wet granulation method, and examples thereof include agitation granulation, fluidized bed granulation, extrusion granulation, kneading granulation, etc. Methods for adding a binder include adding it in powder form together with the pharmaceutical raw materials, as well as adding it dissolved in a solvent as a granulation liquid when granulating other pharmaceutical raw materials.

[0138] The present invention will be explained in more detail below by way of examples, reference examples, test examples, etc., but the present invention is not limited to these.

[0139] In the following examples and reference examples, the following carboxyvinyl polymer, sucralose, hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, copovidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, xanthan gum, light anhydrous silicic acid, magnesium aluminometasilicate, polyethylene glycol 6000, corn starch, crystalline cellulose-carmellose sodium, carmellose, carmellose calcium, and sodium stearyl fumarate were used, but the present invention is not limited to these.Carboxyvinyl polymer: Carbopol 971P (Lubrizol) Sucralose: Sucralose (Merck) Hydroxypropyl cellulose: HPC-L fine (Nippon Soda Co., Ltd.) Hypromellose: TC-5R (Shin-Etsu Chemical Co., Ltd.) Methylcellulose: SM-4 (Shin-Etsu Chemical Co., Ltd.) Povidone (K value: 17): Kollidon 17PF (BASF) Povidone (K value: 29-32): Plasdone K29 / 32 (Ashland) Copovidone: Kollidon VA64 (BASF) Polyvinyl alcohol: GOHSENOL EG-05PW (Mitsubishi Chemical Corporation) Polyvinyl alcohol-polyethylene glycol graft copolymer: Kollicoat IR (BASF) Xanthan gum: Keltrol T (Sumitomo Pharma Food & Chemical Co., Ltd.) Light anhydrous silicic acid: AEROSIL 200 (EVONIK) Magnesium aluminometasilicate: Neusilin FL2 (Fuji Chemical Industry Co., Ltd.) Polyethylene glycol 6000: Macrogol 6000 (SP) (Sanyo Chemical Industries, Ltd.) Corn starch: Nisshoku Pharmacopoeia Cornstarch XX16 (Nihon Shokuhin Kako Co., Ltd.) Microcrystalline cellulose / carmellose sodium: Ceolus RC-A591NF (Asahi Kasei Corporation) Carmellose: NS-300 (Godo Pharmaceutical Co., Ltd.) Carmellose calcium: E.C. G-505 (Godo Pharmaceutical Co., Ltd.) Sodium stearyl fumarate: PRUV (Ashland) The purified water used in the production of the formulation was "Japanese Pharmacopoeia Purified Water" (Takasugi Pharmaceutical Co., Ltd.).

[0140] Examples 1 to 21 and Reference Example 1 Using Compound 1 and additives in the amounts shown in the table below, preparations of Examples 1 to 21 and Reference Example 1 were prepared by the following method.

[0141] (1) Preparation of Compound 1 In order to adjust the coarse crystals of Compound 1 to an appropriate particle size, unground Compound 1 was ground using a particle sizer QUADROCOMIL (Powrex Corporation) to obtain Compound 1 for preparation of a formulation.

[0142] (2) Preparation of Granule A. Compound 1 (60 g), hydroxypropyl cellulose (9.9 g), carboxyvinyl polymer (0.6 g), and sucralose (1.5 g) were placed in a plastic bag as formulation ingredients and mixed in the bag. This mixture was placed in a pharmaceutical mixer YM-Q-7 (Dalton Co., Ltd.), and purified water (20.5 g) was gradually added as granulation water while repeatedly stirring and mixing the mixture and adding purified water. The mixture was then stirred and mixed in the pharmaceutical mixer for 3 minutes to obtain a granule. The granule was then wet-sized using a metal sieve with a 710 μm mesh, spread on a paper plate, and dried at 40°C for 16 hours or more in a thermal dryer (Laboratory Glassware Dryer DRU600TB / Advantec Co., Ltd.) to obtain a dried granule. The dried granule was then dry-sized using a metal sieve with a 850 μm mesh to obtain Granule A.

[0143] (3) Preparation of Granules B Granules B were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), hypromellose (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (3.6 g) was used as the granulation water.

[0144] (4) Preparation of Granules C Granules C were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), methylcellulose (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (2.8 g) was used as the granulation water.

[0145] (5) Preparation of Granules D Granules D were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), povidone (designated K value: 29 to 32) (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as raw materials, and purified water (2.3 g) was used as the granulation water.

[0146] (6) Preparation of Granules E Granules E were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (2.6 g) was used as the granulation water.

[0147] (7) Preparation of Granules F Granules F were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), polyvinyl alcohol (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (4.1 g) was used as the granulation water.

[0148] (8) Preparation of Granules G Granules G were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), polyvinyl alcohol-polyethylene glycol graft copolymer (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (2.7 g) was used as the granulation water.

[0149] (9) Preparation of Granules H Granules H were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), copovidone (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (2.5 g) was used as the granulation water.

[0150] (10) Preparation of Granules I Granules I were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g), povidone (designated K value: 17) (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as raw materials, and purified water (2.5 g) was used as the granulation water.

[0151] (11) Preparation of Granule J Granule J was obtained in the same manner as in the preparation of Granule A, except that Compound 1 (18 g), xanthan gum (2.97 g), carboxyvinyl polymer (0.18 g), and sucralose (0.45 g) were used as the raw materials for the formulation, and purified water (2.5 g) was used as the granulation water.

[0152] (12) Preparation of Granules K Granules K were obtained in the same manner as in the preparation of Granules A, except that Compound 1 (18 g) and hydroxypropyl cellulose (2.97 g) were used as the raw materials for the formulation, and purified water (2.9 g) was used as the granulation water.

[0153] (13) Preparation of Example 1 Granules A (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 1.

[0154] (14) Preparation of Example 2 Granules B (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 2.

[0155] (15) Preparation of Example 3 Granules C (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 3.

[0156] (16) Preparation of Example 4 Granules H (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 4.

[0157] (17) Preparation of Example 5 Granules B (7.2 g) and polyethylene glycol 6000 (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 5.

[0158] (18) Preparation of Example 6 Granule A (7.2 g) and corn starch (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 6.

[0159] (19) Preparation of Example 7 Granules A (7.2 g) and carmellose (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 7.

[0160] (20) Preparation of Example 8 Granules H (7.2 g) and microcrystalline cellulose-carmellose sodium (0.3 g) were placed in a plastic bag and mixed in the bag. The entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 8.

[0161] (21) Preparation of Example 9 Granules A (7.2 g) and polyethylene glycol 6000 (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 9.

[0162] (22) Preparation of Example 10 Granules A (7.2 g) and microcrystalline cellulose-carmellose sodium (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 10.

[0163] (23) Preparation of Example 11 Granules A (7.2 g) and sodium stearyl fumarate (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 11.

[0164] (24) Preparation of Example 12 Granules A (7.2 g) and carmellose calcium (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 12.

[0165] (25) Preparation of Example 13 Granules F (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 13.

[0166] (26) Preparation of Example 14 Granules G (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 14.

[0167] (27) Preparation of Example 15 Granules J (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 15.

[0168] (28) Preparation of Example 16 Granules F (7.2 g) and microcrystalline cellulose-carmellose sodium (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 16.

[0169] (29) Preparation of Example 17 Granules G (7.2 g) and microcrystalline cellulose-carmellose sodium (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 17.

[0170] (30) Preparation of Example 18 Granules A (7.2 g) and magnesium aluminometasilicate (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 18.

[0171] (31) Preparation of Example 19 Granules D (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 19.

[0172] (32) Preparation of Example 20 Granules I (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with 850 μm openings. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 20.

[0173] (33) Preparation of Example 21 Granules K (6.99 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag, mixed in the bag, and the entire mixture was sieved through a metal sieve with an opening of 850 μm. The sieved product was collected in a plastic bag and mixed in the bag to obtain the formulation of Example 21.

[0174] (34) Preparation of Reference Example 1 Granules E (6.21 g) were placed in a plastic bag and mixed in the bag to obtain the formulation of Reference Example 1.

[0175]

[0176] Test Example 1 (Water Dispersibility of Prepared Formulations) The ease of suspension when administered as a suspension was evaluated using the water dispersibility of the formulation as an index. The specific evaluation method is as follows. For each formulation (Examples 1 to 21, Reference Example 1), an amount equivalent to 1000 mg of Compound 1 was weighed into a 20 mL transparent glass bottle (screw tube bottle 20 mL No. 5 / Maruem Co., Ltd.), 8.8 mL of purified water was added, and the lid (screw cap No. 5 / Maruem Co., Ltd.) was attached. Immediately thereafter, the container was turned upside down and stirred 60 times with one hand to confirm the dispersibility of the formulation. The evaluation criteria for dispersibility are as follows. Each formulation was tested in triplicate and evaluated using the average score.

[0177] <Evaluation criteria> Score: Evaluation 5: Uniformly dispersed 4: Uniformly dispersed with no coarse particles or adhesion to the bottle wall that would cause problems with taking the medicine 3: Dispersed with no coarse particles or adhesion to the bottle wall that would cause problems with taking the medicine 2: There are a few coarse particles or adhesion to the bottle wall that would cause problems with taking the medicine, and additional stirring is required 1: There are many coarse particles or adhesion to the bottle wall that would cause problems with taking the medicine, and additional stirring is required

[0178] Test Example 2 (Crystal growth and hydrate formation after suspension) The storage stability of the present drug when suspended was evaluated using the crystal growth and hydrate formation of Compound 1 in the suspension formulation as indicators. The specific evaluation method is as follows.

[0179] For each formulation (Examples 1 to 21, Reference Example 1), an amount equivalent to 1000 mg of Compound 1 was weighed into a 20 mL transparent glass bottle (screw tube bottle 20 mL No. 5 / Maruem Co., Ltd.), 8.8 mL of purified water was added, and the lid (screw cap No. 5 / Maruem Co., Ltd.) was attached. Immediately thereafter, the container was inverted upside down and stirred 60 times with one hand to disperse the contents, and samples that were not sufficiently dispersed at that point were further stirred to form a suspension.

[0180] The suspension was stored at 5°C for 3 days, 7 days, 14 days, and 1 month, and the degree of crystal growth and hydrate formation after each storage period was evaluated by visual and microscopic observation. The evaluation criteria for crystal growth and hydrate formation were as follows:

[0181] <Evaluation criteria> Symbol: Evaluation ×: No crystal growth or hydrate formation is observed by visual observation of the appearance or by observation under a microscope. ○: No crystal growth or hydrate formation is observed by visual observation of the appearance, but is observed under a microscope. ◎: Crystal growth or hydrate formation is observed by visual observation of the appearance and by observation under a microscope. Therefore, the evaluation of × is the best evaluation.

[0182] Preparations that received a score of 2 or more in Test Example 1 and showed poor hydrate formation even on the third day in Test Example 2 were designated as Examples.

[0183] This application claims priority to Japanese Patent Application No. 2022-144675 (filed with the Japan Patent Office on September 12, 2022), the entire contents of which are incorporated herein by reference.

[0184] The present disclosure provides pharmaceutical compositions.

Claims

1. Formula 1: 【Chemistry 1】 A compound represented by or a pharmaceutically acceptable salt or solvate thereof, A binder and Dispersant and A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the binder comprises a binder selected from the group consisting of cellulose-based binders, povidone-based binders, vinyl alcohol-based binders, and thickening polysaccharide binders, The cellulosic binder comprises a binder selected from the group consisting of hydroxypropylcellulose, hypromellose, and methylcellulose; or The povidone-based binder includes a binder selected from the group consisting of povidone and copovidone; or The vinyl alcohol-based binder includes a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer; or The aforementioned thickening polysaccharide binder includes xanthan gum; Pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, wherein the dispersant is selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose dispersants, and fatty acid ester salt dispersants. The inorganic salt dispersant includes a dispersant selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate; or The ether dispersant contains polyethylene glycol 6000; or The starch dispersant contains corn starch; or The cellulosic dispersant comprises a dispersant selected from the group consisting of crystalline cellulose / carmellose sodium, carmellose, and carmellose calcium; or The fatty acid ester salt dispersant comprises sodium stearyl fumarate; Pharmaceutical composition.

4. The aforementioned binder includes a cellulose-based binder, The dispersant includes a dispersant selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants; or The aforementioned binder includes a cellulose-based binder, The dispersant is selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, and cellulose-based dispersants; or The binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, and methylcellulose. The dispersant is selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carmellose, crystalline cellulose / carmellose sodium, magnesium aluminometasilicate, stearyl sodium fumarate, and carmellose calcium; or The binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, and methylcellulose. The dispersant is selected from the group consisting of light anhydrous silicic acid, polyethylene glycol 6000, corn starch, and carmellose; or The binder comprises hydroxypropyl cellulose, The dispersant is selected from the group consisting of light anhydrous silicic acid, corn starch, carmellose, polyethylene glycol 6000, crystalline cellulose / carmellose sodium, magnesium aluminometasilicate, stearyl sodium fumarate, and carmellose calcium; or The binder comprises hydroxypropyl cellulose, The dispersant is selected from the group consisting of light anhydrous silicic acid, corn starch, and carmellose; or The binder comprises hydroxypropyl cellulose, The dispersant contains light anhydrous silicic acid; or The binder comprises hypromellose, The dispersant is selected from the group consisting of light anhydrous silicic acid and polyethylene glycol 6000; or The binder comprises hypromellose, The dispersant contains light anhydrous silicic acid; or The binder includes methylcellulose, The dispersant contains light anhydrous silicic acid; or The aforementioned binder includes a povidone-based binder. The dispersant is selected from the group consisting of inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants; or The aforementioned binder includes a povidone-based binder. The dispersant is selected from the group consisting of inorganic salt dispersants and cellulosic dispersants; or The binder comprises copovidone, The dispersant is selected from the group consisting of light anhydrous silicic acid and crystalline cellulose / carmellose sodium; The pharmaceutical composition according to claim 1.

5. The aforementioned binder includes a cellulose-based binder, The dispersant includes an inorganic salt dispersant; or The binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, and methylcellulose. The dispersant is selected from the group consisting of light anhydrous silicic acid and magnesium aluminometasilicate; or The binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, and methylcellulose. The dispersant contains light anhydrous silicic acid; or The binder is selected from the group consisting of hydroxypropylcellulose and hypromellose. The dispersant comprises light anhydrous silicic acid; The pharmaceutical composition according to claim 1.

6. The aforementioned binder includes a cellulose-based binder, The dispersant includes an ether dispersant; or The binder is selected from the group consisting of hydroxypropylcellulose and hypromellose. The dispersant comprises polyethylene glycol 6000; or The binder comprises hypromellose, The dispersant comprises polyethylene glycol 6000; or The aforementioned binder includes a cellulose-based binder, The dispersant includes a starch dispersant; or The binder comprises hydroxypropyl cellulose, The dispersant contains corn starch; or The aforementioned binder includes a cellulose-based binder, The dispersant includes a cellulosic dispersant; or The binder comprises hydroxypropyl cellulose, The dispersant is selected from carmellose, crystalline cellulose / carmellose sodium, and carmellose calcium; The pharmaceutical composition according to claim 1.

7. The aforementioned binder includes a cellulose-based binder, The dispersant includes a fatty acid ester salt dispersant; or The binder comprises hydroxypropyl cellulose, The dispersant includes sodium stearyl fumarate; or The aforementioned binder includes a povidone-based binder. The dispersant includes a cellulosic dispersant; or The binder comprises copovidone, The dispersant comprises crystalline cellulose and carmellose sodium; The pharmaceutical composition according to claim 1.

8. The aforementioned binder includes a povidone-based binder. The aforementioned dispersant includes an inorganic salt dispersant. A pharmaceutical composition according to claim 1, The binder comprises a binder selected from the group consisting of copovidone, povidone (indicated K value: 29-32), and povidone (indicated K value: 17). The dispersant comprises light anhydrous silicic acid, Pharmaceutical composition.

9. The aforementioned binder includes a vinyl alcohol-based binder. The dispersant includes an inorganic salt dispersant; or The binder comprises a binder selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol-graft copolymer. The dispersant contains light anhydrous silicic acid; or The aforementioned binder comprises polyvinyl alcohol, polyethylene glycol, and graft copolymer. The dispersant comprises light anhydrous silicic acid; The pharmaceutical composition according to claim 1.

10. The aforementioned binder includes a vinyl alcohol-based binder. The aforementioned dispersant includes a cellulose-based dispersant. A pharmaceutical composition according to claim 1, The binder is selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol-graft copolymer. The dispersant comprises crystalline cellulose and carmellose sodium. Pharmaceutical composition.

11. The aforementioned binder includes a thickening polysaccharide binder. The dispersant includes an inorganic salt dispersant; or The binder includes xanthan gum, The dispersant comprises light anhydrous silicic acid; The pharmaceutical composition according to claim 1.

12. The pharmaceutical composition comprises a suspension, and the suspension comprises a carboxyvinyl polymer; or The pharmaceutical composition comprises a sweetener, and the sweetener comprises sucralose; The pharmaceutical composition according to claim 1.

13. The pharmaceutical composition contains 1 mg to 1000 mg of a binder per 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof; or The pharmaceutical composition contains 0.01 to 10% by weight of a dispersant relative to the total weight of the composition; or The pharmaceutical composition comprises 1 mg to 1000 mg of a suspension based on 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof; or The pharmaceutical composition contains 1 mg to 1000 mg of a sweetener per 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof; The pharmaceutical composition according to claim 1.

14. Granules comprising the pharmaceutical composition described in Claim 1.

15. The pharmaceutical composition according to claim 1, wherein it is in the form of granules.

16. A suspension comprising the pharmaceutical composition according to claim 1, which includes granules.

17. The pharmaceutical composition according to claim 1, which is in a suspension state.

18. A method for producing the pharmaceutical composition described in Claim 1 or the suspension described in Claim 16, comprising the step of mixing the compound or a pharmaceutically acceptable salt or solvate thereof with the binder and a dispersant.

19. A pharmaceutical composition according to claim 1 for treating or suppressing oxidative stress disorders, wherein the oxidative stress disorder is: mitochondrial disorder; hereditary mitochondrial disease; Alpers disease; Barth syndrome; β-oxidation deficiency; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive extraocular myopalsy (CPEO); CPT I deficiency; CPT II deficiency; Friedreich's ataxia (FA); glutaric aciduria type II; Kearns-Sayer syndrome (KSS); lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCAD); LCHAD; Leigh syndrome; Leigh-like syndrome; Leber hereditary optic neuropathy (LHON); fatal infant cardiomyopathy (LIC); Luft's disease; multiple acyl-CoA dehydrogenase deficiency (MAD); medium-chain acyl-CoA dehydrogenase deficiency (MC) AD); Mitochondrial myopathy, encephalopathy, lactoacidosis, stroke (MELAS); Myoclonus epilepsy with red rag fibers (MERRF); Mitochondrial recessive ataxia syndrome (MIRAS); Mitochondrial cell disease, mitochondrial DNA depletion; Mitochondrial encephalopathy; Mitochondrial myopathy; Mitochondrial neurogastrointestinal encephalopathy (MNGIE); Neuropathy, ataxia, retinitis pigmentosa (NARP); Pearson syndrome; Pirby Carboxyl carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutation; respiratory chain disorder; short-chain acyl-CoA dehydrogenase deficiency (SCAD); SCHAD; very long-chain acyl-CoA dehydrogenase deficiency (VLCAD); muscle disorders; cardiomyopathy; encephalomyopathy; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); motor neuron disease; neurological disorders; epilepsy; age-related diseases; macular degeneration; diabetes mellitus; Disorders of life; cancer; brain cancer; genetic diseases; Huntington's disease; mood disorders; schizophrenia; bipolar disorder; pervasive developmental disorder; autism spectrum disorder; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett syndrome; PDD-NOS (Psychovascular Disease Not Specified); cerebrovascular accidents; stroke; visual impairment; optic nerve damage; dominant inherited juvenile optic atrophy; optic nerve damage caused by toxins; glaucoma; Stargardt macular dystrophy; diabetic retinopathy; diabetic macular dystrophy;Retinopathy of prematurity; ischemia-reperfusion-related retinal injury; oxygen toxicity; abnormal hemoglobin; thalassemia; sickle cell anemia; seizures; ischemia; renal tubular acidosis; attention deficit hyperactivity disorder (ADHD); neurodegenerative disorders leading to hearing impairment or balance disorders; optic atrophy (DOA); maternal diabetes mellitus with hearing loss (MIDD); chronic fatigue; contrast-induced kidney injury; contrast-induced retinopathy; abetalipoproteinemia; retinitis pigmentosa; Wol A pharmaceutical composition selected from the group consisting of Flamm's disease; Tourette's syndrome; cobalamin c deficiency; methylmalonic aciduria; glioblastoma; Down syndrome; acute tubular necrosis; muscular dystrophy; leukodystrophy; progressive supranuclear palsy; spinal muscular atrophy; hearing loss; noise-induced hearing loss; traumatic brain injury; juvenile Huntington's disease; multiple sclerosis; NGLY-1; multiple system atrophy; adrenal cerebral leukodystrophy; and adrenal spinal nerve disorders.

20. The pharmaceutical composition according to claim 19, wherein the oxidative stress disorder is amyotrophic lateral sclerosis (ALS).

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