Particles for suspension

Abstract

The present disclosure provides particles for suspension, and specifically, the present disclosure is a pharmaceutical composition comprising: a compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof; 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 inorganic salt dispersants, ether dispersants, starch dispersants, cellulose-based dispersants, and fatty acid ester salt dispersants. # imgabs0 #

Description

Technical Field

[0001] The present disclosure provides a pharmaceutical composition. The pharmaceutical composition may contain particles for suspension. Background Art

[0002] International Publication No. WO 2009 / 061744 discloses a method for treating or inhibiting mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactic acidosis 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 method, such as 4-(p-quinolyl)-2-hydroxybutanamide derivatives. This document also describes 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] International Publication No. WO 2016 / 100579 describes polycrystalline and amorphous forms of anhydrates, hydrates and solvates of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, and methods of using such compositions to treat or inhibit oxidative stress disorders, including mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging, and methods of preparing such polycrystalline and amorphous forms.

[0004] International Publication No. WO 2021 / 167095 describes optical resolution of Trolox intermediates and methods for their preparation. Summary of the invention

[0005] As a result of diligent studies, the present inventors have found a granule for suspension having excellent dispersibility properties and inhibited hydrate formation and crystal growth, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0006] For example, the present disclosure provides the following items.

[0007] (Article 1)

[0008] A pharmaceutical composition comprising:

[0009] A compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof:

[0010] [Chemical formula 2]

[0011]

[0012] Adhesives; and

[0013] Dispersant.

[0014] (Article 2)

[0015] A pharmaceutical composition as described in item 1, wherein the binder comprises a binder selected from a cellulose binder, a povidone binder, a vinyl alcohol binder and a thickening polysaccharide binder.

[0016] (Article 3)

[0017] The pharmaceutical composition of clause 2, wherein the cellulose binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose.

[0018] (Article 4)

[0019] A pharmaceutical composition as described in item 2, wherein the povidone binder comprises a binder selected from povidone and copovidone.

[0020] (Article 5)

[0021] The pharmaceutical composition of clause 2, wherein the vinyl alcohol adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer.

[0022] (Article 6)

[0023] A pharmaceutical composition as described in clause 2, wherein the thickening polysaccharide binder comprises xanthan gum.

[0024] (Article 7)

[0025] A pharmaceutical composition as described in any of clauses 1 to 6, wherein the dispersant is selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

[0026] (Article 8)

[0027] A pharmaceutical composition as described in item 7, wherein the inorganic salt dispersant includes a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

[0028] (Article 9)

[0029] The pharmaceutical composition of clause 7, wherein the ether dispersant comprises polyethylene glycol 6000.

[0030] (Article 10)

[0031] The pharmaceutical composition of clause 7, wherein the starch dispersant comprises corn starch.

[0032] (Article 11)

[0033] The pharmaceutical composition of clause 7, wherein the cellulose dispersant comprises a dispersant selected from crystalline cellulose / sodium carboxymethylcellulose, carboxymethylcellulose and calcium carboxymethylcellulose.

[0034] (Article 12)

[0035] A pharmaceutical composition as described in item 7, wherein the fatty acid ester salt dispersant comprises sodium stearyl fumarate.

[0036] (Article 13)

[0037] The pharmaceutical composition according to item 1, wherein

[0038] The binder comprises a cellulose binder, and

[0039] The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

[0040] (Article 14)

[0041] The pharmaceutical composition according to item 1, wherein

[0042] The binder comprises a cellulose binder, and

[0043] The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant and a cellulose dispersant.

[0044] (Article 15)

[0045] The pharmaceutical composition according to item 1, wherein

[0046] The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0047] The dispersant includes a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate and calcium carboxymethyl cellulose.

[0048] (Article 16)

[0049] The pharmaceutical composition according to item 1, wherein

[0050] The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0051] The dispersant includes a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch and carboxymethyl cellulose.

[0052] (Article 17)

[0053] The pharmaceutical composition according to item 1, wherein

[0054] The binder comprises hydroxypropyl cellulose, and

[0055] The dispersant includes a dispersant selected from light anhydrous silicic acid, corn starch, carboxymethyl cellulose, polyethylene glycol 6000, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate and calcium carboxymethyl cellulose.

[0056] (Article 18)

[0057] The pharmaceutical composition according to item 1, wherein

[0058] The binder comprises hydroxypropyl cellulose, and

[0059] The dispersant includes a dispersant selected from light anhydrous silicic acid, corn starch and carboxymethyl cellulose.

[0060] (Article 19)

[0061] The pharmaceutical composition according to item 1, wherein

[0062] The binder comprises hydroxypropyl cellulose, and

[0063] The dispersant includes light anhydrous silicic acid.

[0064] (Article 20)

[0065] The pharmaceutical composition according to item 1, wherein

[0066] The binder comprises hypromellose, and

[0067] The dispersant includes a dispersant selected from light anhydrous silicic acid and polyethylene glycol 6000.

[0068] (Article 21)

[0069] The pharmaceutical composition according to item 1, wherein

[0070] The binder comprises hypromellose, and

[0071] The dispersant includes light anhydrous silicic acid.

[0072] (Article 22)

[0073] The pharmaceutical composition according to item 1, wherein

[0074] The binder comprises methylcellulose, and

[0075] The dispersant includes light anhydrous silicic acid.

[0076] (Article 23)

[0077] The pharmaceutical composition according to item 1, wherein

[0078] The adhesive comprises a povidone adhesive, and

[0079] The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

[0080] (Article 24)

[0081] The pharmaceutical composition according to item 1, wherein

[0082] The adhesive comprises a povidone adhesive, and

[0083] The dispersant includes a dispersant selected from an inorganic salt dispersant and a cellulose dispersant.

[0084] (Article 25)

[0085] The pharmaceutical composition according to item 1, wherein

[0086] The binder comprises copolyvidone, and

[0087] The dispersant includes a dispersant selected from light anhydrous silicic acid and crystalline cellulose / sodium carboxymethyl cellulose.

[0088] (Article 26)

[0089] The pharmaceutical composition according to item 1, wherein

[0090] The binder comprises a cellulose binder, and

[0091] The dispersant includes an inorganic salt dispersant.

[0092] (Article 27)

[0093] The pharmaceutical composition of item 26, wherein

[0094] The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0095] The dispersant includes a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

[0096] (Article 28)

[0097] The pharmaceutical composition of item 27, wherein

[0098] The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0099] The dispersant includes light anhydrous silicic acid.

[0100] (Article 29)

[0101] The pharmaceutical composition of clause 28, wherein

[0102] The binder comprises a binder selected from hydroxypropyl cellulose and hypromellose, and

[0103] The dispersant includes light anhydrous silicic acid.

[0104] (Article 30)

[0105] The pharmaceutical composition according to item 1, wherein

[0106] The binder comprises a cellulose binder, and

[0107] The dispersant includes an ether dispersant.

[0108] (Article 31)

[0109] The pharmaceutical composition of clause 30, wherein

[0110] The binder comprises a binder selected from hydroxypropyl cellulose and hypromellose, and

[0111] The dispersant includes polyethylene glycol 6000.

[0112] (Article 32)

[0113] The pharmaceutical composition of item 31, wherein

[0114] The binder comprises hypromellose, and

[0115] The dispersant includes polyethylene glycol 6000.

[0116] (Article 33)

[0117] The pharmaceutical composition according to item 1, wherein

[0118] The binder comprises a cellulose binder, and

[0119] The dispersant includes a starch dispersant.

[0120] (Article 34)

[0121] The pharmaceutical composition of item 33, wherein

[0122] The binder comprises hydroxypropyl cellulose, and

[0123] The dispersant includes corn starch.

[0124] (Article 35)

[0125] The pharmaceutical composition according to item 1, wherein

[0126] The binder comprises a cellulose binder, and

[0127] The dispersant includes a cellulose dispersant.

[0128] (Article 36)

[0129] The pharmaceutical composition of clause 35, wherein

[0130] The binder comprises hydroxypropyl cellulose, and

[0131] The dispersant includes a dispersant selected from carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose and calcium carboxymethyl cellulose.

[0132] (Article 37)

[0133] The pharmaceutical composition of item 36, wherein

[0134] The binder comprises hydroxypropyl cellulose, and

[0135] The dispersant includes a dispersant selected from crystalline cellulose / sodium carboxymethylcellulose and calcium carboxymethylcellulose.

[0136] (Article 38)

[0137] The pharmaceutical composition of item 36, wherein

[0138] The binder comprises hydroxypropyl cellulose, and

[0139] The dispersant includes carboxymethyl cellulose.

[0140] (Article 39)

[0141] The pharmaceutical composition according to item 1, wherein

[0142] The binder comprises a cellulose binder, and

[0143] The dispersant includes a fatty acid ester salt dispersant.

[0144] (Article 40)

[0145] The pharmaceutical composition of item 39, wherein

[0146] The binder comprises hydroxypropyl cellulose, and

[0147] The dispersant includes sodium stearyl fumarate.

[0148] (Article 41)

[0149] The pharmaceutical composition according to item 1, wherein

[0150] The adhesive comprises a povidone adhesive, and

[0151] The dispersant includes a cellulose dispersant.

[0152] (Article 42)

[0153] The pharmaceutical composition of clause 41, wherein

[0154] The binder comprises copolyvidone, and

[0155] The dispersant includes crystalline cellulose / sodium carboxymethyl cellulose.

[0156] (Article 43)

[0157] The pharmaceutical composition according to item 1, wherein

[0158] The adhesive comprises a povidone adhesive, and

[0159] The dispersant includes an inorganic salt dispersant.

[0160] (Article 44)

[0161] The pharmaceutical composition of clause 43, wherein

[0162] The binder comprises a binder selected from copolyvidone, povidone (nominal K value: 29 to 32) and povidone (nominal K value: 17), and

[0163] The dispersant includes light anhydrous silicic acid.

[0164] (Article 45)

[0165] The pharmaceutical composition of clause 44, wherein

[0166] The binder comprises a binder selected from copolyvidone and povidone (nominal K value: 29 to 32), and

[0167] The dispersant includes light anhydrous silicic acid.

[0168] (Article 46)

[0169] The pharmaceutical composition according to item 1, wherein

[0170] The adhesive comprises a vinyl alcohol adhesive, and

[0171] The dispersant includes an inorganic salt dispersant.

[0172] (Article 47)

[0173] The pharmaceutical composition of clause 46, wherein

[0174] The adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0175] The dispersant includes light anhydrous silicic acid.

[0176] (Article 48)

[0177] The pharmaceutical composition of clause 47, wherein

[0178] The adhesive comprises polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0179] The dispersant includes light anhydrous silicic acid.

[0180] (Article 49)

[0181] The pharmaceutical composition according to item 1, wherein

[0182] The adhesive comprises a vinyl alcohol adhesive, and

[0183] The dispersant includes a cellulose dispersant.

[0184] (Article 50)

[0185] The pharmaceutical composition of clause 49, wherein

[0186] The adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0187] The dispersant includes crystalline cellulose / sodium carboxymethyl cellulose.

[0188] (Article 51)

[0189] The pharmaceutical composition according to item 1, wherein

[0190] The binder comprises a thickening polysaccharide binder, and

[0191] The dispersant includes an inorganic salt dispersant.

[0192] (Article 52)

[0193] The pharmaceutical composition of item 51, wherein

[0194] The binder comprises xanthan gum, and

[0195] The dispersant includes light anhydrous silicic acid.

[0196] (Article 53)

[0197] The pharmaceutical composition of any one of clauses 1 to 52, wherein the pharmaceutical composition comprises a suspending agent.

[0198] (Article 54)

[0199] The pharmaceutical composition of clause 53, wherein the suspending agent comprises a carboxyvinyl polymer.

[0200] (Article 55)

[0201] The pharmaceutical composition of any one of clauses 1 to 54, wherein the pharmaceutical composition comprises a sweetener.

[0202] (Article 56)

[0203] The pharmaceutical composition of clause 55, wherein the sweetener comprises sucralose.

[0204] (Article 57)

[0205] A pharmaceutical composition as described in any one of clauses 1 to 56, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a binder relative to 1000 mg of the compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0206] (Article 58)

[0207] A pharmaceutical composition as described in any of clauses 1 to 57, wherein the pharmaceutical composition comprises 0.01 to 10% by weight of a dispersant relative to the weight of the entire composition.

[0208] (Article 59)

[0209] A pharmaceutical composition as described in any one of clauses 1 to 58, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a suspending agent relative to 1000 mg of a compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0210] (Article 60)

[0211] A pharmaceutical composition as described in any one of clauses 1 to 59, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a sweetener relative to 1000 mg of the compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0212] (Article 61)

[0213] A suspension particle for use in the manufacture of a pharmaceutical composition, comprising the pharmaceutical composition of any one of clauses 1 to 60.

[0214] (Article 62)

[0215] The suspending particles as described in item 61 are suspending particles used for preparing a suspension.

[0216] (Article 63)

[0217] A suspension particle for use in the manufacture of a pharmaceutical composition, wherein the suspension particle is the pharmaceutical composition of any one of clauses 1 to 60.

[0218] (Article 64)

[0219] The suspending particles as described in item 63 are suspending particles used for preparing a suspension.

[0220] (Article 65)

[0221] A pharmaceutical composition as described in any of clauses 1 to 60, which is a suspension particle for use in the manufacture of a pharmaceutical composition.

[0222] (Article 66)

[0223] A pharmaceutical composition according to item 65, which is a suspension granulate for preparing a suspension.

[0224] (Article 67)

[0225] A suspension comprising the pharmaceutical composition of any one of clauses 1 to 60, which is a suspension particle for use in the manufacture of a pharmaceutical composition.

[0226] (Article 68)

[0227] A pharmaceutical composition as described in any one of clauses 1 to 60, which is in a suspended state.

[0228] (Article 69)

[0229] A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of any one of clauses 1 to 60, 65 to 66 or 68, or the suspension of clause 67.

[0230] (Article 70)

[0231] A method for preparing the pharmaceutical composition of any one of clauses 1 to 60, 65 to 66 or 68, or the suspension of clause 67, comprising mixing the compound or a pharmaceutically acceptable salt or solvate thereof, the binder and a dispersant.

[0232] (Article 71)

[0233] A method for preparing a pharmaceutical composition, comprising mixing the suspension particles described in any one of item 61 or 62 with necessary additives and / or a suspension solvent (eg, comprising an aqueous solvent such as purified water).

[0234] (Article 72)

[0235] A method of preparing a pharmaceutical composition for administration to a subject in a medical setting, comprising mixing the suspending particles of any of clauses 63 or 64 with necessary additives and / or a suspending solvent (e.g., including an aqueous solvent such as purified water).

[0236] (Article 73)

[0237] A pharmaceutical composition as described in any of items 1 to 60, 65 to 66 or 68, a particle for suspension as described in any of items 61 to 64, a suspension as described in item 67, or a method as described in any of claims 69 to 72, for treating or inhibiting oxidative stress disorders, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers.

[0238] (Article 74)

[0239] The pharmaceutical composition of any one of clauses 1 to 60, 65, 66 or 68, the particles for suspension of any one of clauses 61 to 64, the suspension of clause 67 or the method of any one of claims 69 to 72 for treating or inhibiting an oxidative stress disorder selected from the group consisting of: mitochondrial disease; inherited mitochondrial disease; Alpers Disease; Barth syndrome; beta oxidation defect; carnitine acylcarnitine 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 acidemia type II; Kearns-Sell syndrome (KSS); lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCAD); LCHAD; Leigh syndrome ( Syndrome; Leber-like syndrome; Leber hereditary optic neuropathy (LHON); fatal infantile cardiomyopathy (LIC); Luft disease; multiple acyl-CoA dehydrogenase deficiency (MAD); medium- and long-chain acyl-CoA dehydrogenase deficiency (MCAD); mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial recessive ataxia syndrome (MIRAS); mitochondrial cytopathies, mitochondrial DNA deletions; mitochondrial encephalopathy; mitochondrial myopathy; myoneurogenic gastrointestinal disease and encephalopathy (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome (Pearson syndrome). 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; encephalomyopathy; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); motor neuron disease; neurological diseases; 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; autism; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett's disorder); PDD-NOS; cerebrovascular accident; stroke; visual impairment; optic neuropathy; dominantly inherited juvenile optic atrophy; optic neuropathy caused by toxic agents; glaucoma;Stargardt's macular dystrophy; diabetic retinopathy; diabetic maculopathy; retinopathy of prematurity; ischemia-reperfusion-related retinal damage; oxygen toxicity; hemoglobinopathies; thalassemia; sickle cell anemia; epilepsy; ischemia; renal tubular acidosis; attention-deficit / hyperactivity disorder (ADHD); neurodegenerative diseases causing hearing or balance impairment; dominant optic atrophy (DOA); maternally inherited diabetes and hearing loss (MIDD); chronic fatigue; contrast-induced renal injury; contrast-induced retinopathy injury; abetalipoproteinemia; retinitis pigmentosa; Wolfram's disease; Tourette syndrome syndrome); cobalamin C deficiency; methylmalonic aciduria; glioblastoma; Down's 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; NGLY1; multiple system atrophy; adrenoleukodystrophy; and adrenomyeloneuropathy.

[0240] (Article 75)

[0241] A pharmaceutical composition as described in any of clauses 1 to 60, 65 to 66 or 68, a particle for suspension as described in any of clauses 61-64, a suspension as described in clause 67, or a method as described in any of claims 69-72, for treating or inhibiting amyotrophic lateral sclerosis (ALS).

[0242] Effects of the Invention

[0243] The present disclosure provides a granule for suspension having excellent dispersibility properties and inhibiting hydrate formation and crystal growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0245] [ Figure 1 ] Figure 1 (Top) 100× and (bottom) 700× microscope images of crystals of the anhydrate of Example 12 stored at 5° C. for 3 days are shown. Since the size varies depending on the magnification of the image display or print, the size in each image can be referred to. The crystals of the anhydrate are very thin rod-shaped crystals, and their yellowness is not high (light yellow).

[0246] [ Figure 2 ] Figure 2(Top) 100× and (Bottom) 700× microscope images of crystals of the hydrate of Example 16 stored at 5° C. for 14 days are shown. The crystals of the hydrate are plate-like or block-like crystals with a high yellowness. Some were found to be crystals formed by a combination of two pairs of crystals.

[0247] [ Figure 3 ] Figure 3 From the left, pictures of each of Example 14, Example 4, Example 20, Example 15, and Example 16 stored at 5° C. for 14 days are shown. Under visual observation, the crystals of the hydrate are light yellow, and the crystals of the hydrate are yellow to orange. If the crystals are found to be yellow to orange by visual observation, the crystals are evaluated as "having a hydrate (⊙)".

[0248] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0249] The present disclosure is described in more detail below. Throughout the specification, unless otherwise explicitly stated, singular expressions should be understood to cover the concept of its plural form. Therefore, unless otherwise explicitly stated, singular articles (such as "one", "a kind of", "the", etc. in the case of English) should also be understood to cover the concept of its plural form. In addition, unless otherwise explicitly stated, the terms used herein should be understood to be used with the meaning commonly used in the art. Therefore, unless otherwise defined, all terms and scientific and technical terms used herein have the same meaning as those commonly understood by those skilled in the art belonging to the present invention. In the event of a conflict, this specification (including definitions) takes precedence.

[0250] The present disclosure is described in further detail below.

[0251] Unless expressly stated otherwise, abbreviations used herein have conventional meanings within the art.

[0252] The term "about" used herein for a value or parameter includes variations about the value or parameter itself. Unless expressly stated otherwise, for example, "about X" includes "X" itself and a value with an acceptable error of ±10% therefrom.

[0253] As used herein, "Trolox" means 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R form is referred to as RTrolox, and the S form is referred to as S Trolox. Trolox can be prepared by synthetic methods well known to those skilled in the art, such as those described in U.S. Pat. No. 3,947,473, U.S. Pat. No. 4,003,919, and U.S. Pat. No. 4,026,907.

[0254] As used herein, "binder" refers to an additive used to impart cohesion to a powder mixture (which includes an active pharmaceutical ingredient and an additive) for molding, an additive that makes the content uniform by fixing the ratio of the active pharmaceutical ingredient to the additive in the formulation, or an additive that improves flowability by increasing the particle size of the solid formulation. Examples thereof include cellulose binders, povidone binders, vinyl alcohol binders, thickening polysaccharide binders, and the like.

[0255] Examples of cellulose binders include hydroxypropyl cellulose, hypromellose, methyl cellulose, hypromellose phthalate, hypromellose acetate succinate, carboxymethyl cellulose, hydroxyethyl cellulose, alginic acid, and the like.

[0256] Examples of polyvidone adhesives include polyvidone, copolyvidone, etc. Polyvidone is a linear polymer of 1-vinyl-2-pyrrolidone. Copolyvidone is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate. Each of polyvidone and copolyvidone can be distinguished by viscosity characteristics (K value). The K value can be found by the K value measurement method specified in the "Povidone" and "Copolyvidone" parts in the official monograph of "Japanese Pharmacopoeia 18th Edition" official monograph. Specifically, for "Povidone", accurately weigh a certain amount of polyvidone calculated on an anhydrous basis specified in the following table, dissolve it in water to an accuracy of 100mL, allow to stand for 60 minutes, and use this solution as a sample solution. According to the instructions of method 1 under viscosity determination at 25°C specified in the Japanese Pharmacopoeia, test with sample solution and water at 25°C, and calculate the K value by the following formula.

[0257] [Formula 1]

[0258]

[0259] c: mass of 100 mL of solution calculated on an anhydrous basis (g)

[0260] v rel. : Ratio of the kinematic viscosity of the sample solution to the kinematic viscosity of water

[0261]

[0262] Specifically, for "copolyvidone", a certain amount of copolyvidone was accurately weighed, equivalent to 1.00 g calculated on a dried basis, and dissolved in water to an accuracy of 100 mL, allowed to stand for 60 minutes, and this solution was used as a sample solution. According to the instructions of Method 1 under the viscosity determination at 25° C. specified in the Japanese Pharmacopoeia, the test was performed at 25° C. with the sample solution and water, and the K value was calculated by the following formula.

[0263] [Formula 2]

[0264]

[0265] c: mass of 100mL solution calculated on the basis of dry product (g)

[0266] v rel. : Ratio of the kinematic viscosity of the sample solution to the kinematic viscosity of water

[0267] A "nominal K value" is described for this product. The nominal K value specified for the product of the raw materials used is described herein. The povidone and copovidone that can be used herein are not limited to such values. The "nominal K value" is a representative value. In the case of povidone, when the actual measurement is performed using the present measurement method, the K value of povidone having a nominal K value of 15 or less is in the range of not less than 85.0% and not more than 115.0% of the nominal K value, and the K value of povidone having a nominal K value exceeding 15 is in the range of not less than 90.0% and not more than 108.0% of the nominal K value. In the case of copovidone, when the actual measurement is performed using the present measurement method, the K value of copovidone is in the range of not less than 90.0% and not more than 110.0% of the nominal K value. For example, if the nominal K value of the raw material of povidone is described as "17", the K value found by the present measurement method is allowed to be 90.0% to 108.0% of its value, ie "15.3 to 18.4".

[0268] For example, the K value of povidone is 10 to 120, preferably 10 to 100, more preferably 10 to 80, still more preferably 15 to 35, and most preferably 25 to 35. Examples of povidone include Kollidon 17PF (BASF) (nominal K value: 17), Plasdone K29 / 32 (Ashland) (nominal K value: 29 to 32), and the like.

[0269] For example, the K value of copovidone is 10 to 120, preferably 10 to 80, and more preferably 15 to 35. Examples of copovidone include Kollidon VA 64 (BASF) (nominal K value: 28), Plasdone S630 (Ashland) (nominal K value: 28) and the like.

[0270] Examples of the vinyl alcohol binder include polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and the like.

[0271] Examples of thickening polysaccharide binders include xanthan gum, gellan gum, guar gum, carrageenan, gum arabic, pectin, pullulan, and the like.

[0272] The content of the "binder" herein is not particularly limited, but for example, 1 mg to 1000 mg, preferably 2 mg to 500 mg, more preferably 5 mg to 300 mg, and still more preferably 20 mg to 200 mg relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0273] As used herein, "dispersant" refers to a substance that improves the fluidity or dispersibility of solid particles, prevents particles from aggregating to some extent when the formulation contacts water, improves the dispersibility of the formulation in water after contact with water, or prevents formulation particles from firmly reaggregating in water. Examples thereof include inorganic salt dispersants, ether dispersants, starch dispersants, cellulose dispersants, fatty acid ester salt dispersants, and the like.

[0274] Examples of the inorganic salt dispersant include light anhydrous silicic acid, magnesium aluminum silicate, and the like.

[0275] Examples of the ether dispersant include polyethylene glycol (polyethylene glycol 600, polyethylene glycol 4000, polyethylene glycol 6000, etc.), propylene glycol, and the like.

[0276] Examples of starch dispersants include corn starch, rice starch, sodium starch glycolate, partially pregelatinized starch, and the like.

[0277] Examples of the cellulose dispersant include crystalline cellulose / sodium carboxymethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and the like.

[0278] Examples of the fatty acid ester salt dispersant include sucrose fatty acid ester, sodium stearyl fumarate, and the like.

[0279] The content of the "dispersant" in the present disclosure is not particularly limited, but is, for example, 0.01 to 10 wt %, preferably 0.1 to 8 wt %, more preferably 0.5 to 5 wt %, still more preferably 1 to 5 wt %, and particularly preferably 2 to 5 wt % relative to the weight of the entire composition.

[0280] As used herein, "suspending agent" refers to a substance added when dispersing / suspending particles in water as a suspension in order to maintain the dispersion of suspended particles, improve ease of administration, etc. A substance having a property of increasing viscosity or a substance having viscosity can be used as a "suspending agent".

[0281] Examples of 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 polymer; cellulose derivatives such as carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and methylcellulose; polyvinyl alcohol, povidone (polyvinyl pyrrolidone), combinations thereof, and the like.

[0282] The content of the "suspending agent" herein is not particularly limited, but is, for example, 0.1 to 600 mg, preferably 1.25 to 300 mg, more preferably 2.5 to 300 mg, and still more preferably 6.25 to 300 mg relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0283] As used herein, a "sweetener" is a flavoring agent used to improve the ease of administration of a formulation or to mask the unpleasant taste of ingredients contained in the formulation by adding a sweet taste to the formulation.

[0284] Examples of the sweetener include aspartame, neotame, advantame, sucralose, saccharin sodium, dipotassium glycyrrhizinate, acesulfame K, maltitol, erythritol, xylitol, trehalose, thaumatin, stevioside and the like.

[0285] The content of the "sweetener" herein is not particularly limited, and is desirably added in an amount sufficient to impart a suitable corrective effect when preparing a suspension, but for example, 0.125 to 900 mg, preferably 1.25 to 600 mg, and more preferably 6.25 to 300 mg relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0286] The pharmaceutical composition of the present disclosure may contain additives that can be used in common formulations, as long as they do not hinder the effects of the present invention. Examples of such additives include, but are not limited to, thickeners, preservatives, stabilizers, buffers, colorants, fragrances, and the like.

[0287] The present disclosure encompasses all forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide (compound of Formula 1) (e.g., tautomers, amorphous, crystalline, various crystalline polymorphs, etc.). The present disclosure also encompasses enantiomers and mixtures thereof. The ratio of the R form of such a mixture is not particularly limited, but is preferably 60% by weight or greater, more preferably 80% by weight or greater, still more preferably 90% by weight or greater, particularly preferably 95% by weight or greater, and most preferably 99% by weight or greater.

[0288] Since the compound of Formula 1 and its pharmaceutically acceptable salts may exist in the form of hydrates and / or solvates, the present disclosure also encompasses such hydrates and solvates, such as ethanol solvates.

[0289] Examples of "pharmaceutically acceptable salts" include, but are not limited to, alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; inorganic metal salts, such as zinc salts; organic basic salts, such as triethylamine, triethanolamine, trishydroxymethylaminomethane and amino acids; inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates and nitrates; organic acid salts, such as acetates, propionates, succinates, lactates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, benzenesulfonates and ascorbates, etc.

[0290] The compound of Formula 1 used in the present disclosure may be crushed as desired.

[0291] In the present disclosure, "medical setting" refers to any setting in which the pharmaceutical compositions of the present disclosure are used, including hospitals, clinics, nursing facilities, and homes (eg, home health care).

[0292] "Modulation" or "modulating" an energy biomarker refers to changing the level of an energy biomarker toward a desired value or changing the level of an energy biomarker in a desired direction (e.g., increasing or decreasing). International Publication No. WO 2016 / 100579 is incorporated by reference. Modulation may include, but is not limited to, normalization and enhancement as defined below.

[0293] "Normalization" of an energy biomarker or "normalizing" an energy biomarker is defined as changing the level of the energy biomarker from a pathological value to a normal value, wherein a normal value of the energy biomarker may be 1) the level of the energy biomarker in a healthy person or subject, or 2) the level of the energy biomarker that alleviates one or more adverse symptoms in a person or subject. That is, normalizing an energy biomarker that is suppressed in a disease state means increasing the level of the energy biomarker toward a normal (healthy) value or toward a value that alleviates adverse symptoms; 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 adverse symptoms.

[0294] "Enhancement" of an energy biomarker or "enhance" an energy biomarker refers to intentionally changing the level of one or more energy biomarkers away from a normal or pre-enhancement value to achieve a beneficial or desired effect. For example, in situations where a significant energy demand is placed on a subject, it may be desirable to increase the level of ATP in the subject to a level that is above the normal level of ATP in the subject. Enhancement may also have a beneficial effect on subjects with a disease or condition, such as mitochondrial disease, where normalizing the energy biomarker may not achieve the best outcome for the subject; in such situations, enhancement of one or more energy biomarkers may be beneficial, for example, higher than normal levels of ATP or lower than normal levels of lactate (lactate) may be beneficial to such a subject.

[0295] Modulating, normalizing or enhancing the energy biomarker Coenzyme Q refers to modulating, normalizing or enhancing one or more variants of Coenzyme Q that are predominant in the species of interest. For example, the predominant variant of Coenzyme Q in humans is Coenzyme Q10. If a species or subject has more than one Coenzyme Q variant present in significant amounts (i.e., present in amounts that can have a beneficial effect on the species or subject when modulated, normalized or enhanced), then 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.

[0296] For the term "respiratory chain disorder", it refers to a disorder in which the utilization of oxygen by mitochondria, cells, tissues or individuals is reduced due to defects or obstacles in proteins or other components contained in the mitochondrial respiratory chain. For "proteins or other components contained in the mitochondrial respiratory chain", it refers to components (including but not limited to proteins, tetrapyrroles and cytochromes) comprising mitochondrial complexes I, II, III, IV and / or V. "Respiratory chain proteins" refer to protein components of those complexes, and "respiratory chain protein disorders" refer to disorders in which the utilization of oxygen by mitochondria, cells, tissues or individuals is reduced due to defects or obstacles in proteins contained in the mitochondrial respiratory chain.

[0297] The term "Parkinson's" (also known as "Parkinsonism" and "Parkinsonian 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 agitan or shaking palsy. It is characterized by tremors, muscle rigidity, and loss of postural reflexes. The disease usually progresses slowly, with an interval of 10 to 20 years before symptoms lead to incapacity. Because animals can mimic the effects of Parkinson's disease, treatment of animals with methamphetamine or MPTP has been used to generate Parkinson's disease models. These animal models have been used to evaluate the efficacy of various Parkinson's disease therapies.

[0298] The term "Friedreich's ataxia" is intended to encompass other related ataxias, and is sometimes also called hereditary ataxias, familial ataxias, or Friedreich's tabes dorsalis.

[0299] The term "ataxia" is a non-specific clinical manifestation, meaning a dysfunction of the part of the nervous system that coordinates movement, such as the cerebellum. People suffering from ataxia have coordination problems because the parts of the nervous system that control movement and balance are affected. Ataxia can affect the fingers, hands, arms, legs, body, speech ability, and eye movements. The word ataxia is often used to describe the uncoordinated symptoms that can be associated with infection, injury, other diseases, or degenerative changes in the central nervous system. Ataxia is also used to represent a group of specific neurodegenerative diseases, which are called hereditary and sporadic ataxias. Ataxia is also often associated with hearing impairment.

[0300] There are three types of ataxia: cerebellar ataxia, including vestibulocerebellar, spinocerebellar, and cerebral-cerebellar dysfunction; sensory ataxia; and vestibular ataxia. Examples of diseases that can be classified as spinocerebellar ataxia or multiple system atrophy are 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 syndrome, alcoholic corticocerebellar atrophy, paraneoplastic cerebellar atrophy associated with malignant tumors, toxic cerebellar atrophy caused by toxic substances, vitamin E deficiency due to tocopherol transfer protein (aTTP) mutation or lipid absorption disorder such as abetalipoproteinemia, cerebellar atrophy associated with endocrine disorders, etc.

[0301] Examples of ataxia symptoms are motor ataxia, truncal ataxia, limb ataxia, etc., autonomic nervous system disorders (such as orthostatic hypotension, dysuria, oligohidrosis, sleep apnea, orthostatic syncope, etc.), lower limb stiffness, nystagmus, oculomotor nerve disorders, pyramidal tract dysfunction, extrapyramidal symptoms (postural adjustment dysfunction, muscle rigidity, akinesia, tremor), dysphagia, tongue atrophy, posterior cord symptoms, muscle atrophy, muscle weakness, deep hyperreflexia, sensory disorders, scoliosis, kyphoscoliosis, foot deformities, stuttering, dementia, manic state, decreased motivation for rehabilitation, etc.

[0302] (Preferred Implementation)

[0303] One embodiment of the present disclosure provides a pharmaceutical composition comprising:

[0304] A compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof:

[0305] [Chemical formula 3]

[0306]

[0307] (Compound 1)

[0308] Adhesives; and

[0309] Dispersant.

[0310] In the present disclosure, the binder may include a binder selected from the group consisting of a cellulose binder, a povidone binder, a vinyl alcohol binder, and a thickening polysaccharide binder.

[0311] In the present disclosure, the cellulose binder may include a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose, and methyl cellulose.

[0312] In the present disclosure, the povidone binder may include a binder selected from povidone and copovidone.

[0313] In the present disclosure, the vinyl alcohol adhesive may include an adhesive selected from polyvinyl alcohol and a polyvinyl alcohol-polyethylene glycol graft copolymer.

[0314] In the present disclosure, the thickening polysaccharide binder may include xanthan gum.

[0315] In the present disclosure, the dispersant may be selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant, and a fatty acid ester salt dispersant.

[0316] In the present disclosure, the inorganic salt dispersant may include a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

[0317] In the present disclosure, the ether dispersant may include polyethylene glycol 6000.

[0318] In the present disclosure, the starch dispersant may include corn starch.

[0319] In the present disclosure, the cellulose dispersant may include a dispersant selected from the group consisting of crystalline cellulose / sodium carboxymethyl cellulose, carboxymethyl cellulose, and calcium carboxymethyl cellulose.

[0320] In the present disclosure, the fatty acid ester salt dispersant may include sodium stearyl fumarate.

[0321] In the present disclosure, the binder may include a cellulose binder, and

[0322] The dispersant may include a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant, and a fatty acid ester salt dispersant.

[0323] In the present disclosure, the binder may include a cellulose binder, and

[0324] The dispersant may include a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, and a cellulose dispersant.

[0325] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0326] The dispersant may include a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate, and calcium carboxymethyl cellulose.

[0327] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0328] The dispersant may include a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch and carboxymethyl cellulose.

[0329] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0330] The dispersant may include a dispersant selected from light anhydrous silicic acid, corn starch, carboxymethyl cellulose, polyethylene glycol 6000, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate, and calcium carboxymethyl cellulose.

[0331] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0332] The dispersant may include a dispersant selected from light anhydrous silicic acid, corn starch, and carboxymethyl cellulose.

[0333] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0334] The dispersant may include light anhydrous silicic acid.

[0335] In the present disclosure, the binder may include hypromellose, and

[0336] The dispersant may include a dispersant selected from light anhydrous silicic acid dispersants and polyethylene glycol 6000.

[0337] In the present disclosure, the binder may include hypromellose, and

[0338] The dispersant may include light anhydrous silicic acid.

[0339] In the present disclosure, the binder may include methyl cellulose, and

[0340] The dispersant may include light anhydrous silicic acid.

[0341] In the present disclosure, the adhesive may include a povidone adhesive, and

[0342] The dispersant may include a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant, and a fatty acid ester salt dispersant.

[0343] In the present disclosure, the adhesive may include a povidone adhesive, and

[0344] The dispersant may include a dispersant selected from an inorganic salt dispersant and a cellulose dispersant.

[0345] In the present disclosure, the adhesive may include copolyvidone, and

[0346] The dispersant may include a dispersant selected from light anhydrous silicic acid and crystalline cellulose / sodium carboxymethyl cellulose.

[0347] In the present disclosure, the binder may include a cellulose binder, and

[0348] The dispersant may include an inorganic salt dispersant.

[0349] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0350] The dispersant may include a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

[0351] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and

[0352] The dispersant may include light anhydrous silicic acid.

[0353] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose and hypromellose, and

[0354] The dispersant may include light anhydrous silicic acid.

[0355] In the present disclosure, the binder may include a cellulose binder, and

[0356] The dispersant may include an ether dispersant.

[0357] In the present disclosure, the binder may include a binder selected from hydroxypropyl cellulose and hypromellose, and

[0358] The dispersant may include polyethylene glycol 6000.

[0359] In the present disclosure, the binder may include hypromellose, and

[0360] The dispersant may include polyethylene glycol 6000.

[0361] In the present disclosure, the binder may include a cellulose binder, and

[0362] The dispersant may include a starch dispersant.

[0363] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0364] The dispersant may include corn starch.

[0365] In the present disclosure, the binder may include a cellulose binder, and

[0366] The dispersant may include a cellulosic dispersant.

[0367] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0368] The dispersant may include a dispersant selected from carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose.

[0369] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0370] The dispersant may include a dispersant selected from crystalline cellulose / sodium carboxymethylcellulose and calcium carboxymethylcellulose.

[0371] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0372] The dispersant may include carboxymethyl cellulose.

[0373] In the present disclosure, the binder may include a cellulose binder, and

[0374] The dispersant may include a fatty acid ester salt dispersant.

[0375] In the present disclosure, the binder may include hydroxypropyl cellulose, and

[0376] The dispersant may include sodium stearyl fumarate.

[0377] In the present disclosure, the adhesive may include a povidone adhesive, and

[0378] The dispersant may include a cellulosic dispersant.

[0379] In the present disclosure, the adhesive may include copolyvidone, and

[0380] The dispersant may include light anhydrous silicic acid.

[0381] In the present disclosure, the adhesive may include a povidone adhesive, and

[0382] The dispersant may include an inorganic salt dispersant.

[0383] In the present disclosure, the binder may include a binder selected from copolyvidone, povidone (nominal K value: 29 to 32) and povidone (nominal K value: 17), and

[0384] The dispersant may include light anhydrous silicic acid.

[0385] In the present disclosure, the binder may include a binder selected from copolyvidone and povidone (nominal K value: 29 to 32), and

[0386] The dispersant may include light anhydrous silicic acid.

[0387] In the present disclosure, the adhesive may include a vinyl alcohol adhesive, and

[0388] The dispersant may include an inorganic salt dispersant.

[0389] In the present disclosure, the binder may include a binder selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0390] The dispersant may include light anhydrous silicic acid.

[0391] In the present disclosure, the adhesive may include polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0392] The dispersant may include light anhydrous silicic acid.

[0393] In the present disclosure, the adhesive may include a vinyl alcohol adhesive, and

[0394] The dispersant may include a cellulosic dispersant.

[0395] In the present disclosure, the binder may include a binder selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and

[0396] The dispersant may include crystalline cellulose / sodium carboxymethyl cellulose.

[0397] In the present disclosure, the adhesive may include a thickening polysaccharide adhesive, and

[0398] The dispersant may include an inorganic salt dispersant.

[0399] In the present disclosure, the binder may include xanthan gum, and

[0400] The dispersant may include light anhydrous silicic acid.

[0401] In the present disclosure, the pharmaceutical composition may include a suspending agent.

[0402] In the present disclosure, the suspending agent may include a carboxyvinyl polymer.

[0403] In the present disclosure, the pharmaceutical composition may include a sweetener.

[0404] In the present disclosure, the sweetener may include sucralose.

[0405] In the present disclosure, the pharmaceutical composition may include 1 mg to 1000 mg of a binder relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0406] In the present disclosure, the pharmaceutical composition may contain 0.01 to 10 wt % of the dispersant relative to the weight of the entire composition.

[0407] In the present disclosure, the pharmaceutical composition may contain 1 mg to 1000 mg of the suspending agent relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0408] In the present disclosure, the pharmaceutical composition may include 1 mg to 1000 mg of a sweetener relative to 1000 mg of the compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof.

[0409] One embodiment of the present disclosure provides particles for suspension for manufacturing a pharmaceutical composition, comprising the pharmaceutical composition according to any one of the aforementioned embodiments.

[0410] In the present disclosure, the suspending particles may be suspending particles used for preparing a suspension.

[0411] One embodiment of the present disclosure provides particles for suspension for use in the manufacture of a pharmaceutical composition, wherein the particles for suspension are the pharmaceutical composition according to any one of the aforementioned embodiments.

[0412] In the present disclosure, the suspending particles may be suspending particles used for preparing a suspension.

[0413] One embodiment of the present disclosure provides the pharmaceutical composition according to any one of the aforementioned embodiments, which is a suspension particle for manufacturing a pharmaceutical composition.

[0414] In the present disclosure, the pharmaceutical composition may be suspension particles for preparing a suspension.

[0415] One embodiment of the present disclosure provides a suspension comprising the pharmaceutical composition according to any one of the aforementioned embodiments, which is a suspension particle for preparing the pharmaceutical composition.

[0416] In the present disclosure, the pharmaceutical composition may be in a suspended state.

[0417] One embodiment of the present disclosure provides 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 the pharmaceutical composition of any one of the aforementioned embodiments or the suspension of the aforementioned embodiments.

[0418] One embodiment of the present disclosure provides a method for preparing the pharmaceutical composition of any one of the aforementioned embodiments or the suspension of the aforementioned embodiments, comprising mixing the compound or a pharmaceutically acceptable salt or solvate thereof, the binder and a dispersant.

[0419] One embodiment of the present disclosure provides a method for preparing a pharmaceutical composition, which comprises mixing the suspension particles according to any one of the aforementioned embodiments with necessary additives and / or a suspension solvent (eg, comprising an aqueous solvent, such as purified water).

[0420] One embodiment of the present disclosure provides a method of preparing a pharmaceutical composition for administration to a subject in a medical setting, comprising mixing the suspension particles of any of the preceding embodiments with necessary additives and / or a suspension solvent (eg, comprising an aqueous solvent such as purified water).

[0421] One embodiment of the present disclosure provides the pharmaceutical composition of any of the preceding embodiments, the particles for suspension of any of the preceding embodiments, the suspension of any of the preceding embodiments, or the method of any of the preceding embodiments for treating or inhibiting oxidative stress disorders, regulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers.

[0422] One embodiment of the present disclosure provides a pharmaceutical composition according to any one of the preceding embodiments, a particle for suspension according to any one of the preceding embodiments, or a method according to any one of the preceding embodiments, for treating or inhibiting an oxidative stress disorder selected from the group consisting of: mitochondrial disease; inherited mitochondrial disease; Alpers disease; Barthel syndrome; beta-oxidation deficiency; carnitine acylcarnitine 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 acidemia type II; Kearns-Sell syndrome (KSS); lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCAD); LCHAD; Leber syndrome; Leber-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 myopathy, encephalopathy, lactic acidosis, stroke (MELAS); myoclonic Epilepsy with ragged red fibers (MERRF); mitochondrial recessive ataxia syndrome (MIRAS); mitochondrial cytopathy, mitochondrial DNA deletion; mitochondrial encephalopathy; mitochondrial myopathy; myoneural gastrointestinal disease and encephalopathy (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutation; respiratory chain disorders; short-chain acyl-CoA dehydrogenase deficiency (SCAD); SCHAD; very long-chain acyl-CoA dehydrogenase deficiency (VLCA D); myopathy; cardiomyopathy; encephalomyopathy; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); motor neuron disease; neurological diseases; 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; autism; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett's syndrome; PDD-NOS; cerebrovascular accident; stroke; visual impairment; optic nerve menstrual lesions; dominant juvenile optic atrophy; optic neuropathy caused by toxic agents; glaucoma; Stargardt macular dystrophy; diabetic retinopathy; diabetic maculopathy; retinopathy of prematurity; retinal damage associated with ischemia-reperfusion; oxygen toxicity; hemoglobinopathies; thalassemia; sickle cell anemia; epilepsy; ischemia; renal tubular acidosis; attention-deficit / hyperactivity disorder (ADHD); neurodegenerative diseases resulting in hearing or balance impairment; dominant optic atrophy (DOA); maternally inherited diabetes and hearing loss (MIDD);chronic fatigue; contrast-induced renal injury; contrast-induced retinopathy injury; abetalipoproteinemia; retinitis pigmentosa; Wolfram'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; NGLY1; multiple system atrophy; adrenoleukodystrophy; and adrenoleuroneuropathy.

[0423] One embodiment of the present disclosure provides the pharmaceutical composition, the suspension, the particles for suspension, or the method according to any one of the preceding embodiments, for treating or inhibiting amyotrophic lateral sclerosis (ALS).

[0424] Diseases that can be treated or inhibited by the compositions and methods of the present disclosure

[0425] Various disorders / diseases are believed to be caused or exacerbated by oxidative stress that affects normal electron flow in cells, such as mitochondrial diseases, disorders of impaired energy processing, neurodegenerative diseases, and diseases of aging, and can be treated or inhibited using the compositions of the present disclosure.

[0426] For example, non-limiting examples of oxidative stress disorders include mitochondrial diseases (including inherited mitochondrial diseases), such as Alpers disease, Barthel syndrome, beta oxidation defects, carnitine acylcarnitine 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 acidemia type II, Kearns-Sell syndrome (KSS), lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency (LCAD), LCHAD, Leber's disease or syndrome, Leber-like syndrome, Leber hereditary optic neuropathy (LHON, also known as 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, lactic acidosis, stroke (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mitochondrial cell disease, mitochondrial DNA deletion, mitochondrial encephalopathy, mitochondrial myopathy, myoneurogenic gastrointestinal disease and encephalopathy (MNGIE), neuropathy, ataxia, and pigmented retinopathy meningitis (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), myopathies such as cardiomyopathy and encephalomyopathy; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease); motor neuron disease; neurological diseases such as epilepsy age-related diseases, particularly those for which CoQIO is proposed to treat, such as macular degeneration, diabetes (e.g., type 2 diabetes), 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 autism, Asperger's syndrome, childhood disintegrative disorder (CDD), Rett syndrome, and PDD-NOS; cerebrovascular accidents, such as stroke;Visual disorders, such as those caused by neurodegenerative diseases of the eye, such as optic neuropathy, Leber hereditary optic neuropathy, dominant juvenile optic atrophy, optic neuropathy caused by toxic agents, glaucoma, age-related macular degeneration ("dry" or non-exudative macular degeneration and "wet" or exudative macular degeneration), Stargardt's macular dystrophy, diabetic retinopathy, diabetic maculopathy, retinopathy of prematurity or retinal damage associated with ischemia-reperfusion; disorders caused by energy impairment including those due to hypoxia, oxygen toxicity or oxygen toxicity and qualitative or quantitative interruption of oxygen transport, such as hemoglobinopathies, for example thalassemia or sickle cell anemia; other diseases related to mitochondrial dysfunction, such as excitotoxicity, neuronal damage, such as those associated with epilepsy, stroke and ischemia; and Other disorders include renal tubular acidosis; attention-deficit / hyperactivity disorder (ADHD); neurodegenerative diseases resulting in hearing or balance impairment; dominant optic atrophy (DOA); maternally inherited diabetes and hearing loss (MIDD); chronic fatigue; contrast-induced renal injury; contrast-induced retinopathy injury; abetalipoproteinemia; retinitis pigmentosa; Wolfram'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 (e.g., noise-induced hearing loss); traumatic brain injury; juvenile Huntington's disease; multiple sclerosis; NGLY1; multiple system atrophy; adrenoleukodystrophy; and adrenomyoeloneuropathy. It is understood that certain specific diseases or disorders may belong to more than one category; for example, Huntington's disease is a genetic disease as well as a neurological disease. In addition, certain oxidative stress diseases and disorders may also be considered mitochondrial diseases. International Publication No. WO 2016 / 100579 is incorporated by reference. ;

[0427] The compound represented by Formula 1 (Compound 1) has an unpleasant taste, which is masked by a sweetener in this formulation. The particles are combined with a binder and prepared as granules (macroparticles) to obtain manufacturability and handling during distribution, and a dispersant is used to impart fluidity. Dispersibility is imparted with a dispersant to suspend in water. When designing formulations with such characteristics, the suspended particle size / hydration growth of the drug is observed over time after the suspension is prepared.

[0428] Such changes impair the properties of the formulation. Size growth of suspended particles reduces dispersion stability and drug uniformity in the suspension with which it is associated, and hydration of the drug leads to discoloration and changes in appearance via growth of hydrates / growth of particle size. Increased size of particles or drugs has an adverse effect on ease of oral administration (foreign body sensation, etc.) and causes clogging of feeding tubes administered therethrough in patients treated via gastrostomy tubes.

[0429] The pharmaceutical composition of the present disclosure has excellent dispersibility, which is beneficial for preparing a suspension, and inhibits hydrate formation and crystal growth, such inhibition being beneficial over time after preparing a suspension.

[0430] (Preparation method)

[0431] Crude crystals of compound 1 are crushed as needed to obtain compound 1 for preparing a formulation. Although the active pharmaceutical ingredient / raw material is usually crushed as needed to design a homogeneous and uniform formulation, when there is no problem in the design of the formulation, the active pharmaceutical ingredient / raw material can be used directly. For example, compound 1 can be obtained by the method described in WO 2021 / 167095.

[0432] The specific example of the preparation method of the preparation is described below; however, the preparation method of the preparation is not limited thereto. Compound 1, a binder, a suspending agent and a sweetener are mixed as the raw materials of the preparation. The mixture is loaded into a preparation mixer. Purified water is gradually added as granulation water, and the mixture is mixed / stirred, and the mixture is repeatedly mixed / stirred and purified water is added to obtain particles. The particles are subjected to wet sieving and dried via a sieve to obtain dry particles. The dry particles are subjected to dry sieving via a sieve to obtain particles.

[0433] The granules and the dispersant are mixed, and the whole amount is sieved with a sieve. The sieved products are mixed to obtain a formulation.

[0434] In addition to the preparation method described above, the formulation can also be prepared by, for example, the following method. Mix compound 1, suspending agent, sweetener and (if necessary) adhesive as formulation raw materials. The mixture is loaded into a stirring granulator, purified water or an aqueous adhesive solution is added, and the mixture is stirred and granulated to obtain particles. If necessary, the particles are subjected to wet screening and dried with a fluidized bed granulator or the like to obtain dry particles. Dry particles are subjected to dry screening as required to obtain particles. The formulation can be obtained by mixing particles and dispersants.

[0435] As a granulation method, a wet granulation method is preferred, and examples thereof include a stirring granulation method, a fluidized bed granulation method, an extrusion granulation method, and a kneading granulation method. Examples of a method of adding a binder include adding it in a powder form together with the formulation raw materials, and adding the binder by dissolving it in a solvent as a granulation liquid when granulating other formulation raw materials. [Example]

[0436] The present invention is described in more detail below by way of Examples, Reference Examples, Test Examples, etc., but the present invention is not limited thereto.

[0437] The following examples, reference examples, etc. use the following carboxyvinyl polymer, sucralose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone, copovidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, xanthan gum, light anhydrous silicic acid, magnesium aluminum silicate, polyethylene glycol 6000, corn starch, crystalline cellulose / sodium carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium and sodium stearyl fumarate, but the present invention is not limited thereto.

[0438] *Carboxyvinyl polymer: Carbopol 971P (Lubrizol)

[0439] *Sucralose: Sucralose (Merck)

[0440] *Hydroxypropylcellulose: HPC-L fine powder = (Nippon Soda Co., Ltd.)

[0441] *Hydroxypropyl methylcellulose: TC-5R (Shin-Etsu Chemical Co., Ltd.)

[0442] *Methylcellulose: SM-4 (Shin-Etsu Chemical Co., Ltd.)

[0443] *Polyvidone (nominal K value: 17): Kollidon 17PF (BASF)

[0444] *Polyvidone (nominal K value: 29 to 32): Plasdone K29 / 32 (Ashland)

[0445] * Copolyvidone: Kollidon VA 64 (BASF)

[0446] *Polyvinyl alcohol: GOHSENOL EG-05PW (Mitsubishi Chemical Corporation)

[0447] *Polyvinyl alcohol / polyethylene glycol / graft copolymer: Kollicoat IR (BASF)

[0448] *Xanthan gum: Keltrol T (Sumitomo Pharma Food & Chemical Co., Ltd.)

[0449] *Light anhydrous silicic acid: AEROSIL 200 (EVONIK)

[0450] *Magnesium aluminum silicate: Neusilin FL2 (Fuji Chemical Industries Co., Ltd.)

[0451] *Macrogol 6000 (SP) (Sanyo Chemical Industries, Ltd.)

[0452] *Corn starch: Japanese food and medical grade corn starch XX16 (Nihon Shokuhin Kako Co., Ltd.)

[0453] *Crystalline cellulose / sodium carboxymethyl cellulose: Ceolus RC-A591NF (Asahi Kasei Corporation)

[0454] *Carboxymethyl cellulose: NS-300 (Gotoku Chemical Company Ltd.)

[0455] *Carboxymethylcellulose calcium: ECG-505 (Gotoku Chemical Company Ltd.)

[0456] *Sodium stearyl fumarate: PRUV (Ashland)

[0457] The purified water used to make the formulations was “Japanese Pharmacopoeia Purified Water” (Takasugi Pharmaceutical Co., Ltd.).

[0458] Examples 1 to 21 and Reference Example 1

[0459] The formulations of Examples 1 to 21 and Reference Example 1 were prepared by the following method by using Compound 1 and additives in the amounts specified in the following table.

[0460] (1) Preparation of Compound 1

[0461] The uncrushed Compound 1 was crushed using a pulverizer QUADROCOMIL (Powrex Corp) to adjust the crude crystals of Compound 1 to a suitable particle size to obtain Compound 1 for preparing a formulation.

[0462] (2) Preparation of Granule A

[0463] Compound 1 (60 g), hydroxypropylcellulose (9.9 g), carboxyvinyl polymer (0.6 g) and sucralose (1.5 g) were placed in a plastic bag as the raw materials of the formulation and mixed therein. The mixture was loaded into a preparation mixer YM-Q-7 (DALTON Corporation). Purified water (20.5 g) was gradually added as granulation water while repeatedly mixing / stirring the mixture and adding purified water. The mixture was then stirred and mixed with the preparation mixture for 3 minutes to obtain particles. The particles were subjected to wet sieving through a metal sieve with a pore size of 710 μm, expanded on a paper plate, and dried at 40°C with a hot dryer (laboratory glassware dryer DRU600TB / Advantec) for 16 hours or more to obtain dry particles. The dry particles were subjected to dry sieving through a metal sieve with a pore size of 850 μm to obtain particles A.

[0464] (3) Preparation of Granule B

[0465] Granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (3.6 g) was used as granulation water to obtain Granules B.

[0466] (4) Preparation of Granule C

[0467] Granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (2.8 g) was used as granulation water to obtain Granules C.

[0468] (5) Preparation of Particle D

[0469] Granules were prepared by the same preparation method as Granules A, except that Compound 1 (18 g), povidone (nominal K value: 29 to 32) (2.97 g), carboxyvinyl polymer (0.18 g) and sucralose (0.45 g) were used as raw materials for the formulation and purified water (2.3 g) was used as granulation water to obtain Granules D.

[0470] (6) Preparation of Granule E

[0471] Granules were prepared by the same preparation method as Granule A, except that Compound 1 (18 g), carboxyvinyl polymer (0.18 g) and sucralose (0.45 g) were used as raw materials for the formulation and purified water (2.6 g) was used as granulation water to obtain Granules E.

[0472] (7) Preparation of Granule F

[0473] Granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (4.1 g) was used as granulation water to obtain Granules F.

[0474] (8) Preparation of Granule G

[0475] Granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (2.7 g) was used as granulation water to obtain Granules G.

[0476] (9) Preparation of Particle H

[0477] The granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (2.5 g) was used as granulation water to obtain granules H.

[0478] (10) Preparation of Granules I

[0479] The granules were prepared by the same preparation method as Granules A, except that Compound 1 (18 g), povidone (nominal K value: 17) (2.97 g), carboxyvinyl polymer (0.18 g) and sucralose (0.45 g) were used as raw materials for the formulation and purified water (2.5 g) was used as granulation water to obtain Granules I.

[0480] (11) Preparation of Particle J

[0481] Granules were prepared by the same preparation method as 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 raw materials for the formulation and purified water (2.5 g) was used as granulation water to obtain Granule J.

[0482] (12) Preparation of Particle K

[0483] Granules were prepared by the same preparation method as Granule A, except that Compound 1 (18 g) and hydroxypropylcellulose (2.97 g) were used as raw materials for formulation and purified water (2.9 g) was used as granulation water, to obtain Granules K.

[0484] (13) Preparation of Example 1

[0485] Granule A (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was retrieved in a plastic bag and mixed therein to obtain the formulation of Example 1.

[0486] (14) Preparation of Example 2

[0487] Granule B (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 2.

[0488] (15) Preparation of Example 3

[0489] Granule C (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 3.

[0490] (16) Preparation of Example 4

[0491] Granules H (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 4.

[0492] (17) Preparation of Example 5

[0493] Granule B (7.2 g) and polyethylene glycol 6000 (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having a pore size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 5.

[0494] (18) Preparation of Example 6

[0495] Granule A (7.2 g) and corn starch (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 6.

[0496] (19) Preparation of Example 7

[0497] Granule A (7.2 g) and carboxymethyl cellulose (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 7.

[0498] (20) Preparation of Example 8

[0499] Granules H (7.2 g) and crystalline cellulose / sodium carboxymethylcellulose (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 8.

[0500] (21) Preparation of Example 9

[0501] Granule A (7.2 g) and polyethylene glycol 6000 (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having a pore size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 9.

[0502] (22) Preparation of Example 10

[0503] Granule A (7.2 g) and crystalline cellulose / sodium carboxymethylcellulose (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 10.

[0504] (23) Preparation of Example 11

[0505] Granule A (7.2 g) and sodium stearyl fumarate (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve with an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 11.

[0506] (24) Preparation of Example 12

[0507] Granule A (7.2 g) and carboxymethylcellulose calcium (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve with an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 12.

[0508] (25) Preparation of Example 13

[0509] Granules F (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 13.

[0510] (26) Preparation of Example 14

[0511] Granule G (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 14.

[0512] (27) Preparation of Example 15

[0513] Granule J (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 15.

[0514] (28) Preparation of Example 16

[0515] Granules F (7.2 g) and crystalline cellulose / sodium carboxymethylcellulose (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 16.

[0516] (29) Preparation of Example 17

[0517] Granule G (7.2 g) and crystalline cellulose / sodium carboxymethylcellulose (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 17.

[0518] (30) Preparation of Example 18

[0519] Granule A (7.2 g) and magnesium aluminum silicate (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 18.

[0520] (31) Preparation of Example 19

[0521] Granule D (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 19.

[0522] (32) Preparation of Example 20

[0523] Granules I (7.2 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 20.

[0524] (33) Preparation of Example 21

[0525] Granules K (6.99 g) and light anhydrous silicic acid (0.3 g) were placed in a plastic bag and mixed therein. The entire amount was sieved through a metal sieve having an aperture size of 850 μm. The sieved product was recovered in a plastic bag and mixed therein to obtain the formulation of Example 21.

[0526] (34) Preparation of Reference Example 1

[0527] Granules E (6.21 g) were put into a plastic bag and mixed therein to obtain a formulation of Reference Example 1.

[0528]

[0529]

[0530] Test Example 1 (Water Dispersion of the Prepared Formulation)

[0531] The ease of suspension when the formulation of the present invention is administered as a suspension is evaluated by using the water dispersion of the formulation as an indicator. The specific evaluation method is described below.

[0532] Each formulation (Examples 1 to 21 and Reference Example 1) in an amount corresponding to 1000 mg of Compound 1 was measured in a 20 mL volume transparent glass bottle (screw cap bottle 20 ml No. 5 / Maruemu Corporation). 8.8 mL of purified water was placed therein and a cap (screw cap No. 5 / Maruemu Corporation) was placed thereon. Immediately thereafter, the mixture was stirred up and down with one hand so that the container would be inverted 60 times. The dispersibility of the formulation was studied. The dispersibility evaluation criteria are specified below. Each formulation was tested at n = 3 to evaluate its average score.

[0533] <Evaluation Criteria>

[0534] Score: Assessment

[0535] 5: Homogeneous dispersion

[0536] 4: Homogeneous dispersion, without large and coarse particles, which can cause problems during oral administration or adhere to the inner wall of the bottle

[0537] 3: Dispersed, no large or coarse particles, which can cause problems during oral administration or adhere to the inner wall of the bottle

[0538] 2: Has a small amount of large and coarse particles, which can cause problems during oral administration or adhere to the inner wall of the bottle, requiring additional stirring

[0539] 1: Has many large and coarse particles, which can cause problems during oral administration or adhere to the inner wall of the bottle, requiring additional stirring

[0540] Test Example 2 (Crystal Growth and Hydrate Formation after Preparation of Suspension)

[0541] When the formulation of the present invention is prepared as a suspension, the stability of the formulation of the present invention with respect to storage is evaluated by using the crystal growth and hydrate formation of Compound 1 in the suspension formulation as indicators. The specific method is described below.

[0542] Each formulation (Examples 1 to 21 and Reference Example 1) in an amount corresponding to 1000 mg of Compound 1 was measured in a 20 mL volume transparent glass bottle (screw cap bottle 20 ml No. 5 / Maruemu Corporation). 8.8 mL of purified water was placed therein and a cap (screw cap No. 5 / Maruemu Corporation) was placed thereon. Immediately thereafter, the container was stirred up and down with one hand so that the container would be inverted 60 times to disperse the mixture. At this time, the insufficiently dispersed sample was further stirred to prepare a suspension.

[0543] The formulation prepared as a suspension was stored at 5°C for 3 days, 7 days, 14 days or 1 month. The degree of crystal growth and hydrate formation during each storage period was evaluated by visual inspection of appearance and microscopic observation. The evaluation criteria for crystal growth and hydrate formation were specified as follows.

[0544] <Evaluation Criteria>

[0545] Symbol: Evaluate

[0546] ×: No crystal growth or hydrate formation was found by visual inspection or microscopic observation

[0547] ○: No crystal growth or hydrate formation was observed by visual inspection, but crystal growth or hydrate formation was observed by microscopic observation

[0548] X: Crystal growth and hydrate formation were found both through visual inspection of appearance and microscopic observation. Therefore, the evaluation of × was the best evaluation.

[0549] [Table 3-1]

[0550] Test results for each formulation

[0551]

[0552] [Table 3-2]

[0553]

[0554]

[0555] [Table 3-3]

[0556]

[0557] The formulations having a score of 2 or more in Test Example 1 and having a hydrate formation of × even in 3 days in Test Example 2 were used as Examples.

[0558] Industrial Applicability

[0559] The present disclosure provides a pharmaceutical composition.

[0560] This application is based on patent application No. 2022-144675 filed in Japan (filing date: September 12, 2022), the contents of which are incorporated herein in their entirety.

Claims

1. A pharmaceutical composition comprising: A compound represented by Formula 1 or a pharmaceutically acceptable salt or solvate thereof: [Chemical formula 1] Adhesives; and Dispersant.

2. The pharmaceutical composition of claim 1, wherein the binder comprises a binder selected from the group consisting of a cellulose binder, a povidone binder, a vinyl alcohol binder, and a thickening polysaccharide binder.

3. The pharmaceutical composition of claim 2, wherein the cellulose binder comprises a binder selected from the group consisting of hydroxypropyl cellulose, hypromellose and methyl cellulose.

4. The pharmaceutical composition of claim 2, wherein the povidone binder comprises a binder selected from the group consisting of povidone and copovidone.

5. The pharmaceutical composition of claim 2, wherein the vinyl alcohol adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer.

6. The pharmaceutical composition of claim 2, wherein the thickening polysaccharide binder comprises xanthan gum.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the dispersant is selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

8. The pharmaceutical composition of claim 7, wherein the inorganic salt dispersant comprises a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

9. The pharmaceutical composition of claim 7, wherein the ether dispersant comprises polyethylene glycol 6000.

10. The pharmaceutical composition of claim 7, wherein the starch dispersant comprises corn starch.

11. The pharmaceutical composition of claim 7, wherein the cellulose dispersant comprises a dispersant selected from the group consisting of crystalline cellulose / sodium carboxymethylcellulose, carboxymethylcellulose and calcium carboxymethylcellulose.

12. The pharmaceutical composition of claim 7, wherein the fatty acid ester salt dispersant comprises sodium stearyl fumarate.

13. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

14. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant and a cellulose dispersant.

15. The pharmaceutical composition of claim 1, wherein The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and The dispersant includes a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch, carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate and calcium carboxymethyl cellulose.

16. The pharmaceutical composition of claim 1, wherein The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and The dispersant includes a dispersant selected from light anhydrous silicic acid, polyethylene glycol 6000, corn starch and carboxymethyl cellulose.

17. The pharmaceutical composition of claim 1, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes a dispersant selected from light anhydrous silicic acid, corn starch, carboxymethyl cellulose, polyethylene glycol 6000, crystalline cellulose / sodium carboxymethyl cellulose, magnesium aluminum silicate, sodium stearyl fumarate and calcium carboxymethyl cellulose.

18. The pharmaceutical composition of claim 1, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes a dispersant selected from light anhydrous silicic acid, corn starch and carboxymethyl cellulose.

19. The pharmaceutical composition of claim 1, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes light anhydrous silicic acid.

20. The pharmaceutical composition of claim 1, wherein The binder comprises hypromellose, and The dispersant includes a dispersant selected from light anhydrous silicic acid and polyethylene glycol 6000.

21. The pharmaceutical composition of claim 1, wherein The binder comprises hypromellose, and The dispersant includes light anhydrous silicic acid.

22. The pharmaceutical composition of claim 1, wherein The binder comprises methylcellulose, and The dispersant includes light anhydrous silicic acid.

23. The pharmaceutical composition of claim 1, wherein The adhesive comprises a povidone adhesive, and The dispersant includes a dispersant selected from an inorganic salt dispersant, an ether dispersant, a starch dispersant, a cellulose dispersant and a fatty acid ester salt dispersant.

24. The pharmaceutical composition of claim 1, wherein The adhesive comprises a povidone adhesive, and The dispersant includes a dispersant selected from an inorganic salt dispersant and a cellulose dispersant.

25. The pharmaceutical composition of claim 1, wherein The binder comprises copolyvidone, and The dispersant includes a dispersant selected from light anhydrous silicic acid and crystalline cellulose / sodium carboxymethyl cellulose.

26. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes an inorganic salt dispersant.

27. The pharmaceutical composition of claim 26, wherein The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and The dispersant includes a dispersant selected from light anhydrous silicic acid and magnesium aluminum silicate.

28. The pharmaceutical composition of claim 27, wherein The binder comprises a binder selected from hydroxypropyl cellulose, hypromellose and methyl cellulose, and The dispersant includes light anhydrous silicic acid.

29. The pharmaceutical composition of claim 28, wherein The binder comprises a binder selected from hydroxypropyl cellulose and hypromellose, and The dispersant includes light anhydrous silicic acid.

30. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes an ether dispersant.

31. The pharmaceutical composition of claim 30, wherein The binder comprises a binder selected from hydroxypropyl cellulose and hypromellose, and The dispersant includes polyethylene glycol 6000.

32. The pharmaceutical composition of claim 31, wherein The binder comprises hypromellose, and The dispersant includes polyethylene glycol 6000.

33. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes a starch dispersant.

34. The pharmaceutical composition of claim 33, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes corn starch.

35. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes a cellulose dispersant.

36. The pharmaceutical composition of claim 35, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes a dispersant selected from carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose and calcium carboxymethyl cellulose.

37. The pharmaceutical composition of claim 36, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes a dispersant selected from crystalline cellulose / sodium carboxymethylcellulose and calcium carboxymethylcellulose.

38. The pharmaceutical composition of claim 36, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes carboxymethyl cellulose.

39. The pharmaceutical composition of claim 1, wherein The binder comprises a cellulose binder, and The dispersant includes a fatty acid ester salt dispersant.

40. The pharmaceutical composition of claim 39, wherein The binder comprises hydroxypropyl cellulose, and The dispersant includes sodium stearyl fumarate.

41. The pharmaceutical composition of claim 1, wherein The adhesive comprises a povidone adhesive, and The dispersant includes a cellulose dispersant.

42. The pharmaceutical composition of claim 41, wherein The binder comprises copolyvidone, and The dispersant includes crystalline cellulose / sodium carboxymethyl cellulose.

43. The pharmaceutical composition of claim 1, wherein The adhesive comprises a povidone adhesive, and The dispersant includes an inorganic salt dispersant.

44. The pharmaceutical composition of claim 43, wherein The binder comprises a binder selected from copolyvidone, povidone (nominal K value: 29 to 32) and povidone (nominal K value: 17), and The dispersant includes light anhydrous silicic acid.

45. The pharmaceutical composition of claim 44, wherein The binder comprises a binder selected from copolyvidone and povidone (nominal K value: 29 to 32), and The dispersant includes light anhydrous silicic acid.

46. ​​The pharmaceutical composition of claim 1, wherein The adhesive comprises a vinyl alcohol adhesive, and The dispersant includes an inorganic salt dispersant.

47. The pharmaceutical composition of claim 46, wherein The adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and The dispersant includes light anhydrous silicic acid.

48. The pharmaceutical composition of claim 47, wherein The adhesive comprises polyvinyl alcohol / polyethylene glycol / graft copolymer, and The dispersant includes light anhydrous silicic acid.

49. The pharmaceutical composition of claim 1, wherein The adhesive comprises a vinyl alcohol adhesive, and The dispersant includes a cellulose dispersant.

50. The pharmaceutical composition of claim 49, wherein The adhesive comprises an adhesive selected from polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol / graft copolymer, and The dispersant includes crystalline cellulose / sodium carboxymethyl cellulose.

51. The pharmaceutical composition of claim 1, wherein The binder comprises a thickening polysaccharide binder, and The dispersant includes an inorganic salt dispersant.

52. The pharmaceutical composition of claim 51, wherein The binder comprises xanthan gum, and The dispersant includes light anhydrous silicic acid.

53. A pharmaceutical composition as described in any one of claims 1 to 52, wherein the pharmaceutical composition comprises a suspending agent.

54. The pharmaceutical composition of claim 53, wherein the suspending agent comprises a carboxyvinyl polymer.

55. A pharmaceutical composition as described in any one of claims 1 to 54, wherein the pharmaceutical composition comprises a sweetener.

56. The pharmaceutical composition of claim 55, wherein the sweetener comprises sucralose.

57. The pharmaceutical composition of any one of claims 1 to 56, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a binder relative to 1000 mg of a compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

58. A pharmaceutical composition as described in any one of claims 1 to 57, wherein the pharmaceutical composition comprises 0.01 to 10 wt % of a dispersant relative to the weight of the entire composition.

59. A pharmaceutical composition as described in any one of claims 1 to 58, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a suspending agent relative to 1000 mg of a compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

60. The pharmaceutical composition of any one of claims 1 to 59, wherein the pharmaceutical composition comprises 1 mg to 1000 mg of a sweetener relative to 1000 mg of the compound represented by Formula I or a pharmaceutically acceptable salt or solvate thereof.

61. A suspension particle for use in the manufacture of a pharmaceutical composition, comprising the pharmaceutical composition of any one of claims 1 to 60.

62. The suspending particles according to claim 61, which are used for preparing suspending particles for suspension.

63. A suspension particle for use in the manufacture of a pharmaceutical composition, wherein the suspension particle is the pharmaceutical composition of any one of claims 1 to 60.

64. The suspension particles according to claim 63, which are suspension particles for preparing a suspension.

65. The pharmaceutical composition of any one of claims 1 to 60, which is a suspension particle for the manufacture of a pharmaceutical composition.

66. The pharmaceutical composition of claim 65, which is a suspension granulate for preparing a suspension.

67. A suspension comprising the pharmaceutical composition of any one of claims 1 to 60, which is a suspension particle for preparing a pharmaceutical composition.

68. The pharmaceutical composition of any one of claims 1 to 60, which is in a suspended state.

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