Amorphous material and composition containing said amorphous material

Abstract

An amorphous solid dispersion containing compound (I); an amorphous form comprising compound (I) and an organic acid; an amorphous solid dispersion containing the amorphous form; a medicinal composition containing the amorphous form or amorphous solid dispersion; and methods for producing these.

Description

Technical Field

[0001] The present disclosure relates to an amorphous substance containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, a composition containing the amorphous substance, and the like. The contents of all documents described in this specification are incorporated herein by reference.

Background Art

[0002] 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as compound (I) or brexpiprazole) has a dopamine D2 receptor partial agonist action, a serotonin 5-HT receptor antagonist action and an adrenergic α1 receptor antagonist action. In addition to these actions, compound (I) also has a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action), and is known to have a broad therapeutic spectrum against central nervous system diseases (especially schizophrenia) (Patent Document 1). Also, brexpiprazole is known as a drug that is poorly soluble in water (a poorly soluble drug). Since poorly soluble drugs also have low solubility in the digestive tract, absorption from the digestive tract mucosa may be poor, which can be a problem. Therefore, formulation design to improve the solubility and oral absorbability of poorly soluble drugs is still an important technical issue for the expression of the drug efficacy of poorly soluble drugs at present.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The object of the present invention is to provide an amorphous solid dispersion containing compound (I) that has excellent dissolution properties and, more preferably, excellent stability; an amorphous body containing compound (I) and an organic acid; an amorphous solid dispersion containing the amorphous body; a pharmaceutical composition containing the amorphous body or amorphous solid dispersion; and methods for preparing these. [Means for solving the problem]

[0005] The inventors have found that by adding a specific polymer to compound (I), an amorphous solid dispersion of compound (I) exhibiting excellent elution properties can be obtained.

[0006] Furthermore, the inventors have also found that an amorphous body containing compound (I) and an organic acid can be obtained, and that the amorphous solid dispersion containing compound (I) and the organic acid exhibits excellent elution properties and, preferably, stability of the compound (I) contained therein.

[0007] This disclosure includes, for example, the following subjects: Section 1. An amorphous body comprising 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one and at least one organic acid. Section 2. The amorphous material described in item 1, wherein the organic acid is a carboxylic acid. Section 2a. The amorphous material according to item 1, wherein the organic acid is a monocarboxylic acid, a dicarboxylic acid, or a tricarboxylic acid. Section 2b. The amorphous body according to item 1, 2, or 2a, wherein the organic acid is a carboxylic acid having 1 to 8 carbon atoms. Section 2c. The amorphous body according to claim 1, 2, 2a, or 2b, wherein the organic acid is at least one carboxylic acid selected from the group consisting of acetic acid, lactic acid, malic acid, citric acid, oxalic acid, tartaric acid, propionic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, and phthalic acid. Section 2d. The amorphous body according to claim 1, 2, 2a, 2b, or 2c, wherein the organic acid is at least one carboxylic acid selected from the group consisting of acetic acid, lactic acid, malic acid, tartaric acid, propionic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, and phthalic acid. Section 3. An amorphous body according to item 1, 2, 2a, 2b, 2c, or 2d, wherein the organic acid is lactic acid. Section 3a. The amorphous body according to item 1, 2, 2a, 2b, 2c, 2d, or 3, wherein the ratio of 7-[4-(4-benzo[b]thiophene-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one to an organic acid is in the range of 100:0.1 to 60 by mass ratio. Section 4. An amorphous solid dispersion comprising an amorphous body as described in item 1, 2, 2a, 2b, 2c, 2d, 3, or 3a, and at least one enteric-coated polymer. Section 5. An amorphous solid dispersion comprising 7-[4-(4-benzo[b]thiophene-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one and at least one enteric-coated polymer. Section 6. The amorphous solid dispersion according to item 4 or 5, wherein the enteric-coated polymer is a nonionic, water-soluble polymer. Section 7. An amorphous solid dispersion according to any one of claims 4 to 6, wherein the enteric-coated polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose and its derivatives, and polyvinylpyrrolidone. Section 7a. An amorphous solid dispersion according to any one of claims 4 to 7, wherein the enteric-coated polymer is hypromellose acetate succinate. Section 7b. An amorphous solid dispersion according to item 4, 5, 6, 7, or 7a, wherein the ratio of 7-[4-(4-benzo[b]thiophene-4-ylpiperazin-1-yl)butoxy]-1H-quinoline-2-one to an enteric-coated polymer is in the range of 100:10 to 500 by mass ratio. Section 8. An amorphous body according to item 1, 2, 2a, 2b, 2c, 2d, 3, or 3a, which is a spray-dried powder, or an amorphous solid dispersion according to item 4, 5, 6, 7, 7a, or 7b. Section 8a. An amorphous solid dispersion according to claim 4, 5, 6, 7, 7a, 7b, or 8, characterized in that, in an HPLC chromatogram obtained after storing 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one at 40°C under sealed conditions for 4 weeks, the proportion of the peak area area of ​​8-(1-benzothiophene-4-yl)-8-aza-5-azoniaspiro[4.5]decane is 0.1% or less, when the total area of ​​the peak areas of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one and its degradation products is taken as 100%. Section 9. A method for producing an amorphous solid dispersion according to any one of claims 1 to 3, or according to claim 4, 5, 6, 7, 7a, 7b, 8, or 8a, comprising the step of spray-drying a mixture comprising 7-[4-(4-benzo[b]thiophene-4-ylpiperazin-1-yl)butoxy]-1H-quinoline-2-one and at least one of an enteric-coated polymer and an organic acid. Section 10. At least one selected from the group consisting of amorphous bodies according to claims 1, 2, and 3, and amorphous solid dispersions according to claims 4, 5, 6, 7, 7a, 7b, 8, and 9, Hydrophilic polymers and A pharmaceutical composition containing the following: Section 10a. The pharmaceutical composition according to item 10, comprising 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one in an amount ranging from 5 mg to 60 mg. Section 10b. A pharmaceutical composition according to item 10 or 10a, comprising an amorphous body and / or an amorphous solid dispersion in an amount of 10 to 40% by mass relative to the weight of a core tablet (uncoated tablet). Section 11. The pharmaceutical composition according to item 10, 10a, or 10b, wherein the hydrophilic polymer is at least one selected from the group consisting of a cellulose-based water-soluble polymer, a polyalkylene oxide, a polyalkylene glycol, and polyvinyl alcohol. Item 11a. The pharmaceutical composition according to item 10, 10a, 10b, or 11, wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose. Item 11b. The pharmaceutical composition according to item 10, 10a, or 10b or item​​​​​​​​​​​​​​​​​​​Schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorders, mood disorders, bipolar disorder, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorders, somatoform disorders, factitious disorder, dissociative disorders, sexual disorders, eating disorders, sleep disorders, adjustment disorders, substance-related disorders, anhedonia, delirium, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognition in schizophrenia A pharmaceutical composition according to paragraphs 10, 10a, 10b, 11, 11a, 11b, 12, 13, 14, or 15 for preventing or treating at least one central nervous system disorder selected from the group consisting of cognitive impairment resulting from disorder, treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism spectrum disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide amorphous bodies and amorphous solid dispersions of compound (I) that have excellent dissolution properties and, more preferably, excellent stability, and are suitable for use in pharmaceutical compositions, particularly sustained-release oral pharmaceutical compositions.

[0009] Furthermore, diseases responsive to compound (I) or its salts include, for example: schizophrenia, treatment-resistant, intractable or chronic schizophrenia, ataxic affective disorder, psychotic disorders, mood disorders, bipolar disorders (e.g., bipolar I disorder and bipolar II disorder), depression, endogenous depression, major depressive disorder, melancholy and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorders (e.g., panic attacks, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatoform disorders (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorders, dissociative disorders, sexual disorders (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorders (e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorders, adjustment disorders, substance-related disorders (e.g., For example, alcohol abuse, addiction and drug addiction, stimulant addiction, narcotic addiction, etc.), anhedonia (for example, anhedonia, iatrogenic anhedonia, anhedonia due to psychological or mental causes, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.), delirium, cognitive impairment, cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and related disorders, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, intractable or chronic schizophrenia, etc., vomiting, motion sickness, obesity, migraines, pain, intellectual disability, autism spectrum disorder (autism), Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia (for example, agitation associated with Alzheimer's disease), borderline personality disorder, and various other central nervous system disorders. [Brief explanation of the drawing]

[0010] [Figure 1] The results of investigating the elution rate of amorphous solid dispersions containing compound (I), prepared using various enteric-coated polymers, are shown. [Figure 2] The results of measuring the elution rate of compound (I) from each amorphous solid dispersion obtained using compound (I), an enteric-coated polymer, and various organic acids are shown. [Figure 3]The results of X-ray diffraction analysis for amorphous solid dispersions of compound (I), or amorphous solid dispersions of compound (I) and lactic acid, are shown. [Figure 4a] The TGA analysis results for each amorphous solid dispersion obtained using compound (I), enteric-coated polymer, and lactic acid are shown. [Figure 4b] The DSC analysis results for each amorphous solid dispersion obtained using compound (I), enteric-coated polymer, and lactic acid are shown. [Figure 5] The results of NMR measurements performed on amorphous solid dispersions and their raw materials are shown below. [Figure 6] The results of measuring the dissolution rate of compound (I) from hydrogel matrix tablets (with enteric coating) containing each amorphous solid dispersion obtained using compound (I), an enteric-coated polymer, and lactic acid are shown. [Modes for carrying out the invention]

[0011] The embodiments included in this disclosure will be described in more detail below. This disclosure preferably includes, but is not limited to, amorphous solid dispersions containing compound (I), amorphous bodies containing compound (I) and organic acids, amorphous solid dispersions containing said amorphous bodies, pharmaceutical compositions containing said amorphous bodies or amorphous solid dispersions, and methods for preparing the same. This disclosure includes everything disclosed herein and recognizable to those skilled in the art.

[0012] As stated above, the amorphous materials included in this disclosure include compound (I) and organic acids. In this specification, such amorphous materials may be referred to as "amorphous materials of this disclosure".

[0013] As organic acids, carboxylic acids are preferred, and monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids are more preferred. Hydroxy acids (also called hydroxycarboxylic acids) are also preferred. For example, carboxylic acids having 1 to 8 (1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms are preferred. Furthermore, the carboxylic acid may be substituted with one or more (e.g., 1, 2, or 3) -OH groups. Furthermore, the carboxylic acid may have one aromatic ring (especially a benzene ring) or heterocycle in its structure. Furthermore, the carboxylic acid may be linear or branched, and may be saturated or unsaturated.

[0014] More specifically, examples include acetic acid, lactic acid, malic acid, citric acid, oxalic acid, tartaric acid, propionic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, and phthalic acid. Lactic acid is particularly preferred.

[0015] Organic acids can be used individually or in combination of two or more. When using a combination of two or more organic acids, a combination of citric acid, tartaric acid, and fumaric acid is particularly preferred.

[0016] The amorphous solid dispersions included in this disclosure include the amorphous materials and enteric polymers of this disclosure. In this specification, such amorphous solid dispersions may be referred to as "amorphous solid dispersions of this disclosure".

[0017] The enteric-coated polymer can be any polymer that does not dissolve at low pH but dissolves at a neutral pH (e.g., pH 5-6) or higher. For example, polymers that dissolve at pH 5, 5.5, 6.0, or 6.5 or higher (preferably not dissolving at pH levels below these) are preferred. Specifically, examples include nonionic water-soluble polymers, preferably hypromellose (hydroxypropyl methylcellulose) or its derivatives, polyvinylpyrrolidone, etc.

[0018] In this specification, hypromellose derivatives are preferably esters of hypromellose and carboxylic acids (preferably monocarboxylic acids or dicarboxylic acids). Examples of such carboxylic acids include acetic acid, lactic acid, malic acid, citric acid, oxalic acid, tartaric acid, propionic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, and phthalic acid. These carboxylic acids may form esters individually or in combination of two or more. Examples of preferred esters of hypromellose and carboxylic acids include hypromellose acetate succinate ester and hypromellose phthalate ester.

[0019] The amorphous solid dispersions of this disclosure can be prepared, for example, by spray-drying a mixture containing compound (I), an organic acid, and an enteric polymer. The amorphous solid dispersion thus obtained contains an amorphous body (i.e., the amorphous body of this disclosure) comprising compound (I) and the organic acid.

[0020] Preferably, the mixture to be subjected to spray drying is a composition obtained by dissolving compound (I), an organic acid, and an enteric-coated polymer in an organic solvent. As the organic solvent, a dichloromethane / ethanol mixture is preferred. The mixture is preferably one in which dichloromethane and ethanol are in a mass ratio of about 80-50:20-50, and more preferably one in which the mass ratio is about 80-60:20-40. When using a dichloromethane / ethanol mixture as the organic solvent, it is preferable to prepare the mixture to be subjected to spray drying by, for example, dissolving an organic acid in ethanol, then adding and mixing dichloromethane, further dissolving the enteric-coated polymer in this mixture, and finally adding and dissolving compound (I). Spray drying can be carried out by known methods.

[0021] The ratio of compound (I) to organic acid contained in the amorphous material or amorphous solid dispersion of this disclosure is, for example, about 100:0.1 to 60 by mass ratio. The upper or lower limit of the range (0.1 to 60) may be, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59. For example, the range may be approximately 0.5 to 55 or 1 to 50.

[0022] To improve the stability of amorphous materials or amorphous solid dispersions, it is desirable to incorporate as much organic acid as possible, within a range that does not cause precipitation of organic acid salts. For example, when lactic acid is used as the organic acid, the ratio of compound (I) to organic acid is preferably about 100:30 to 60 by mass, and more preferably about 100:40 to 60.

[0023] Furthermore, the ratio of compound (I) to enteric polymer contained in the amorphous solid dispersion of this disclosure can be, for example, about 100:10 to 500 by mass ratio. The upper or lower limit of the range (10-500) may be, for example, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, or 490. For example, the range may be approximately 20-400 or 50-300.

[0024] The amorphous solid dispersions of this disclosure preferably exhibit excellent stability. In this specification, "excellent stability" means, for example, preferably, that after storing the amorphous solid dispersion of this disclosure at 40°C under sealed conditions for 4 weeks, the peak area of ​​the chromatogram obtained by HPLC measurement of 8-(1-benzothiophen-4-yl)-8-aza-5-azoniaspiro[4.5]decane (also referred to herein as compound (D)), which is one of the degradation products of compound (I), is 0.1% or less of the total peak area of ​​compound (I) and its degradation products. Here, the above storage conditions are based on the revised version (Pharmaceutical Affairs Bureau Review and Management Division Notification No. 0603001, June 3, 2003) of the "Stability Testing Guidelines" (Pharmaceutical Affairs Bureau Review and Management Division Notification No. 565, May 1, 2001) established based on the standards of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Regarding humidity, this application has not considered it, based on section 2.2.7.2 of the same guidelines concerning "formulations packaged in impermeable containers."

[0025] In this specification, "decomposition products" refers to impurities generated when the active pharmaceutical ingredient undergoes a chemical change during the manufacture or storage of a pharmaceutical product due to the action of light, heat, pH, and water, or due to reactions with pharmaceutical additives or direct containers / stoppering systems.

[0026] The pharmaceutical compositions included in this disclosure contain the amorphous material or amorphous solid dispersion of the disclosure. Preferably, they further contain a hydrophilic polymer. In this specification, such pharmaceutical compositions may be referred to as "pharmaceutical compositions of the disclosure."

[0027] The pharmaceutical compositions of this disclosure are preferably oral pharmaceutical compositions, and more preferably solid pharmaceutical compositions. More preferably, they are oral solid pharmaceutical compositions.

[0028] The dosage forms of the pharmaceutical compositions disclosed herein are not particularly limited, but examples include tablets, pills, powders, granules, gels, capsules, and powder inhalants.

[0029] Examples of hydrophilic polymers that can be used include cellulose-based water-soluble polymers, polyalkylene oxides (e.g., polyethylene oxide), polyalkylene glycols (e.g., polyethylene glycol), and polyvinyl alcohol.

[0030] As the cellulosic polymer, cellulosic water-soluble polymers known in the field of pharmaceutical formulation can be preferably used. For example, those having a structure in which some of the OH groups of cellulose are replaced by methyl groups and / or hydroxypropyl groups are preferred. For example, hypromellose (hydroxypropyl methylcellulose) or its derivatives are preferred. Also, for example, hydroxypropyl cellulose, methylcellulose, etc., are preferred.

[0031] Hydrophilic polymers can be used individually or in combination of two or more types.

[0032] As a hydrophilic polymer, for example, a viscosity of 2.5 to 35,000 mmHg in a 2% aqueous solution. 2 Cellulose-based water-soluble polymers with a viscosity of 2.5 to 17.5 mm² can be used. In particular, a viscosity of 2% aqueous solution of 2.5 to 17.5 mm² can be used. 2 A cellulose-based water-soluble polymer of / s is preferred.

[0033] Furthermore, the hydrophilic polymer may be the same polymer as the enteric polymer or a different polymer. Also, since the pharmaceutical composition containing the amorphous solid dispersion of this disclosure contains the enteric polymer, if the enteric polymer is a hydrophilic polymer, the pharmaceutical composition is included in the pharmaceutical composition containing a hydrophilic polymer.

[0034] In particular, if the pharmaceutical composition of this disclosure is a solid pharmaceutical composition, it is preferable that it contains the amorphous body of this disclosure or a mixture of the amorphous solid dispersion of this disclosure and a hydrophilic polymer.

[0035] When the pharmaceutical composition of the present disclosure is an oral solid pharmaceutical composition, a particularly preferred embodiment is a hydrogel sustained-release composition. This composition contains the amorphous body or amorphous solid dispersion of the present disclosure as an active ingredient, and further contains the hydrophilic polymer. A preferred form of the hydrogel sustained-release composition is a hydrogel matrix tablet. Hydrogel matrix tablets are a known technique in which the hydrogel formed by absorbing water in the gastrointestinal tract (after the coating film dissolves due to the rise in pH after gastric excretion in the case of enteric-coated tablets) controls drug release.

[0036] As the sustained-release base (hydrogel-forming base) in hydrogel matrix tablets, the above-mentioned hydrophilic polymers can be used, and more specifically, for example, cellulose-based water-soluble polymers, polyalkylene oxides (e.g., polyethylene oxide), polyalkylene glycols (e.g., polyethylene glycol), polyvinyl alcohol, etc. can be used. In this disclosure, as described above, it is preferable to use a cellulose-based polymer. When a cellulose-based polymer (e.g., hypromellose) is used as the sustained-release base, the viscosity of the cellulose-based polymer as a 2% aqueous solution should be 80 to 35,000 mmHg, depending on the desired dissolution rate. 2 It is preferable to use the / s version.

[0037] The sustained-release base can be contained, for example, in an amount of 30-90% by mass or 50-80% by mass relative to the weight of the core tablet.

[0038] Hydrogel matrix tablets may further contain other additives. Examples of such additives include disintegrants, lubricants, and fluidizers. A preferred disintegrant is, for example, sodium starch glycolate. The disintegrant may be contained in an amount of, for example, 10 to 50% by mass or 20 to 40% by mass relative to the mass of the core tablet. A preferred lubricant is, for example, magnesium stearate. The lubricant may be contained in an amount of, for example, 0.1 to 5% by mass or 0.2 to 3% by mass relative to the mass of the core tablet. A preferred fluidizer is, for example, silicon dioxide (especially light anhydrous silicic acid). The fluidizer may be contained in an amount of, for example, 0.1 to 5% by mass or 0.1 to 3% by mass relative to the mass of the core tablet.

[0039] Hydrogel matrix tablets are more preferably equipped with an enteric coating. Known enteric coating compositions can be used for the enteric coating. For example, an enteric coating composition containing an enteric base such as Eudragit, a plasticizer such as triethyl citrate, and a lubricant such as talc is preferably used. The enteric coating may be contained in an amount of approximately 1 to 40 parts by mass or 10 to 30 parts by mass per 100 parts by mass of the core tablet.

[0040] While not particularly limited, it is preferable that the oral pharmaceutical compositions of this disclosure maintain a steady-state blood concentration of compound (I) in humans (especially adults) for one week in the range of, for example, 15 ng / mL to 400 ng / mL or 50 ng / mL to 300 ng / mL.

[0041] Compound (I) is already marketed in 0.5 mg, 1 mg, and 2 mg tablets (non-release controlled formulations) in numerous countries, including Japan, the United States, and Europe, as a treatment for schizophrenia. The standard tablets have demonstrated safety and efficacy against central nervous system disorders such as schizophrenia in clinical trials, and detailed pharmacokinetic analyses have also been conducted. Considering this information regarding the standard tablets, it can be understood that any oral pharmaceutical composition that can maintain a steady-state blood concentration of compound (I) of approximately 15 ng / mL to 400 ng / mL or 50 ng / mL to 300 ng / mL in humans can be used to prevent or treat central nervous system disorders such as schizophrenia, similar to the standard tablets already on the market.

[0042] Therefore, the oral pharmaceutical compositions of this disclosure may be administered orally at a frequency less than once a day, for example, once a week. Preferably, one tablet of the oral pharmaceutical composition of this disclosure may be administered at a time, or two or more tablets at a time, for example, two, three, four, or five tablets at a time. Furthermore, those skilled in the art can appropriately determine the dosage of the oral pharmaceutical composition of this disclosure to achieve the above blood concentrations from pharmacokinetic information for the above-mentioned ordinary tablets and evaluations based on single-dose and continuous-dose protocols for the oral pharmaceutical composition of this disclosure. For example, the dosage of compound (I) per dose may be approximately 5 mg to 60 mg, or 10 mg to 60 mg, 20 mg to 60 mg, or 45 mg to 60 mg.

[0043] In this specification, the term "comprising" includes both "consisting essentially of" and "consisting of." Furthermore, this disclosure encompasses all any combination of the constituent elements described herein.

[0044] Furthermore, the various characteristics (properties, structure, function, etc.) described in each embodiment of this disclosure above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0045] The embodiments of this disclosure will be described in more detail below with examples, but the embodiments of this disclosure are not limited to the examples below. Unless otherwise specified below, compound (I) (brexpiprazole) was used after being synthesized according to a known method and then ground with a hammer mill.

[0046] Preparation of an amorphous solid dispersion of compound (I) (brexpiprazole) 205.5 g of an 80% dichloromethane / 20% ethanol (w / w) mixture was dissolved with 6 g of compound (I) and 12 g of various enteric-coated polymers (solid concentration 8 w / w%). The resulting solution was spray-dried using an atomizer under the following conditions to obtain an amorphous solid dispersion (specifically, a spray-dried powder). • Flow rate (mL / min): 8 • Atomizing air (M Pa): 0.15 ·Inlet temperature (℃): 75 Drying Air (m³ / min): 0.45 ·Overnight vacuum drying at 50℃

[0047] The following enteric-coated polymers were used. HPMC AS-LF (Hypromellose acetate succinate: Shin-Etsu Chemical Co., Ltd., AQOAT) (Soluble at pH 5.5 or higher) HPMC AS-MF (Hypromellose acetate succinate: Shin-Etsu Chemical Co., Ltd., AQOAT) (Soluble at pH 6.0 or higher) HPMC AS-HF (Hypromellose acetate succinate: Shin-Etsu Chemical Co., Ltd., AQOAT) (Soluble at pH 6.8 or higher) TC-5R (Hypromellose: Shin-Etsu Chemical Co., Ltd.) (Viscosity of a 2% aqueous solution at 20°C (Japanese Pharmacopoeia) is approximately 6 mPa·s) HP-50 (Hypromellose phthalate: Shin-Etsu Chemical Co., Ltd.) (Dissolves at pH 5.0 or higher. Also, the viscosity of a 10% solution of methanol / dichloromethane mixture (1:1) at 20°C (Japanese Pharmacopoeia) is approximately 55 mPa·s.) HP-55 (Hypromellose phthalate: Shin-Etsu Chemical Co., Ltd.) (Dissolves at pH 5.5 or higher. Also, the viscosity of a 10% solution of methanol / dichloromethane mixture (1:1) at 20°C (Japanese Pharmacopoeia) is approximately 40 mPa·s.) K-25 (Polyvinylpyrrolidone: BASF, Kollidon 25)

[0048] The release rate of compound (I) from each obtained amorphous solid dispersion was evaluated by measuring the elution rate of compound (I) at 1-hour intervals over 24 hours. The elution test was performed according to the paddle method specified in the Dissolution Test of the 17th Edition of the Japanese Pharmacopoeia. 900 mL of the Dissolution Test Solution No. 2 (pH approximately 7, potassium dihydrogen phosphate, disodium hydrogen phosphate) listed in the Japanese Pharmacopoeia was used as the test solution, and the test was performed at 37°C and a paddle rotation speed of 50 rpm. Sampling was performed over time, and compound (I) in the sampled solution was quantified using a UV detector (absorbance measurement wavelengths: 323 nm and 380 nm). The first wavelength (323 nm) was set as the wavelength at which the absorbance of the active ingredient could be detected to the maximum extent, and the second wavelength (380 nm) was set as the wavelength at which absorbance from the active ingredient could not be detected. The elution rate was defined as the elution mass percentage (%) of compound (I) when the total amount (mass) of compound (I) contained in each amorphous solid dispersion was set to 100%. Furthermore, the extraction rate of compound (I) itself (hammer milled product; labeled HM), which has not been dispersed as an amorphous solid, was also examined using the same elution test. The results are shown in Figure 1.

[0049] These results indicate that amorphous solid dispersions containing compound (I), prepared using any of the enteric-coated polymers, exhibit excellent elution properties.

[0050] In the following studies, unless otherwise specified, HPMC AS-HF was used as the enteric-coated polymer for preparing amorphous solid dispersions.

[0051] Study on the stability of compound (I) in amorphous solid dispersions. To investigate the stability of compound (I) in an amorphous solid dispersion prepared using HPMC AS-HF as an enteric-coated polymer, the amount of decomposition products of compound (I) that formed after storage was measured.

[0052] Specifically, after storing the amorphous solid dispersion at 40°C under sealed conditions for 4 weeks, the extent to which compound (D) (8-(1-benzothiophen-4-yl)-8-aza-5-azoniaspiro[4.5]decane), one of the degradation products of compound (I) (brexpiprazole), was formed was examined by HPLC.

[0053] [ka]

[0054] More specifically, 50 mg of the amorphous solid dispersion was weighed out on a compound (I) basis, and a 50% MeCN / 50% MeOH solution was added to completely dissolve it, making a total volume of 100 mL. 10 mL of this solution was taken out, and a 1% acetic acid solution was added to make a total volume of 25 mL. This was filtered using a 0.45 μm filter, and 50 μL was injected into an HPLC. The measurement conditions for HPLC were as follows: HPLC: LC-2010C (Shimadzu) Measurement wavelength (nm): 274 Analytical column: Capcell Pak C18, MGII 3μm, 4.6mm ID × 150mm (Shiseido) Flow rate (mL / min): 1.7 Mobile phase: 0.01 mol / L sodium sulfate solution / acetonitrile / methanol / acetic acid = 140 / 45 / 15 / 2 Injection volume (μL): 50 Measurement time (min): 30

[0055] In the obtained HPLC chromatogram, the ratio of the peak area of ​​compound (D) to the total area of ​​the peak area of ​​compound (I) and the peak area of ​​the degradation product of compound (I) was calculated, with the total area being 100%.

[0056] Based on the above analysis, it was found that compound (D) was produced at a concentration of 0.14%.

[0057] Next, various organic acids were further dissolved in the solution, and an amorphous solid dispersion was prepared by spray drying under the same conditions as above. To investigate the stability of the obtained amorphous solid dispersion, it was stored at 40°C under sealed conditions for 4 weeks, and then the amount of compound (D) formed was measured by HPLC under the same conditions as above.

[0058] The dissolving solution was prepared by dissolving 6 g of compound (I), 12 g of enteric-coated polymer (HPMC AS-HF), and 0.6 g, 0.3 g, or 0.06 g of various organic acids in 213.9 g or 210.5 g of an 80% dichloromethane / 20% ethanol (w / w) mixture. The dissolution procedure involved completely dissolving the organic acids in ethanol, then adding and mixing the dichloromethane, further dissolving the enteric-coated polymer (HPMC AS-HF), and finally adding and dissolving compound (I).

[0059] However, when preparing a solution using lactic acid as the organic acid, the solution composition was as follows: 430 g of an 80% dichloromethane / 20% ethanol (w / w) mixture, to which 20 g of compound (I), 40 g of enteric-coated polymer (HPMC AS-HF), and 10 g of lactic acid (50% of compound (I)) or 0.2 g (1% of compound (I)) were dissolved. (The order of dissolution was the same as described above.)

[0060] Furthermore, when preparing a solution by dissolving citric acid, tartaric acid, and fumaric acid as organic acids, the composition of the solution was changed to a 60% dichloromethane / 40% ethanol (w / w) mixture, and 16 g of compound (I), 32 g of enteric-coated polymer (HPMC AS-HF), and various organic acids (1.6 g of citric acid, 0.8 g of tartaric acid, and 1.6 g of fumaric acid) were dissolved in 912 g of this mixture (the order of dissolution was the same as above). Also, only in this case, the spray drying conditions were changed as follows. • Flow rate (mL / min): 10 • Atomizing air (M Pa): 0.15 ·Inlet temperature (℃): 80 ·Outlet temperature(℃): 49~50 Drying Air (m³ / min): 0.40 ·Overnight vacuum drying at 50℃

[0061] The amount of compound (D) in amorphous solid dispersions obtained using various organic acids after storage at 40°C under sealed conditions for 4 weeks is shown in the table below. In the table, the percentage of each organic acid represents the ratio of the mass of the organic acid contained in the solution to the mass of compound (I) contained in the solution subjected to spray drying, which is set to 100%.

[0062] The raw material, lactic acid, is a liquid with a purity of 85-92%, containing approximately 10% water as an impurity. The water is removed by spray drying, leaving approximately 8.8g / 10g of lactic acid after preparation. The same results are observed in the following studies.

[0063] [Table 1]

[0064] It was found that the degradation of compound (I) during long-term storage was suppressed in each amorphous solid dispersion obtained using various organic acids. Furthermore, all amorphous solid dispersions obtained in this test maintained their amorphous state stably even after long-term storage. In other words, it was found that the time-dependent stability of compound (I) contained in each amorphous solid dispersion obtained using various organic acids was improved. This was considered to be satisfactory stability in light of the revised version (Pharmaceutical Affairs Bureau Review Division Director's Notification No. 0624001, June 24, 2003) of the "Guidelines on Impurities in Formulations of New Active Ingredient-Containing Pharmaceuticals" (Pharmaceutical Affairs Bureau Review Division Director's Notification No. 539, June 23, 1997), which is established based on ICH standards.

[0065] Furthermore, the release rate of compound (I) from each amorphous solid dispersion obtained using various organic acids was evaluated by measuring the elution rate of compound (I) at 1-hour intervals over 24 hours. This elution test was performed in the same manner as described above. The results are shown in Figure 2. In Figure 2, Comp. represents compound (I). HF represents HPMC AS-HF. Cit, Tar, Fum, Lac, Suc, and Adi represent citric acid, tartaric acid, fumaric acid, lactic acid, succinic acid, and adipic acid, respectively. HM represents compound (I) itself (hammer milled product) that has not been dispersed into an amorphous solid.

[0066] As can be seen from these results, the amorphous solid dispersions obtained using various organic acids showed improved elution rates compared to the amorphous solid dispersion obtained without using organic acids (Comp. / HF). In particular, the elution rates were significantly improved when lactic acid or a combination of organic acids (citric acid, tartaric acid, and fumaric acid) were used.

[0067] Analysis of amorphous solid dispersions by X-ray diffraction (XRD) Solvent (i), obtained by dissolving 12 g of compound (I) in 162 g of a 70% dichloromethane / 30% ethanol (w / w) mixture, or solvent (ii), obtained by dissolving 12 g of compound (I) and 6 g of lactic acid, were spray-dried in the same manner as described above to obtain amorphous solid dispersions (i) and (ii).

[0068] The amorphous solid dispersions (i) and (ii) were then analyzed by X-ray diffraction immediately after preparation and after being stored in a sealed state at 40°C for 3 days.

[0069] The conditions for the X-ray diffraction method are shown below. Model: X'Pert Pro MPD (Spectris) Voltage (kV): 45 Current (mA): 40 Configuration: Spinner reflect-trans Scan axis: 2 theta Starting angle: 3.000 End angle: 40.000 Step size: 0.0167113 Time per step: 3.175 Scan speed (° / s): 0.668451 Wobble axis: Omega Number of steps: 5 Step size: 1.000

[0070] The results of this analysis are shown in Figure 3. The results for amorphous solid dispersion (i) are shown on the right side of Figure 3, and the results for amorphous solid dispersion (ii) are shown on the left side. In amorphous solid dispersion (i), many peaks appeared after storage at 40°C for 3 days, suggesting that some amorphous material had transformed into crystals. In contrast, in amorphous solid dispersion (ii), the pattern did not change even after storage at 40°C for 3 days, suggesting that the amorphous state was stably maintained.

[0071] Thermal analysis (TGA and DSC) of amorphous solid dispersions Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on amorphous solid dispersions (ii).

[0072] The following measuring instruments were used. The amount of sample (amorphous solid dispersion (ii)) was approximately 5 mg in each case. TGA: TGA Q5000 (TA Instruments) DSC: DSC Q2000 (TA Instruments)

[0073] For TGA analysis, the temperature was increased to 250°C at a rate of 10°C / min. For DSC analysis, the temperature was first increased to 100°C at a rate of 10°C / min to volatilize any trace amounts of dichloromethane and ethanol that were thought to remain, then cooled to 25°C at a rate of 10°C / min, and then increased again to 150°C at a rate of 10°C / min.

[0074] The results are shown in Figure 4a (TGA analysis) and Figure 4b (DSC analysis). In Figure 4a, no peaks indicating exothermic reaction were measured (see the area enclosed by the dotted circle). In Figure 4b, no peaks indicating weight change were measured (see the area enclosed by the dotted circle). These results suggest that the amorphous solid dispersion (ii) has not transformed into a crystal (it remains amorphous), and therefore the stability of the amorphous solid dispersion (ii) is confirmed.

[0075] NMR measurement of amorphous solid dispersions The amorphous solid dispersion (ii) was analyzed by NMR. Similarly, the compound (I) itself, HPMC AS-HF, and lactic acid, which were not dispersed as an amorphous solid, were also analyzed by NMR. Furthermore, the amorphous solid dispersion prepared from the solution of HPMC AS-HF and lactic acid (also called "amorphous solid dispersion (iii)") was also analyzed by NMR. The solution prepared by dissolving HPMC AS-HF and lactic acid consisted of 40 g of HPMC AS-HF and 10 g of lactic acid in 430 g of a 70% methylene chloride / 30% ethanol (w / w) mixture. The NMR measurement conditions are shown below. Measuring instrument: ECA-500 (JEOL RESONANCE Co., Ltd.) Observation nucleus: 1 H Sample amount: approximately 5 mg Solvent: DMSO-d6 Reference value for chemical shift: 2.49 ppm (DMSO) Total number of times: 8

[0076] The results are shown in Figure 5. In Figure 5, the peak positions of compound (I) and amorphous solid dispersion (ii) are shifted (see the dotted line in the figure). From this, it was found that in amorphous solid dispersion (ii), compound (I) and lactic acid interact molecularly. Furthermore, it was found that the amorphous material contained in amorphous solid dispersion (ii) is an amorphous material composed of compound (I) and lactic acid.

[0077] Preparation and evaluation of tablets A hydrogel sustained-release formulation (hydrogel matrix tablet) containing an amorphous solid dispersion (ii) was manufactured according to a standard known manufacturing process. Specifically, these raw materials were mixed and compressed to prepare hydrogel matrix tablets (plain tablets) so that each tablet contained 41.4 mg of amorphous solid dispersion (ii) (including 12 mg of compound (I)), 80 mg of hypromellose, 60 mg of sodium starch glycolate, and 0.6 mg of magnesium stearate. Hydrogel matrix tablets are a known technology in which the hydrogel formed by absorbing moisture in the gastrointestinal tract (in the case of coated tablets, the coating film dissolves due to the rise in pH after gastric emptying) controls drug release.

[0078] Furthermore, the hydrogel matrix tablets (plain tablets) were subjected to enteric coating to prepare enteric-coated tablets. Specifically, 9.1 mg of methacrylate copolymer LD (Eudragit L30D-55, Evonik), 4.55 mg of talc, and 0.91 mg of triethyl citrate were added to each tablet and enterically coated using a general-purpose coating machine according to conventional methods. Subsequently, color coating was performed using OPADRY 03A420002 (5.4 mg) to obtain enteric-coated tablets.

[0079] The release rate of compound (I) from the obtained enteric-coated tablets was evaluated by measuring the dissolution rate of compound (I) at 1-hour intervals over 24 hours. This dissolution test was performed in the same manner as described above. The results are shown in Figure 6. The enteric-coated agent showed an excellent supersaturated dissolution profile.

[0080] Evaluation of blood concentration of compound (I) after oral administration to humans. The blood concentration of compound (I) after oral administration of the oral pharmaceutical composition of this disclosure to humans was evaluated based on the following single-dose protocol. The formulation used in this evaluation (test formulation) is a hydrogel matrix tablet prepared according to this disclosure, containing an amorphous solid dispersion of compound (I) as the active ingredient. In the single-dose protocol, a regular tablet of compound (I) (a tablet containing compound (I) that has not been amorphous solid dispersed) was administered as a single dose, and after drug discontinuation, 12 mg of the test formulation (one 12 mg tablet) was administered as a single dose. The PK parameters of compound (I) were analyzed. The median tmax (time to reach peak plasma concentration) was prolonged compared to the regular tablet. From these results, it is considered that using the oral pharmaceutical composition of this disclosure maintains the desired blood concentration of compound (I) for a once-weekly formulation (e.g., 15 ng / mL to 400 ng / mL at steady state).

Claims

1. An amorphous body comprising 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one and at least one organic acid, wherein the organic acid is a carboxylic acid having 1 to 8 carbon atoms.

2. The amorphous body according to claim 1, wherein the organic acid is lactic acid.

3. An amorphous solid dispersion comprising 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one, at least one organic acid, and at least one enteric-coated polymer, wherein the organic acid is a carboxylic acid having 1 to 8 carbon atoms.

4. The amorphous solid dispersion according to claim 3, wherein the organic acid is lactic acid.

5. The amorphous solid dispersion according to claim 3 or 4, wherein the enteric-coated polymer is a nonionic, water-soluble polymer.

6. The amorphous solid dispersion according to any one of claims 3 to 5, wherein the enteric polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose and its carboxylic acid esters, and polyvinylpyrrolidone.

7. An amorphous body according to claim 1 or 2, or an amorphous solid dispersion according to any one of claims 3 to 6, which is a spray-dried powder.

8. The process includes a step of spray-drying a mixture containing 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one and an organic acid, or both an enteric-coated polymer and an organic acid. A method for producing an amorphous solid dispersion according to any one of claims 1, 2, and 7, wherein the organic acid is a carboxylic acid having 1 to 8 carbon atoms.

9. At least one selected from the group consisting of an amorphous body according to any one of claims 1, 2, and 7 and an amorphous solid dispersion according to any one of claims 3 to 7, Hydrophilic polymers and A pharmaceutical composition containing the following:

10. The pharmaceutical composition according to claim 9, wherein the hydrophilic polymer is at least one selected from the group consisting of cellulose-based water-soluble polymers, polyalkylene oxides, polyalkylene glycols, and polyvinyl alcohols.

11. The pharmaceutical composition according to claim 9 or 10, which is an oral solid pharmaceutical composition.

12. The pharmaceutical composition according to claim 11, wherein the steady-state blood concentration of 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one after oral administration to humans is maintained in the range of 15 ng / mL to 400 ng / mL for one week.

13. A pharmaceutical composition according to any one of claims 9 to 12, for administering 7-[4-(4-benzo[b]thiophen-4-ylpiperazine-1-yl)butoxy]-1H-quinoline-2-one once a week in a dose of 5 mg to 60 mg.

14. A pharmaceutical composition according to any one of claims 9 to 13 for preventing or treating a central nervous system disorder.

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