Oral pharmaceutical composition containing heterocyclic compound

Abstract

To provide a controlled release oral pharmaceutical composition comprising a salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.SOLUTION: The present invention provides a controlled release oral solid pharmaceutical composition comprising a fumaric acid salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, and further comprising a cellulose-based water-soluble polymer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to an oral pharmaceutical composition (more preferably, a controlled release oral pharmaceutical composition) containing a salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one. The contents of all documents described in this specification are incorporated herein by reference. [Background technology]

[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) or a salt thereof has a dopamine D2 receptor partial agonist effect, a serotonin 5-HT 2A It has an adrenergic α1 receptor antagonist effect and an adrenergic α1 receptor antagonist effect. In addition to these effects, compound (I) or a salt thereof also has a serotonin uptake inhibitory effect (or a serotonin reuptake inhibitory effect), and is known to have a wide therapeutic spectrum for central nervous system disorders (especially schizophrenia) (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2006-316052 A Summary of the Invention [Problem to be solved by the invention]

[0004] In the treatment of central nervous system diseases such as schizophrenia, it is generally important to keep a drug in plasma at a therapeutically effective concentration for a long period of time. Therefore, a pharmaceutical composition for oral administration that can be taken infrequently is useful in that it can increase patient compliance and reduce the relapse rate in treatment. In order to obtain a pharmaceutical composition for oral administration that can be taken infrequently, it is considered to contain a high dose of an active ingredient in the composition, but in order to maintain a therapeutically effective blood concentration, it is required that the active ingredient is released from the composition at an appropriate rate and continuously, without excessive release due to factors on the body side after administration.

[0005] Currently, the use of compound (I) or a salt thereof in the treatment of schizophrenia is recommended to be administered orally once a day, but oral administration once a day imposes an excessive burden on many patients who require long-term administration. Therefore, there is a demand for an orally administrable pharmaceutical composition suitable for administration less frequently than once a day. [Means for solving the problem]

[0006] Means for Solving the Problems The present inventors have conducted intensive studies to provide an orally administrable pharmaceutical composition for a salt of compound (I) suitable for administration less frequently than once a day, and have found that a solid oral pharmaceutical composition exhibiting an excellent supersaturated dissolution concentration profile can be obtained by using a combination of a fumarate salt of compound (I) and a cellulose-based water-soluble polymer.

[0007] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. A controlled release oral solid pharmaceutical composition comprising a fumarate salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one as an active ingredient, and further comprising a cellulose-based water-soluble polymer. Section 2. The cellulose-based water-soluble polymer is hydroxypropyl methylcellulose, hydroxypropyl Item 2. The composition according to item 1, wherein the cellulose acetate layer is at least one selected from the group consisting of cellulose acetate and methylcellulose. Section 3. Item 3. The composition according to item 1 or 2, which is an osmotic pump type composition. Section 4. Item 3. The composition according to item 1 or 2, which is a hydrogel sustained-release formulation. Section 5. Item 5. The composition according to item 4, which is provided with an enteric coating. Section 6. Item 6. The composition according to any one of items 1 to 5, comprising 5 mg to 60 mg of fumarate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, calculated as the weight of the free base. Section 7. Item 7. The composition according to any one of Items 1 to 6, which maintains a steady-state blood concentration of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one in the range of 15 ng / mL to 400 ng / mL for one week when orally administered to a human. Section 8. Item 8. The composition according to any one of items 1 to 7, for administering the fumarate salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one in a dose of 5 mg to 60 mg calculated as the weight of the free base once a week. Section 9. Item 9. The composition according to any one of Items 1 to 8, for preventing or treating a central nervous system disease. Section 10. 10. The composition according to claim 9, for preventing or treating a central nervous system disorder selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorder, mood disorder, bipolar disorder, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, cognitive impairment, cognitive impairment associated with a neurodegenerative disease, cognitive impairment caused by a neurodegenerative disease, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Section A-1. Item 11. The composition according to any one of items 1 to 10, which contains a salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one as an active ingredient, and the sustained release time of the active ingredient is between 5 and 30 hours. Section A-2. In the drug layer, 5 to 200 mg of the fumarate salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, calculated based on the weight of the free base; 5 to 94% by weight of a hydrophilic polymer based on the drug layer weight; a cellulose-based water-soluble polymer, 5 to 40% by weight based on the weight of the drug layer; an osmotic pressure adjusting agent, ranging from 1% to 50% by weight based on the weight of the drug layer; 0.1 to 5% by weight of a lubricant based on the weight of the drug layer; and A fluidizing agent of 0.1 to 5% by weight based on the weight of the drug layer The push layer contains 50 to 90% by weight of a highly swellable polymer based on the weight of the push layer; 5 to 50% by weight of an osmotic pressure regulator based on the weight of the push layer; 0.1 to 5% by weight of a lubricant based on the weight of the push layer; and 0.1 to 2% by weight of pigment based on the weight of the push layer Contains Further, the core preparation contains 5 to 25 parts by mass of a semipermeable membrane and 1 to 15 parts by mass of a water-soluble polymer membrane, relative to 100 parts by mass of the core preparation, 70 to 100% by mass of a cellulose-based polymer based on the weight of the semipermeable membrane; and Flux regulator of 0.01 to 30% by mass based on the weight of the semipermeable membrane Contains Item 4. The composition according to item 3, which may have a color coating layer. Section A-3. The fumarate salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, equivalent to 5-200 mg by weight of the free base; 30-90% by weight of sustained release base material based on the weight of the core tablet; 1 to 50% by weight of a hydration promoter based on the weight of the core tablet; and 0.1 to 5% by weight of lubricant based on the weight of the core tablet Contains Item 5. The composition according to item 4, comprising 1 to 40 parts by mass of an enteric coating per 100 parts by mass of the core formulation. Effect of the Invention

[0008] The present disclosure provides a means for preventing initial excessive release of an active ingredient (i.e., a salt of compound (I)) from a pharmaceutical composition even when administered in a high dose, and for sustained release of the active ingredient in a therapeutically effective amount over a long period of time. This allows the therapeutically effective blood concentration of the active ingredient to be maintained for a long period of time. Thus, the present disclosure makes it possible to treat diseases responsive to a salt of compound (I) (e.g., schizophrenia) with less frequent administration than conventionally, and is therefore effective in improving patient compliance with medication.

[0009] In addition, examples of diseases responsive to compound (I) or a salt thereof include the following: schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorder, mood disorder, bipolar disorder (e.g., bipolar I disorder and bipolar II disorder), depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder (e.g., panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatoform disorder (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorder, dissociative disorder, sexual disorder (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorder (e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorder, adjustment disorder, substance-related disorder (e.g., various disorders of the central nervous system, such as alcohol abuse, intoxication and drug addiction, stimulant addiction, narcotic addiction, etc.), anhedonia (e.g., 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, migraine, pain, mental retardation, autistic disorder (autism), Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome, impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's dementia), borderline personality disorder, etc. [Brief description of the drawings]

[0010] [Figure 1a] 1 shows the results of a dissolution test of a fumarate salt of Compound (I) or an oral pharmaceutical composition (osmotic pump type preparation) containing Compound (I). [Figure 1b] 1 shows the results of a dissolution test of a fumarate salt of Compound (I) or an oral pharmaceutical composition (osmotic pump type preparation) containing Compound (I). [Figure 2a]1 shows the results of a dissolution test of an oral pharmaceutical composition (osmotic pump type preparation) containing a fumarate salt of Compound (I). [Figure 2b] 1 shows the results of a dissolution test of an oral pharmaceutical composition (osmotic pump type preparation) containing a fumarate salt of Compound (I). [Diagram 3] 1 shows the results of a dissolution test of an oral pharmaceutical composition (hydrogel sustained-release formulation) containing the fumarate salt of Compound (I). [Figure 4a] 1 shows an infrared absorption spectrum of the fumarate salt of compound (1). [Figure 4b] 1 shows the powder X-ray diffraction pattern of the fumarate salt of compound (1). [Diagram 5] An example of an osmotic pump type composition, which is one embodiment of a controlled release oral pharmaceutical composition, is shown below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present disclosure preferably encompasses oral pharmaceutical compositions, methods for producing said oral pharmaceutical compositions, and the like, but is not limited thereto, and the present disclosure encompasses everything disclosed in the present specification and recognizable by a person skilled in the art.

[0012] The oral pharmaceutical composition included in the present disclosure contains a salt of compound (I). The oral pharmaceutical composition may be referred to as the "oral pharmaceutical composition of the present disclosure." Compound (I) is a compound represented by the following formula (I). Compound (I) or a salt thereof can be produced by the method described in JP 2006-316052 A (which is incorporated herein in its entirety by reference) or a method similar thereto.

[0013] [ka]

[0014] The salt of compound (I) is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include various metal salts, salts of inorganic bases, salts of organic bases, inorganic acid salts, and organic acid salts. Examples of metal salts include alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), etc. Examples of salts of inorganic bases include ammonium salts, salts with alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), etc. Examples of salts of organic bases include salts with tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholines (e.g., N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc. Inorganic acid salts Examples of the salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc. Examples of the salts of organic acids include formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate, benzoate, etc. Among these, hydrochloride, sulfate, fumarate, phosphate, citrate, and tartrate are preferred, and fumarate is particularly preferred.

[0015] Salts of compound (I) include anhydrides, solvates with solvents (e.g., hydrates, methanolates, ethanolates, acetonitrates, etc.), various crystal forms of anhydrides and solvates, and mixtures thereof. Compound (I) or its salts also include isomers such as geometric isomers, stereoisomers, and optical isomers.

[0016] The salt of compound (I) may be a pharma- ceutically acceptable co-crystal salt. Here, a co-crystal or co-crystal salt refers to a crystalline substance that is composed of two or more distinct solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, etc.). Co-crystal salts can be prepared by known co-crystallization methods.

[0017] The oral pharmaceutical composition of the present disclosure is suitable for maintaining a constant dissolution concentration of the salt of compound (I) even in the lower part of the digestive tract. In addition, it is preferably suitable for releasing the salt of compound (I) at a uniform rate over a long period of time. In other words, it is suitable as a controlled release oral pharmaceutical composition.

[0018] Here, the dissolution rate and sustained release time from the oral pharmaceutical composition containing a salt of Compound (I) can be expressed by measuring the dissolution rate and sustained release time of the salt of Compound (I) according to the second method of dissolution test in the Japanese Pharmacopoeia (paddle method) using a buffer solution of pH 5.0 or less (specifically, 0.05 mol / L acetate buffer (pH 4.3, acetic acid, sodium acetate)) that satisfies sink conditions as a test solution.

[0019] The term "dissolution rate" refers to the ratio of the dissolved salt of compound (I) to the total amount of the salt of compound (I) contained in the oral pharmaceutical composition. Thus, the dissolution rate can also be said to be the ratio of the dissolved compound (I) to the total amount of compound (I) contained in the oral pharmaceutical composition. The term "sustained release time" refers to the time from the start of the measurement in the dissolution test until the final dissolution rate is reached. The term "final dissolution rate" refers to the dissolution rate when the plateau is reached in the dissolution test, and the term "final dissolution amount" refers to the dissolution amount when the final dissolution rate is reached in the dissolution test. In the dissolution test, when the dissolution rate at a certain time point (baseline time point) is compared with the dissolution rate 2 hours after the baseline time point, the dissolution rate 2 hours after the baseline time point is within ±1% of the dissolution rate at the baseline time point (more preferably, when the dissolution rate 2 hours after the baseline time point is compared with the dissolution rate 2 hours after the baseline time point, the dissolution rate 2 hours after the baseline time point is within ±1%), so that the plateau can be said to be reached at the shortest baseline time point from the start of the test. However, the dissolution rate at the reference time point is assumed to be more than 20% (in other words, if the dissolution rate does not exceed 20%, it is not a plateau).

[0020] The sustained release time is preferably 5 hours or more. Also, it is preferably 30 hours or less. More preferably, it is 5 to 30 hours. The upper or lower limit of the range may be, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 hours. The sustained release time is, for example, more preferably 10 to 24 hours, and even more preferably 15 to 24 hours.

[0021] In addition, as for the oral pharmaceutical composition of the present disclosure, the final dissolution amount is It is preferably 80 mass % or more, and more preferably 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 mass % or more of the total amount of the salt of Compound (I) contained in the oral pharmaceutical formulation.

[0022] In addition, the maintenance of a constant dissolution concentration in the lower gastrointestinal tract can be evaluated by measuring the supersaturated dissolution concentration profile per dissolution time of a salt of Compound (I) using a phosphate buffer solution of about pH 7 simulating the lower gastrointestinal tract as a test liquid, in accordance with the second method of the Japanese Pharmacopoeia dissolution test (paddle method) as described above.

[0023] In achieving "sustained release", the initial release of the salt of Compound (I) from the composition may occur immediately after the start of the release test, or after a certain period of time (e.g., 1 to 3 hours) has elapsed since the start of the measurement. However, it is not preferable for the time it takes for the amount of release to reach 5% by mass or more of the final amount of release to exceed 5 hours.

[0024] The "supersaturated dissolution profile" can be evaluated by quantifying the concentration of the drug that is temporarily dissolved at or above the solubility of Compound (I) over time in a paddle method dissolution test using the above-mentioned phosphate buffer solution of about pH 7 (a test solution simulating the lower gastrointestinal tract). A preferred supersaturated dissolution profile is a profile in which the dissolution rate reaches a peak between 4 and 18 hours after the start of the dissolution test, and the peak is preferably 1 or 1.5 μg / mL or more, more preferably 2, 2.5, or 3 μg / mL or more, and even more preferably 3.5, 4, 4.5, 5, 5.5, or 6 μg / mL or more, calculated as Compound (I) (free base). A higher supersaturated concentration increases the contribution of absorption in the lower gastrointestinal tract, leading to an increase in BA (bioavailability) and PTF. It is expected that the peak trough ratio (PTR) will decrease. This reduction makes it easier to fit into the PK (pharmacokinetics) target range.

[0025] The manner in which the salt of Compound (I) is released from the oral pharmaceutical composition at a constant rate over a long period of time is not particularly limited, and can be achieved by various techniques known in the field of sustained release formulations. Suitable sustained release approaches include those using a diffusion-controlled composition, a dissolution-controlled composition, or an osmotic pump composition, and among these, the most suitable sustained release approaches include an osmotic pump (particularly an osmotic-controlled release oral delivery system: OROS) composition and a hydrogel sustained release system. From the viewpoint of ease of handling, such an oral pharmaceutical composition is preferably an oral solid pharmaceutical composition (particularly a solid preparation).

[0026] In addition, the oral pharmaceutical composition of the present disclosure preferably contains a cellulose-based water-soluble polymer. The cellulose-based water-soluble polymer is preferably contained in the drug-containing composition. As the cellulose-based water-soluble polymer, for example, a cellulose-based water-soluble polymer known in the field of pharmaceuticals can be preferably used. In addition, for example, a structure in which a part of the OH groups of cellulose has a hydrogen atom substituted with a methyl group and / or a hydroxypropyl group is preferable. Specifically, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc. are preferable. The cellulose-based water-soluble polymer can be used alone or in combination of two or more kinds.

[0027] In particular, when a fumarate salt is used as the salt of compound (I), a solid oral pharmaceutical composition exhibiting a significantly excellent supersaturated dissolution profile can be obtained by using the fumarate salt in combination with a cellulose-based water-soluble polymer.

[0028] Next, the present disclosure will be described in more detail by taking as an example an osmotic pump type composition, which is a preferred oral solid pharmaceutical composition. The formulation of the osmotic pump type composition can be called an osmotic pump type formulation.

[0029] Osmotic pump compositions generally have a structure in which a drug and a substance (osmotic agent) such as a salt that generates osmotic pressure as needed are surrounded by a semipermeable membrane, and the semipermeable membrane has holes through which the drug can be released. Fluid (e.g., water) enters the semipermeable membrane according to osmotic pressure, dissolving the drug and osmotic agent, which increases the osmotic pressure gradient across the semipermeable membrane, and further fluid enters the semipermeable membrane, further dissolving and releasing the drug. Osmotic pump compositions are advantageous in that the release rate of the drug does not depend on the pH of the environment, so that even when the composition passes through the gastrointestinal tract and encounters significantly different pH environments, it can continuously release the drug at a uniform rate according to the osmotic pressure over a long period of time.

[0030] An embodiment of the oral pharmaceutical composition of the present disclosure, which is an osmotic pump composition, will be described below with reference to the drawings. In FIG. 5, an osmotic pump composition 1 (hereinafter, sometimes simply referred to as formulation 1) includes a wall 2 surrounding an internal compartment 5 in which a composition containing a salt of compound (I) is present. The wall 2 is provided with at least one drug release port 3 that communicates between the external environment and the internal compartment. The internal compartment 5 includes a bilayer compressed core having a drug layer 6 and a push layer 7. The drug release port 3 is preferably provided in the wall 2 so as to communicate between the internal compartment 5 on the drug layer 6 side and the external environment. There may be one or more drug release ports 3. For example, there may be two or three.

[0031] The wall 2 is a semipermeable membrane that is permeable to water and external liquids but not to drugs, osmotically active ingredients, etc. The drug layer 6 contains a salt of compound (I) in a state of a mixture with an additive. The push layer 7 does not contain a salt of compound (I) but contains an osmotically active ingredient and a highly swellable polymer. The osmotically active ingredient means a water-soluble ingredient such as an inorganic salt and a sugar and / or sugar alcohol, which has a property of increasing the electrolyte concentration in the formulation. The highly swellable polymer means a polymer (preferably a polymer having a relatively large molecular weight) that absorbs a liquid and swells. The highly swellable polymer absorbs a liquid and swells, thereby releasing the salt of compound (I) through the drug release port 3. The drug layer 6 and the push layer 7 may also contain additives such as a hydrophilic polymer, an osmotic pressure adjuster, a hydration enhancer, a pH adjuster, a binder, a fluidizing agent, an antioxidant, a lubricant, and a dye.

[0032] In the osmotic pump composition, after oral ingestion, liquid such as water permeates the semipermeable membrane and penetrates into the composition, and the salt of compound (I) in the drug layer becomes releasable due to the generated osmotic pressure, and at the same time, the highly swellable polymer in the push layer swells. Then, as bodily fluid continues to infiltrate into the internal compartment, the releasable salt of compound (I) is released through the release port 3. The release of the salt of compound (I) causes further infiltration of bodily fluid, further swelling of the push layer, and sustained release of the salt of compound (I) is achieved.

[0033] The semipermeable membrane to be used is preferably one that is highly permeable to external liquids such as water and biological fluids, but is substantially impermeable to salts of Compound (I), osmotic pressure adjusting agents, highly swellable polymers, etc. Note that such semipermeable membranes are substantially nonerodible and can withstand the effects of biological fluids. It is preferred that the polymer be insoluble in water.

[0034] Representative polymers used to form semipermeable membranes include semipermeable homopolymers and semipermeable copolymers, including cellulose-based polymers such as cellulose esters, cellulose ethers, and cellulose ester-ethers. More specifically, examples of the polymers include cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tri-cellulose alkanylates, mono-, di-, and tri-alkenylates, and mono-, di-, and tri-alloylates. Among these, cellulose acetate is preferred. The semipermeable membrane can be prepared from such polymers by known methods.

[0035] In addition to the above, the following can be used as the semipermeable polymer for forming the semipermeable membrane of the osmotic pump composition: cellulose acetaldehyde dimethyl acetate; cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylamino acetate; semipermeable polyurethane; semipermeable sulfonated polystyrene; crosslinked selective semipermeable polymers formed by coprecipitation of anions and cations, such as those disclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142; semipermeable polymers, such as those disclosed in U.S. Pat. No. 3,133,132; semipermeable polystyrene derivatives; semipermeable poly(sodium styrenesulfonate); semipermeable poly(vinylbenzyltrimethylammonium chloride); and 10 .mu.m to 10 .mu.m, expressed as a hydrostatic pressure difference or osmotic pressure difference per atmosphere when passing through the semipermeable wall. -5 ~10 -2 A semipermeable polymer that exhibits a liquid permeability of (cc ml / cm hr atm).

[0036] The polymers used to form the semipermeable membrane as exemplified above may be used alone or in combination of two or more kinds.

[0037] The semipermeable membrane may contain a flux-regulating agent. A flux-regulating agent refers to a substance added to help regulate the liquid permeability or amount of liquid passing through the semipermeable membrane. That is, the flux-regulating agent includes a substance that acts to improve flux (hereinafter referred to as a flux enhancer) or a substance that acts to reduce flux (hereinafter referred to as a flux reducer). A flux enhancer is essentially hydrophilic, and a flux reducer is essentially hydrophobic.

[0038] The flux regulator includes, for example, polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like.

[0039] Representative flux enhancers include low molecular weight glycols such as polyethylene glycol (average molecular weight in the range of 190 to 9000, e.g., polyethylene glycol 300, 400, 600, 1500, 3000, 3350, 4000, 6000, or 8000, polypropylene glycol, polybutylene glycol, and polyamylene glycol; polyalkylene diols such as poly(1,3-propanediol), poly(1,4-butanediol), and poly(1,6-hexanediol); 1,3-butylene glycol, 1,4-pentamethylene glycol, and 1,4-hexamethylene glycol; alkylene triols, such as glycerin, 1,2,3-butanetriol, 1,2,4-hexanetriol, and 1,3,6-hexanetriol; esters, such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate, and glycerol acetate ester. Suitable flux enhancers include difunctional block copolymer polyoxyalkylene derivatives of propylene glycol known as the pluronics (BASF).

[0040] Representative flux reducers include phthalates substituted with alkyl or alkoxy or with both alkyl and alkoxy groups, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di(2-ethylhexyl)phthalate]; aryl phthalates, such as triphenyl phthalate, and butyl benzyl phthalate; insoluble salts, such as calcium sulfate, barium sulfate, calcium phosphate, and the like; insoluble oxides, such as titanium dioxide; polymers in the form of powders, granules, and the like, such as polystyrene, polymethyl methacrylate, polycarbonate, and polysulfone; esters, such as citrate esters esterified with long chain alkyl groups; and inert and water impermeable fillers. agents; resins compatible with cellulosic wall-forming materials, and the like.

[0041] The flux regulators exemplified above may be used alone or in combination of two or more kinds.

[0042] Other materials may be contained in the semipermeable membrane for the purpose of imparting flexibility and elongation properties to the semipermeable membrane, making the semipermeable membrane less brittle, or imparting tear strength to the semipermeable membrane. Examples of materials suitable for addition for such purposes include plasticizers, and include phthalate-based plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, linear phthalates having 6 to 11 carbon atoms, di-isononyl phthalate, and di-isodecyl phthalate. Plasticizers also include non-phthalates such as triacetin, dioctyl azelate, epoxidized tallate, triisooctyl trimellitate, triisononyl trimellitate, sucrose acetate isobutyrate, and epoxidized soybean oil. When such plasticizers are contained in the semipermeable membrane, the blending ratio is, for example, about 0.01% by mass to 30% by mass or more based on the total amount of all components of the semipermeable membrane.

[0043] The push layer comprises a composition for pushing the salt of Compound (I) and is in a layered arrangement in contact with the drug layer, for example as shown in FIG. 5. As described above, the push layer comprises a highly swellable polymer that absorbs and swells with an aqueous or biological fluid to push the salt of Compound (I) through the outlet of the formulation. The highly swellable polymer is preferably a swellable hydrophilic polymer that swells or expands highly upon interaction with water or aqueous biological fluid, typically exhibiting a 2-50 fold increase in volume. The highly swellable polymer may be crosslinked or uncrosslinked, and in preferred embodiments is at least crosslinked to produce a polymer network that is too large to exit the formulation. Thus, in preferred embodiments, the expandable composition is retained within the formulation during its useful life.

[0044] The highly swellable polymers used include poly(alkylene oxides) having a number average molecular weight of 10,000,000 to 15,000,000, such as polyethylene oxide, and poly(alkali carboxymethylcellulose) having a number average molecular weight of 500,000 to 3,500,000 (wherein the alkali is sodium, potassium, or lithium). Further examples of highly swellable polymers include polymers that form hydrogels, such as Carbopol®, acidic carboxy polymers, acrylic polymers crosslinked with polyallyl sucrose, also known as carboxypolymethylene, and carboxyvinyl polymers having a molecular weight of 250,000 to 4,000,000; Cyanamer® polyacrylamide; crosslinked water-swellable indene maleic anhydride polymers; Good-rite® polyacrylic acid having a molecular weight of 80,000 to 200,000; Aqua-Keeps®, acrylate polymeric polysaccharides composed of condensed glucose units such as diester crosslinked polyglucans; etc. Representative polymers that form hydrogels are disclosed, for example, in U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, etc.

[0045] The highly swellable polymers exemplified above may be used alone or in combination of two or more kinds.

[0046] An osmotic agent, also called an osmotic solute or an osmotically effective agent, can be included in both the drug layer and the push layer. There are no particular limitations on the osmotic agent, so long as it provides an osmotic gradient across the semipermeable membrane. Examples of osmotic agents include inorganic salts, inorganic acids, organic salts, organic acids, and the like. , sugar, and sugar alcohols. Examples of inorganic salts include sodium chloride, sodium hydrogen carbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tripotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate), potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, sodium hydrogen sulfite, potassium hydrogen sulfite, lithium sulfate, and potassium acid phosphate. Examples of inorganic acids include acids that form the above-mentioned inorganic salts. Examples of organic salts include sodium fumarate (disodium fumarate), sodium hydrogen fumarate (monosodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), sodium hydrogen maleate, sodium maleate (disodium maleate), sodium hydrogen citrate (sodium dihydrogen citrate, disodium hydrogen citrate), sodium citrate (trisodium citrate), and the like. Examples of organic acids include acids that form the above-mentioned organic salts. Examples of sugars and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose, and the like. These may be anhydrous or solvates (e.g., hydrates). These may be used alone or in combination of two or more.

[0047] In addition, the drug layer preferably contains an additive having an ion common to the salt of compound (I). For example, when the salt of compound (I) is a fumarate, examples of additives having a common ion include fumaric acid, monosodium fumarate, and disodium fumarate. In this case, the common ion is a fumarate ion. Those skilled in the art can appropriately understand the ion common to the salt according to the type of the salt of compound (I) used, and can select and use an additive having the common ion. Other examples of additives having a common ion to the salt of compound (I) that can be used are as described above.

[0048] Suitable solvents for use in preparing the osmotic pump composition or each of its components include aqueous or inert organic solvents that do not adversely affect the materials used in the composition, such as one or more selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, alicyclic, aromatic, heterocyclic solvents, and mixtures thereof.

[0049] Representative solvents include, for example, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts such as sodium chloride and calcium chloride, and mixtures thereof (e.g., acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol, etc.).

[0050] The drug layer comprises a composition formed from a therapeutically effective amount of a salt of Compound (I) and a carrier. The carrier may include a hydrophilic polymer. The hydrophilic polymer can provide hydrophilic polymer particles in the drug composition that contribute to a uniform release rate and controlled release pattern of the salt of Compound (I). These polymers include, for example, hydrophilic polymers having a number average molecular weight of 100, The drug composition may include poly(alkylene oxide) having a number average molecular weight of 40,000 to 400,000, such as poly(ethylene oxide), poly(methylene oxide), poly(butylene oxide) and poly(hexylene oxide); poly(carboxymethylcellulose) having a number average molecular weight of 40,000 to 400,000, such as poly(alkali carboxymethylcellulose), poly(sodium carboxymethylcellulose), poly(potassium carboxymethylcellulose) and poly(lithium carboxymethylcellulose); hydroxypropyl alkylcellulose having a number average molecular weight of 9,200 to 125,000, such as hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl butylcellulose and hydroxypropyl pentylcellulose, for improving the release properties of the composition; and poly(vinylpyrrolidone) having a number average molecular weight of 7,000 to 75,000, for improving the flow properties of the composition. Of these, the preferred polymer is poly(ethylene oxide) having a number average molecular weight of 100,000 to 300,000.

[0051] Other carriers that may be included in the drug layer include carbohydrates that exhibit sufficient osmotic activity to be used alone or with other osmotic modifiers. Such carbohydrates include monosaccharides, disaccharides, and polysaccharides. Representative examples thereof include sugars such as maltodextrin (i.e., glucose polymers produced by hydrolysis of corn starch), lactose, glucose, raffinose, sucrose, mannitol, and sorbitol. Preferred maltodextrins have a dextrose equivalence (DE) of 20 or less, preferably about 4 to about 20, and more preferably a DE of 9 to 20. The use of maltodextrins with a DE of 9 to 12 is preferred. Carbohydrates (preferably maltodextrins) can be used in the drug layer without the addition of a separate osmotic modifier, and are preferred from the viewpoint of long-term stability of the composition.

[0052] The drug layer is, for example, a homogenous dry composition formed by compression of the carrier and drug. The drug layer may be formed from particles of milled drug and added polymer. Granulation may be carried out using known techniques, including, for example, granulation, spray drying, sieving, freeze drying, crushing, grinding, and chopping. Such granulation may be carried out using equipment such as: high speed agitator granulators, extrusion granulators, fluidized bed granulators, and roller compactors.

[0053] The drug layer may contain a surfactant and a disintegrant. Examples of such surfactants include surfactants having an HLB value of about 10 to 25 (specifically, polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-20-monolaurate, polyoxyethylene-40-stearate, sodium oleate, etc.). Examples of disintegrants include starch, clay, cellulose, algin, gum, crosslinked starch, cellulose, and polymers. Suitable disintegrants include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum, etc.

[0054] The drug layer may also contain light anhydrous silicic acid.

[0055] The formation of a semipermeable membrane on the surface of the bilayer compressed core can be carried out, for example, by using pan coating. Specifically, it can be carried out by spraying a composition that forms a semipermeable membrane onto the surface of a bilayer compressed core composed of a drug layer and a push layer that are rolling in a rotating pan. Coating means other than pan coating can also be used to cover the compressed core. For example, the semipermeable membrane may be formed by a technique using an air suspension operation. This technique is carried out by suspending a compressed core in a stream of air and the semipermeable membrane-forming composition and rolling until a semipermeable membrane is formed on the core. Air suspension is suitable for independently forming a semipermeable membrane. Such air suspension techniques are known (e.g., U.S. Pat. No. 2,799,241). It is also possible to use a Wurster® air suspension coater or an Aeromatic® air suspension coater.

[0056] After coating with the semipermeable membrane, the solvent is removed, for example, by drying the semipermeable membrane in a forced air oven or a temperature and humidity controlled oven. Drying conditions can be appropriately selected taking into account available equipment, ambient conditions, solvent, coating material, coating thickness, etc.

[0057] The oral pharmaceutical composition of the present disclosure can be manufactured by utilizing known formulation techniques. For example, it can be manufactured by existing wet granulation techniques or dry granulation techniques. In the case of using wet granulation techniques, an organic solvent such as denatured anhydrous alcohol is used as a granulation solution, and the drug and additives are mixed in a granulator and continuously granulated using the above solvent to obtain granules. The granulation solution is added until a wet mixture is produced, and the wet mass mixture is passed through a screen previously installed on an oven tray. The mixture is then dried in a forced air oven. Another granulation method includes granulation of each layer of powder components in a fluidized bed granulator. After the powder components are dry mixed in a granulator, a granulation liquid is sprayed onto the powder. The coated powder is dried in the granulator. The dried granules obtained by these methods are sized in a granulator equipped with a crushing mechanism, lubricants such as magnesium stearate are added, and the granules are mixed into granules using a blender (e.g., a V-type blender or a tote blender). The composition thus obtained is pressed into layers, for example, using a Manesty® press or a Korsch LCT press. In the case of a bilayer core, the drug-containing layer is pressed first, and then a wet mixture of the push layer, which is similarly prepared by wet granulation techniques, is pressed against the drug-containing layer. The bilayer compressed core is optionally provided with a water-soluble polymer coat, and then coated with a semipermeable membrane material as described above. One or more exits (holes) are provided at the end of the drug layer of the composition. If necessary, a water-soluble overcoat may be applied, and the overcoat coating may be colored or clear.

[0058] Alternatively, for example, when using a dry granulation technique, a layered product is prepared from a premixed composition in a roller type compression molding machine, and the layered product is sized using a screen grinder equipped with a crushing mechanism. The sized granules are mixed with a lubricant such as magnesium stearate in the same manner as above, mixed into granules using a blender, and pressed in the same manner as in the above-mentioned manufacturing method.

[0059] At least one outlet is provided in the osmotic pump composition. The outlet can be provided during the preparation of the composition or during the drug delivery by the composition in a liquid environment during use. The term outlet encompasses, for example, passageway, opening, orifice, and bore. It also encompasses pores formed by erosion, dissolution, or leaching of a substance or polymer from the outer wall. Such substances or polymers include, for example, erodible poly(glycolic acid) or poly(lactic acid) in a semipermeable membrane; gelatinous filaments; water-removable poly(vinyl alcohol); leachable compounds, such as fluid-removable pore-forming substances selected from the group consisting of inorganic and organic salts, oxides, or carbohydrates. The release port is formed by exuding at least one substance selected from the group consisting of sorbitol, mannitol, lactose, fructose, maltitol, maltose, dextrin, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, and sodium citrate, to provide a release port having a pore size suitable for uniformly controlling the release of the drug. The release port can be any shape, such as a circle, a rectangle, a square, an ellipse, etc., as long as it allows the release of the drug from the composition at a uniform rate. The osmotic pump composition can have one or more release ports provided at regular intervals. The diameter of the release port is not particularly limited as long as it can cooperate with the compressed core to control the release of the drug, but is preferably 0.1 mm to 3 mm. For the formation of the release port, a wide variety of perforation techniques can be used, including mechanical perforation and laser perforation, which penetrate the semipermeable membrane. Devices for forming such release ports are known (e.g., U.S. Pat. No. 3,916,899, U.S. Pat. No. 4,088,864).

[0060] The amount of the salt of Compound (I) to be incorporated into the oral pharmaceutical composition may be, for example, less than 1 mg to 200 mg or more equivalent in terms of the weight of the free base per preparation. For example, the drug layer of the osmotic pump type composition in the Examples described below contains 30 mg (equivalent to the free base) of Compound (I). The osmotic pump type composition has a T of about 10 hours or more. 90 Within about 3-4 hours after administration, the salt of Compound (I) begins to be released at a steady rate, which continues for an extended period of at least about 12 hours, after which drug release continues for several more hours until the formulation is exhausted.

[0061] The oral pharmaceutical composition of the present disclosure preferably releases drug over a long period of time with a relatively uniform release rate.When administered to a patient, the oral pharmaceutical composition of the present disclosure can provide blood plasma drug concentrations that are less variable over a long period of time than conventional formulations (e.g., fast-release formulations).When the oral pharmaceutical composition of the present disclosure is administered, it can provide a therapeutically effective average steady-state plasma concentration that preferably peaks later than the steady-state peak plasma concentration that appears after administration of conventional formulations (e.g., fast-release formulations), and the peak is smaller.

[0062] The present disclosure includes a method of treating disease states and conditions responsive to treatment with Compound (I) by orally administering to a patient an oral pharmaceutical composition of the present disclosure, e.g., in a formulation adapted to release a salt of Compound (I) at a uniform release rate over a period of at least about 4 hours, preferably 5 to 30 hours, more preferably 10 to 24 hours, and even more preferably 15 to 24 hours.

[0063] It is preferred to practice the above method for the purpose of orally administering the oral pharmaceutical composition of the present disclosure to a patient less frequently than once a day for the treatment of schizophrenia. Other disease states and conditions that may be clinically diagnosed as symptoms of schizophrenia may be treated with the controlled release oral pharmaceutical composition of the present disclosure.

[0064] Although not particularly limited, the oral pharmaceutical composition of the present disclosure is orally administered to humans (especially adults). It is preferable that the steady state blood concentration of Compound (I) when administered is maintained within the range of, for example, 15 ng / mL to 400 ng / mL or 50 ng / mL to 300 ng / mL for one week. Ordinary tablets (non-controlled release formulations) of 0.5 mg, 1 mg, and 2 mg containing compound (I) have already been marketed as a treatment for schizophrenia in many countries, including Japan, the United States, and Europe. The safety and efficacy of ordinary tablets against central nervous system disorders such as schizophrenia have been confirmed in clinical trials, and detailed pharmacokinetic analysis has also been conducted. Considering this information on ordinary tablets, it can be understood that an oral pharmaceutical composition that can maintain a blood concentration of compound (I) of about 15 ng / mL to 400 ng / mL or 50 ng / mL to 300 ng / mL at steady state when administered to humans can be used to prevent or treat central nervous system disorders such as schizophrenia, similar to ordinary tablets already on the market. Thus, the oral pharmaceutical composition of the present disclosure may be orally administered less frequently than once a day, for example, once a week. The oral pharmaceutical composition of the present disclosure may be administered in one tablet per administration, or in two or more tablets per administration, for example, two, three, four, or five tablets per administration. In addition, a person skilled in the art would understand the pharmacokinetic information for the above-mentioned regular tablets and the oral pharmaceutical composition of the present disclosure. The dose of the oral pharmaceutical composition of the present disclosure for achieving the above-mentioned blood concentration can be appropriately determined from an evaluation based on a single administration protocol and a continuous administration protocol for the administration of the compound (I). For example, the dose per administration may be equivalent to about 5 mg to 60 mg, or about 10 mg to 60 mg, 20 mg to 60 mg, or about 45 mg to 60 mg of the free base of the compound (I).

[0065] As described above, among the oral pharmaceutical compositions of the present disclosure, a particularly preferred embodiment is an osmotic pump type oral solid pharmaceutical formulation.The particularly preferred embodiments of the osmotic pump type oral solid pharmaceutical formulation are described in more detail below.Note that the following description may overlap with the above description in part.Note that the following description does not prevent the above description from being applied.

[0066] The osmotic pump type oral solid pharmaceutical formulation is preferably an osmotic pump type oral solid pharmaceutical formulation having a structure in which a core formulation formed by laminating a drug layer and a push layer is coated with a semipermeable membrane, and the drug layer is preferably a pharmaceutical formulation containing a salt of compound (I). One embodiment of the formulation is the formulation shown in Figure 5.

[0067] The mass ratio of the drug layer to the push layer can be, for example, about 20 to 125 parts by mass of the push layer per 100 parts by mass of the drug layer. The upper or lower limit of this range can be, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 parts by mass. For example, the range can be about 35 to 100 parts by mass, or 40 to 60 parts by mass.

[0068] The mass ratio of the drug layer to the push layer may be, for example, about 0.8 to 5. The upper or lower limit of the range may be, for example, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9. For example, the mass ratio of the drug layer to the push layer may be about 1 to 4, or 2 to 3. Also, more specifically, it may be 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

[0069] The salt of compound (I) is not particularly limited as long as it is a pharma- ceutically acceptable salt, and examples thereof include the above-mentioned various metal salts, salts of inorganic bases, salts of organic bases, inorganic acid salts, and organic acid salts, etc. Although not particularly limited, preferred examples include fumarate, hydrochloride, and sulfate, etc., and fumarate is particularly preferred.

[0070] The salt includes the solvate form, and may be contained in the pharmaceutical preparation in the form of a solvate. Examples of the solvate include hydrate, methanol solvate, ethanol solvate, etc. The solvate may be monosolvate, disolvate, trisolvate, etc. For example, monohydrate, dihydrate, trihydrate, etc. A particularly preferred example of the solvate of such a salt is fumarate monohydrate.

[0071] The amount of the salt of Compound (I) contained in the drug layer can be, for example, about 5 to 200 mg equivalent in terms of the weight of the free base. The upper or lower limit of the range can be, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 195 mg. For example, the range can be, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 195 mg equivalent in terms of the weight of the free base. In other words, the amount may be equivalent to about 5 to 60 mg, about 15 to 150 mg, or about 20 to 100 mg.

[0072] The amount of the salt of Compound (I) contained in the drug layer can be, for example, about 1 to 35% by mass of the drug layer. The upper or lower limit of the range can be, for example, 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, or 34% by mass. For example, the range can be about 2 to 30% by mass or about 5 to 20% by mass.

[0073] The drug layer may contain additives other than the salt, such as an osmotic pressure regulator, a hydrophilic polymer, and the like.

[0074] The osmotic pressure regulator contained in the drug layer is not particularly limited as long as it shows an osmotic pressure gradient through the semipermeable membrane. Examples of the osmotic pressure regulator include inorganic salts, inorganic acids, organic salts, organic acids, sugars, and sugar alcohols. Examples of the inorganic salt include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tripotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate), potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, sodium hydrogen sulfite, potassium hydrogen sulfite, lithium sulfate, and potassium acid phosphate. Examples of the inorganic acid include the acids that form the inorganic salts described above. Examples of organic salts include sodium fumarate (disodium fumarate), sodium hydrogen fumarate (monosodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), sodium hydrogen maleate, sodium maleate (disodium maleate), sodium hydrogen citrate (sodium dihydrogen citrate, disodium hydrogen citrate), sodium citrate (trisodium citrate), and the like. Examples of organic acids include acids that form the above-mentioned organic salts. Examples of sugars and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose, and the like. These may be anhydrous or solvates (e.g., hydrates). These may be used alone or in combination of two or more. In addition, the osmotic pressure regulator contained in the drug layer is preferably one that has a common ion with the salt of compound (I). For example, when the salt is a fumarate, examples of the osmotic pressure regulator having a common ion include fumaric acid, monosodium fumarate, and disodium fumarate. In addition, the osmotic pressure regulator can be used alone or in combination of two or more kinds.

[0075] The content of the osmotic pressure regulator in the drug layer may be, for example, about 1 to 50% by mass relative to the weight of the drug layer. The upper or lower limit of the range may be, for example, 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, or 49% by mass. For example, the range may be 10 to 38% by mass or 15 to 35% by mass.

[0076] Examples of the hydrophilic polymer contained in the drug layer include polyethylene oxide and polyethylene glycol. As the polyethylene oxide, low viscosity polyethylene oxide is preferable. More specifically, as the polyethylene oxide, Polyethylene oxide having an average molecular weight of about 100,000 to 300,000 is preferred, and polyoxyethylene oxide having an average molecular weight of about 150,000 to 250,000 or about 180,000 to 220,000 is more preferred. In addition, as the polyethylene glycol, for example, one having an average of about 4,000 to 8,000 ethylene oxide units polymerized is preferred, and one having an average of about 4,500 to 7,500, 5,000 to 7,000, or 5,500 to 6,500 units polymerized is more preferred. In addition, as the hydrophilic polymer contained in the drug layer, for the purpose of inhibiting recrystallization of the drug in the formulation, cellulose-based water-soluble polymers such as methylcellulose, hydroxypropylcellulose, and hydroxypropyl alkylcellulose (e.g., hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl butylcellulose, and hydroxypropyl pentylcellulose, etc.), polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone, copolyvidone, etc. can also be blended. As the hydroxypropyl alkylcellulose, hydroxypropyl methylcellulose is particularly preferred. In addition, the hydroxypropyl methylcellulose is preferably, for example, hydroxypropyl methylcellulose containing about 16 to 30% of methoxy groups, more preferably about 27 to 30%. The hydrophilic polymers may be used alone or in combination of two or more.

[0077] As described above, in the oral pharmaceutical composition of the present disclosure, the drug-containing composition preferably contains a water-soluble cellulose polymer. Therefore, the drug layer preferably contains a water-soluble cellulose polymer as a hydrophilic polymer.

[0078] The content of the hydrophilic polymer in the drug layer is, for example, about 5 to 94% by mass relative to the weight of the drug layer. The upper or lower limit of this range is, for example, 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, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 1, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, or 93% by mass. For example, the range may be 20 to 90% by mass. Furthermore, when the drug-containing composition particularly contains a water-soluble cellulose polymer, the content of the water-soluble cellulose polymer in the drug layer may be, for example, about 5 to 40% by mass relative to the weight of the drug layer, or may be, for example, 10 to 30% by mass or 10 to 20% by mass.

[0079] In addition, when the drug layer simultaneously contains, as the hydrophilic polymer, in particular, (i) polyethylene oxide and (ii) at least one selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, hydroxypropyl alkyl cellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone, and copolyvidone, the drug layer may contain, for example, about 10 to 60% by mass of (i) and about 5 to 40% by mass of (ii) relative to the weight of the drug layer.

[0080] The drug layer may further contain other additives. Examples of such additives include lubricants and flow agents. A preferred example of the lubricant is magnesium stearate. A preferred example of the flow agent is silicon dioxide (particularly light anhydrous silicic acid).

[0081] In the drug layer, the lubricant (particularly magnesium stearate) can be contained in an amount of, for example, about 0.1 to 5% by mass or 0.2 to 3% by mass relative to the drug layer weight. Also, the fluidizing agent (particularly silicic acid) can be contained in an amount of, for example, about 0.1 to 5% by mass or 0.2 to 3% by mass relative to the drug layer weight. It can be contained at about 1 to 3 mass %.

[0082] The push layer also contains a component for pushing out the salt of compound (I). Such a component may be, for example, a highly swellable polymer. Examples of highly swellable polymers include polyalkylene oxides, more specifically, polyethylene oxides. The polyethylene oxide contained in the push layer is preferably a high-viscosity polyethylene oxide. More specifically, polyethylene oxides having an average molecular weight of about 3 to 7 million, 4 to 7 million, or 4 to 6 million are preferred.

[0083] The amount of the highly swellable polymer in the push layer depends on factors such as the properties and content of the drug in the drug layer, but is not particularly limited as long as it is an amount that allows the drug in the drug layer to be dissolved at a desired release rate by swelling. For example, the highly swellable polymer may be contained in an amount of about 50 to 90% by mass, 50 to 85% by mass, 50 to 80% by mass, 55 to 75% by mass, or 60 to 70% by mass relative to the weight of the push layer.

[0084] The push layer may further contain other additives. For example, it may contain an osmotic pressure regulator. Examples of the osmotic pressure regulator contained in the push layer include inorganic salts, inorganic acids, organic salts, organic acids, sugars, and sugar alcohols. Examples of the inorganic salts include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tripotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate), potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, sodium hydrogen sulfite, potassium hydrogen sulfite, lithium sulfate, and potassium acid phosphate. Examples of the inorganic acids include acids that form the above-mentioned inorganic salts. Examples of organic salts include sodium fumarate (disodium fumarate), sodium hydrogen fumarate (monosodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), sodium hydrogen maleate, sodium maleate (disodium maleate), sodium hydrogen citrate (sodium dihydrogen citrate, disodium hydrogen citrate), sodium citrate (trisodium citrate), and the like. Examples of organic acids include acids that form the above-mentioned organic salts. Examples of sugars and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose, and the like. These may be anhydrous or solvates (e.g., hydrates).

[0085] Among the osmotic pressure regulators contained in the push layer, sodium chloride, potassium chloride, sodium hydrogen fumarate, sodium fumarate, sodium hydrogen carbonate, sodium carbonate, sodium hydrogen phosphate, sodium phosphate, potassium hydrogen phosphate, potassium phosphate, sodium sulfate, fructose, sucrose, xylitol, sorbitol, glucose, mannitol, erythritol, and lactose are preferred, and sodium hydrogen carbonate is particularly preferred. The osmotic pressure regulators may be used alone or in combination of two or more.

[0086] The push layer may contain the osmotic pressure regulator in an amount of, for example, about 5 to 50 mass %, 15 to 50 mass %, 20 to 50 mass %, 25 to 45 mass %, or 30 to 40 mass % relative to the weight of the push layer.

[0087] The push layer may further contain other additives. Examples of such additives include lubricants, flow agents, and colorants. Examples of lubricants include stearin. A preferred example of the fluidizing agent is magnesium anhydride. A preferred example of the fluidizing agent is silicon dioxide (particularly light anhydrous silicic acid). A preferred example of the pigment is iron oxide.

[0088] The push layer may contain a lubricant (particularly magnesium stearate) in an amount of, for example, 0.1 to 5% by mass relative to the weight of the push layer. A flow agent (particularly silicic acid) may be contained in an amount of, for example, 0.1 to 5% by mass or 0.1 to 3% by mass. A pigment (particularly iron oxide) may be contained in an amount of, for example, 0.1 to 2% by mass.

[0089] As described above, the semipermeable membrane for coating the core preparation contains, for example, a cellulose-based polymer, preferably cellulose acetate. The semipermeable membrane may also contain a flux regulator. As described above, the flux regulator is preferably, for example, polyethylene glycol (particularly, having an average molecular weight of about 2000 to 6000, 3000 to 5000, or 3000 to 6000).

[0090] The cellulose polymer may be contained in the semipermeable membrane in an amount of, for example, about 70 to 100% by mass or about 75 to 95% by mass relative to the weight of the semipermeable membrane, and the flux regulator may be contained in an amount of, for example, about 0.01 to 30% by mass or about 5 to 25% by mass relative to the weight of the semipermeable membrane.

[0091] The amount of coating of the semipermeable membrane is preferably an amount that provides high permeability to external liquids such as water and biological fluids, but is substantially impermeable to salts of Compound (I), osmotic pressure regulators, highly swellable polymers, etc. The amount of the semipermeable membrane can be, for example, about 5 to 25 parts by mass relative to 100 parts by mass of the core preparation. The upper or lower limit of this range may be, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 parts by mass. For example, the range may be about 5 to 25 parts by mass.

[0092] In addition, in an osmotic pump type oral solid pharmaceutical formulation, a water-soluble polymer coating may be provided between the core formulation and the semipermeable membrane. In other words, the formulation may have a structure in which a water-soluble polymer membrane and a semipermeable membrane are laminated (preferably coated) on the core formulation in this order.

[0093] The water-soluble polymer film may be, for example, one of the hydrophilic polymers described above as the hydrophilic polymer that may be contained in the drug layer. Among them, preferred examples include hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinylpyrrolidone. The water-soluble polymer may be used alone or in combination of two or more. When the water-soluble polymer film contains hydroxypropylmethylcellulose, for example, 60 to 100% by mass of the water-soluble polymer film may be hydroxypropylmethylcellulose. When the water-soluble polymer film contains polyvinylpyrrolidone, for example, 0 to 40% by mass of the water-soluble polymer film may be polyvinylpyrrolidone.

[0094] The amount of the water-soluble polymer film can be, for example, about 1 to 15 parts by mass relative to 100 parts by mass of the core preparation.

[0095] The oral solid pharmaceutical formulation of the present disclosure can be used, for example, as a plain tablet containing the above-mentioned components and not coated with a color coating layer. It is also preferable to use a coated tablet coated with a color coating layer, for example, from the viewpoint of providing the formulation with distinguishability, long-term storage stability, and prevention of deterioration due to light. The coating layer may contain a coating agent, a plasticizer, Pharmaceutical additives such as dispersants and antifoaming agents that are usually used in coating (film) treatment of orally administered pharmaceuticals can be added as necessary. When a color coating layer is provided, the color coating layer is preferably the outermost layer. For the color coating layer, a known coating agent can be used, for example, a representative premix additive such as Opadry can be used as the coating agent. For example, a coating agent containing hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc. as a base material and containing a colorant, lubricant, plasticizer, etc. can be preferably used.

[0096] A preferred example of the osmotic pump type oral solid pharmaceutical formulation of the present disclosure comprises a drug layer containing 5 to 200 mg of a fumarate salt of Compound (I) converted into the weight of the free base, 5 to 94% by mass of a hydrophilic polymer relative to the drug layer weight (including 5 to 40% by mass of a cellulose-based water-soluble polymer relative to the drug layer weight), 1 to 50% by mass of an osmotic pressure regulator relative to the drug layer weight, 0.1 to 5% by mass of a lubricant relative to the drug layer weight, and 0.1 to 5% by mass of a fluidizer relative to the drug layer weight, and a highly swelling polymer relative to the push layer weight. the push layer weight is 50 to 90% by mass, an osmotic pressure regulator is 5 to 50% by mass, a lubricant is 0.1 to 5% by mass, and a dye is 0.1 to 2% by mass, based on the push layer weight; and further comprises 5 to 25 parts by mass of a semipermeable membrane and 1 to 15 parts by mass of a water-soluble polymer membrane, based on 100 parts by mass of the core formulation, wherein the semipermeable membrane contains 70 to 100% by mass of a cellulose-based polymer and 0.01 to 30% by mass of a flux regulator, based on the semipermeable membrane weight, and may have a color coating layer.

[0097] As described above, another preferred embodiment of the oral pharmaceutical composition of the present disclosure is a hydrogel sustained release composition. That is, the hydrogel sustained release composition (hydrogel sustained release formulation) of the present disclosure preferably contains the fumarate salt of compound (I) as an active ingredient, and further contains a cellulose-based water-soluble polymer. A preferred example of the hydrogel sustained release composition is a hydrogel matrix tablet. The hydrogel matrix tablet is a known technology in which a hydrogel formed by absorbing water in the digestive tract (in the case of an enteric-coated tablet, the coating film dissolves due to an increase in pH after gastric excretion) controls drug release.

[0098] The hydrophilic polymers mentioned above can be used as the sustained release base (hydrogel-forming base) in the hydrogel matrix tablet, 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. The above hydrophilic polymers can be used alone or in combination of two or more as the sustained release base, but it is particularly preferable to contain at least one cellulose-based water-soluble polymer. In addition, when a hydrophilic polymer other than a cellulose-based water-soluble polymer (e.g., polyethylene oxide) is mainly used as the sustained release base, it is preferable to combine it with at least one cellulose-based water-soluble polymer.

[0099] As the cellulose-based water-soluble polymer, for example, a cellulose-based water-soluble polymer known in the field of pharmaceutical preparations can be preferably used. Also, for example, a structure in which a part of the OH groups of cellulose has a hydrogen atom substituted with a methyl group and / or a hydroxypropyl group is preferable. Specifically, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, etc. are preferable. The cellulose-based water-soluble polymer can be used alone or in combination of two or more kinds. The cellulose-based water-soluble polymer may be any cellulose-based water-soluble polymer, for example, a cellulose-based water-soluble polymer having a viscosity of 2.5 to 35,000 mm as a 2% aqueous solution. 2 / s using cellulose-based water-soluble polymer It is possible to use a 2% aqueous solution with a viscosity of 2.5 to 17.5 mm. 2 / s cellulose-based water-soluble polymers are preferred.

[0100] In addition, when a cellulose-based water-soluble polymer (e.g., hypromellose) is mainly used as the sustained-release base, the cellulose-based water-soluble polymer has a viscosity of 80 to 35,000 mm as a 2% aqueous solution depending on the desired dissolution rate. 2In this case, the term "mainly" using a hydrophilic polymer means that the amount of the hydrophilic polymer is 50% by mass or more, for example, 80% by mass or more, or 90% by mass or more, based on the total mass of the sustained release base.

[0101] The sustained release base can be contained in an amount of, for example, about 30 to 90% by mass or about 50 to 80% by mass relative to the weight of the core tablet.

[0102] The hydrogel matrix tablet may further contain other additives, such as a hydration promoter, a lubricant, and a flow agent.

[0103] Examples of the hydration promoter include inorganic salts, inorganic acids, organic salts, organic acids, sugars, and sugar alcohols. Examples of the inorganic salt include sodium chloride, sodium hydrogen carbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tripotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate), potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, sodium hydrogen sulfite, potassium hydrogen sulfite, lithium sulfate, and potassium acid phosphate. Examples of the inorganic acid include the acids that form the inorganic salts described above. Examples of organic salts include sodium fumarate (disodium fumarate), sodium hydrogen fumarate (monosodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), sodium hydrogen maleate, sodium maleate (disodium maleate), sodium hydrogen citrate (sodium dihydrogen citrate, disodium hydrogen citrate), sodium citrate (trisodium citrate), and the like. Examples of organic acids include acids that form the above-mentioned organic salts. Examples of sugars and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose, and the like. These may be anhydrous or solvates (e.g., hydrates). These may be used alone or in combination of two or more. In addition, the hydration promoter is preferably one having a common ion with the fumarate salt of compound (I). For example, fumaric acid, monosodium fumarate, disodium fumarate, etc. can be exemplified. The hydration promoter can be contained, for example, in an amount of about 1 to 50% by mass or about 10 to 30% by mass relative to the weight of the core tablet.

[0104] A preferred example of the lubricant is magnesium stearate. The lubricant may be contained in an amount of about 0.1 to 5% by mass or about 0.2 to 3% by mass, based on the weight of the core tablet. A preferred example of the fluidizing agent is silicon dioxide (particularly light anhydrous silicic acid). The fluidizing agent may be contained in an amount of about 0.1 to 5% by mass or about 0.1 to 3% by mass, based on the weight of the core tablet.

[0105] The hydrogel matrix tablet is preferably provided with an enteric coating. For the enteric coating, a known enteric coating composition can be used. 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 can be preferably used. For example, the enteric coating can be applied to a core tablet. The amount of the additive may be about 1 to 40 parts by mass or about 10 to 30 parts by mass relative to 100 parts by mass of the agent.

[0106] A preferred example of the hydrogel sustained-release formulation of the present disclosure is a formulation containing 5 to 200 mg of the fumarate salt of Compound (I) calculated as the weight of the free base, 30 to 90% by mass of a sustained-release base material relative to the weight of the core tablet, 1 to 50% by mass of a hydration enhancer relative to the weight of the core tablet, and 0.1 to 5% by mass of a lubricant relative to the weight of the core tablet, and having 1 to 40 parts by mass of an enteric coating relative to 100 parts by mass of the core formulation.

[0107] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes all arbitrary combinations of the constituent features described in this specification.

[0108] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter included in the present disclosure. In other words, the present disclosure includes all subject matter consisting of all combinations of each combinable characteristic described in this specification. EXAMPLES

[0109] The present disclosure will be described in more detail below with reference to examples and test examples, but the present disclosure is not limited to these examples. Compound (I) refers to 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.

[0110] Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one fumarate A suspension of 32.5 L of water, 22.16 kg of ethanol, and 4.22 kg of fumaric acid was stirred. The mixture was refluxed while being stirred for 1 hour to dissolve the mixture (reflux temperature: about 82°C). The resulting solution was filtered while being washed with 11.86 kg of ethanol to obtain a fumaric acid solution. The suspension was dissolved by refluxing with stirring (reflux temperature: about 83°C). The obtained solution was added to the fumaric acid solution, and then filtered while washing with 11.86 kg of ethanol. The filtrate was stirred under reflux for 15 minutes (reflux temperature: about 82°C), cooled to 30°C or less, and separated into solid and liquid. The obtained solid was washed with water, dried at 80°C, and then moistened to obtain 16.86 kg of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one fumarate.

[0111] [Infrared absorption spectrum] The fumarate salt prepared by the above method was measured by the KBr pellet method using a Shimadzu Corporation Fourier transform infrared spectrophotometer (IRPrestige-21). The IR spectrum was measured. As shown in Figure 4a, the IR spectrum was obtained at a wave number of 3657 cm -1 , 1711cm -1 , 1643cm -1 , 1416cm -1 , 1227cm -1 and 839 cm -1 Absorption was observed in the vicinity.

[0112] [Powder X-ray diffraction] The fumarate salt prepared by the above method was analyzed using an X-ray diffraction apparatus manufactured by Bruker AXS. Powder X-ray diffraction was measured using a D8 ADVANCE. The final X-ray diffraction pattern is shown in Figure 4b, where 2θ = 7.6°, 15.1°, and 17. Diffraction peaks were observed at 2θ=9.8°, 11.3°, 12.2°, 14.0°, 16.5°, 17.0°, 21.2°, 22.3°, 22.7°, 23.8°, 24.2°, 24.7°, 25.4°, 26.5°, 26.9°, 27.9°, 28.9°, 31.9°, 32.3°, 32.6°, and 34.2°.

[0113] [Moisture measurement] The water content of the prepared fumarate was measured. Specifically, the water content was measured by the Karl Fischer method (coulometric titration method) using a Metrohm water content measuring device (Titrando 852). As a result, the water content of the fumarate was 3.01% by weight.

[0114] Preparation and evaluation of sustained release drug formulations 1 An osmotic pump-type composition (formulation) comprising a bilayer compressed core consisting of a drug layer and a push layer for providing sustained release of a salt of Compound (I) was prepared according to a conventional known manufacturing process, that is, a drug layer composition containing a salt of Compound (I) and other inactive agents, and a push layer composition containing an osmotic agent and a highly viscous polymer were separately prepared, and each composition was compressed into a bilayer tablet core using known core compression techniques.

[0115] Next, the bilayer compressed core was coated with a composition consisting of a water-soluble polymer. As the composition of the water-soluble polymer, hypromellose (hydroxypropyl methylcellulose; TC-5, Shin-Etsu Chemical Co., Ltd.) and povidone (polyvinylpyrrolidone; Kollidon K30, BASF) (70:30 (W / W%)) were dissolved in water to a solid content of 8% to prepare a coating solution. This water-soluble polymer coating solution was coated on the bilayer compressed core produced as described above using a pan coater until the coating component accounted for 10% of the bilayer compressed core mass.

[0116] Further, the obtained water-soluble coated bilayer compressed core was coated with a semipermeable membrane composition. As the semipermeable membrane composition, cellulose acetate and polyethylene glycol 4000 (85:15 (W / W%)) were dissolved in acetone / water (95:5 (W / W%)) as a solvent to a solid content of 5% to prepare a coating solution. This coating solution was applied to the water-soluble coated bilayer compressed core produced above using a pan coater until the coating component reached 10% of the bilayer compressed core mass, and the core was removed from the pan coater and dried in a shelf dryer at 40°C for 24 hours.

[0117] For the thus obtained coated bilayer compressed core, a drug release port with a diameter of 0.8 mm was formed on the side of the drug layer using an automated laser to form an osmotic pump type preparation.

[0118] The components used in the osmotic pump formulation are shown in Table 1A or Table 1B below.

[0119] [Table 1A] [Table 1B] The resulting preparations of each example were subjected to the following Test Example 1 and evaluated.

[0120] As a low-viscosity polyethylene oxide, POLYOX (trademark) WSR N-80 (average molecular weight of about 200,000, viscosity of 55-90 mPa·s (5% W / V aqueous solution, 25 As the high-density polyethylene oxide, POLYOX (registered trademark) WSR Coagulant (average molecular weight: 5 million, viscosity: 5500-7500 mPa·s (1% W / V aqueous solution, 25° C.)) was used.

[0121] [Test Example 1: Measurement of supersaturated elution concentration profile] The release rate from each preparation was evaluated by measuring the dissolution rate of the salt of Compound (I) at 1- or 2-hour intervals over 18 or 24 hours. The dissolution test was performed according to the Japanese Pharmacopoeia, 15th Edition. The dissolution test was carried out according to the second method (paddle method). As the test liquid, 900 mL of the second dissolution test liquid (pH about 7, potassium dihydrogen phosphate, disodium hydrogen phosphate) listed in the Japanese Pharmacopoeia was used, and the test was carried out at 37°C and a paddle rotation speed of 50 rpm. Sampling was carried out over time, and the amount of compound (I) (free base) 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 main drug could be detected to the maximum, and the second wavelength (380 nm) was set as the wavelength at which the absorbance derived from the main drug was not detected. In the diagram showing the results, Dissolved (μg / mL) indicates the concentration of the dissolved compound (I) (free base).

[0122] In Test Example 1, the pH of the dissolution solution is about 7, and the results of the dissolution test evaluated in Test Example 1 are an index of the extent to which the salt of compound (I) dissolves in the lower part of the digestive tract after the oral pharmaceutical composition is orally administered and passes through the stomach. In Test Example 1, since the solubility of the salt of compound (I) is higher than that of compound (I), the dissolution concentration from the formulation temporarily exceeds the solubility of compound (I) and shows a supersaturated concentration, and then the dissolution concentration decreases with the recrystallization of compound (I). The profile obtained at this time is considered to be a supersaturated dissolution profile, and can be evaluated as an index of absorbability in the lower part of the digestive tract.

[0123] The results of Test Example 1 for the preparations of each example are shown in Figure 1a or Figure 1b. The preparations of the examples (preparations containing the fumarate salt of compound (I)) showed superior supersaturation dissolution profiles compared to the preparations of the comparative examples (preparations containing compound (I)).

[0124] Preparation and evaluation of sustained release drug formulations 2 Furthermore, when an oral pharmaceutical composition showing a superior supersaturated dissolution profile was examined, it was found that the fumarate salt of compound (I) may show a particularly superior supersaturated dissolution profile when a drug-containing composition is prepared in combination with a water-soluble polymer. Therefore, an osmotic pump-type formulation was prepared in the same manner as described above, using a combination of the fumarate salt of compound (I) and various water-soluble polymers according to the composition in Table 2. In Table 2, Metolose SM-4 is methylcellulose, HPC-SL is hydroxypropylcellulose, PVP Kollidon25 is polyvinylpyrrolidone, and Kollicoat IR is polyvinyl alcohol-polyethylene glycol-graft copolymer.

[0125] [Table 2] The supersaturated dissolution profile of each of the preparations obtained was measured in the same manner as in Test Example 1. The results are shown in Figure 2a. The preparations of all of the Examples showed a supersaturated dissolution profile superior (particularly, higher peak height) to the supersaturated dissolution profile of the preparation of Example 1-1 (Figure 1). In particular, the example using the cellulose-based water-soluble polymer showed a relatively high peak height in the supersaturated dissolution profile, which was more preferable.

[0126] Furthermore, the release rate of these preparations was examined in the manner described in Test Example 2 below.

[0127] [Test Example 2: Measurement of release rate] The release rate from each formulation was evaluated by measuring the dissolution rate of the salt of compound (I) at intervals of 30 minutes to 2 hours over a period of 24 hours. The dissolution test was performed according to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). 900 mL of 0.05 mol / L acetate buffer (pH about 4.3, acetic acid, sodium acetate) 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 the amount of compound (I) (free base) in the sampling solution was quantified using a UV detector (absorbance measurement wavelengths: 323 nm and 380 nm). The dissolution rate was determined as the mass ratio (%) of compound (I) (free base) dissolved when the total amount (mass) of compound (I) (free base) contained in the formulation was taken as 100%. In addition, since the dissolution rate value is the same as the dissolution mass ratio (%) of the salt of compound (I) when the total amount (mass) of the salt of compound (I) contained in the formulation is taken as 100%, the dissolution rate value can also be used as the dissolution rate of the salt of compound (I). In the graphs showing the results, Dissolved (%) indicates the dissolution rate.

[0128] In Test Example 2, the pH of the dissolution medium is about 4.3, and the results of the dissolution test evaluated in Test Example 2 are an index of the extent to which the salt of Compound (I) dissolves in the entire digestive tract after the oral pharmaceutical composition is orally administered. From the obtained profile, the sustained release time of the oral pharmaceutical composition can be evaluated.

[0129] The results are shown in Figure 2b. It was found that all the formulations of the Examples showed excellent sustained release properties.

[0130] Preparation and evaluation of sustained release drug formulations 3 A hydrogel sustained-release preparation (hydrogel matrix tablet) was prepared according to the composition shown in Table 3. Specifically, each component was mixed and fluidized bed granulated, and then tableted to prepare a hydrogel matrix tablet (plain tablet). The hydrogel matrix tablet is a known technology in which the hydrogel formed by absorbing moisture in the digestive tract (in the case of a coated tablet, the coating film dissolves due to the increase in pH after gastric excretion) controls drug release. In the composition of Example 3-1 in Table 3, polyethylene oxide and hypromellose are used as sustained-release bases (hydrogel-forming bases), and in the composition of Comparative Example 3-2, polyethylene oxide is used as the sustained-release base (hydrogel-forming base).

[0131] [Table 3] The supersaturated dissolution profile of each of the preparations obtained in the examples was measured in the same manner as in Test Example 1. The results are shown in Figure 3. The preparations of the examples showed superior supersaturated dissolution profiles compared to the preparations of the comparative examples.

[0132] Osmotic pump formulation example Table 4 shows an example of a formulation of an osmotic pump formulation, which is an oral pharmaceutical composition of the present disclosure. In Table 4, the formulations of the components of the drug layer and push layer are shown in parts by weight, and the formulation of the coating layer is shown in parts by weight relative to 100 parts by weight of the core. The "core" refers to the combination of the drug layer and the push layer.

[0133] [Table 4]

[0134] Evaluation of blood concentration of compound (I) after oral administration to humans The steady-state blood concentration of compound (I) when the oral pharmaceutical composition of the present disclosure is orally administered to humans is evaluated based on the following single-dose protocol and continuous administration protocol. The formulation (test formulation) used in this evaluation is an osmotic pump-type formulation prepared according to the present disclosure, containing the fumarate salt of compound (I) as an active ingredient. The dosage and content in the tablet shown below are equivalent to the free base, that is, converted to the weight of compound (I). In the single-dose protocol, 24 mg of the test formulation (one 24 mg tablet) is administered once on an empty stomach. After that, after a drug-free period, 48 mg of the test formulation (two 24 mg tablets) is administered once on an empty stomach. In the continuous administration protocol, the test formulation is repeatedly administered on an empty stomach by any of the following administration methods 1 to 5. In each protocol, the PK parameters of compound (I) are analyzed. At steady state, desirable blood concentrations of Compound (I) are observed to be maintained in a once weekly formulation (eg, 15 ng / mL to 400 ng / mL).

[0135] [Table 5]

Claims

[Claim 1] The invention described in the specification.

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