EA045131B1 - ORAL PHARMACEUTICAL COMPOSITION - Google Patents

Description

Field of technology

The present invention relates to an oral pharmaceutical composition containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-N-quinolin-2-one salt (more preferably an oral pharmaceutical controlled release compositions) and the like. The contents of all documents referred to herein are incorporated herein by reference.

State of the art

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as compound (I) or brexpiprazole) or a salt thereof has partial dopamine _D2 receptor agonist, serotonin 5-HT _2a receptor antagonist and α1 adrenergic receptor antagonist. In addition to these actions, compound (I) or a salt thereof has a serotonin uptake inhibitory effect (or a serotonin reuptake inhibitory effect) and is known to have a broad therapeutic spectrum in diseases of the central nervous system (CNS) (particularly schizophrenia ). (Patent Literature (PTL) 1).

Citation list

Patent literature.

PTL 1: JP 2006-316052 A.

The essence of the invention

Technical problem

When treating CNS diseases such as schizophrenia, it is usually important that the drug is present in the plasma at a therapeutically effective concentration for an extended period of time. Thus, an oral pharmaceutical composition that can be administered at a low frequency is useful because it increases patient compliance and reduces relapse rates during treatment. To obtain a pharmaceutical composition for oral administration that can be administered at a low frequency, one may consider preparing a composition containing a high dose of the active ingredient. However, to maintain a blood concentration effective for treatment, the active ingredient must be continuously released from the composition at an appropriate rate, preventing excessive release after administration due to factors relating to the living body.

In the treatment of schizophrenia using compound (I) or its salt, oral administration once daily is currently recommended. However, once daily oral administration creates an undue burden for many patients who require long-term administration. Thus, there is a need for an orally administered pharmaceutical composition suitable for less frequent administration than once daily administration.

Solution

The inventors of the present invention have conducted extensive research and discovered, for the first time, a composition containing a salt of compound (I) as an orally administered pharmaceutical composition suitable for less frequent administration than once daily administration.

The present description includes the following objects.

The present invention relates to an oral solid controlled-release pharmaceutical composition containing 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1Hquinolin-2-one salt as an active ingredient and additionally containing an additive containing an ion common to the salt.

In yet another aspect, the invention relates to a composition wherein the active ingredient is a fumaric acid salt, a phosphoric acid salt, a hydrochloric acid salt, a sulfuric acid salt, a citric acid salt or a tartaric acid salt 7-[4-(4-benzo[b]thiophene - 4-ylpiperazin1 -yl)butoxy] - 1H-quinolin-2-one.

In another aspect, the invention relates to a composition wherein the active ingredient is the fumaric acid salt of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, and the additive containing an ion common to the salt is at least one compound selected from the group consisting of fumaric acid, monosodium fumarate and disodium fumarate.

In one aspect, the invention relates to a composition further comprising a water-soluble cellulose-based polymer.

In another aspect, the invention provides a composition wherein the water-soluble cellulose-based polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose and methylcellulose.

In yet another aspect, the invention relates to a composition that is an osmotic pump composition.

In another aspect, the osmotic pump composition comprises a drug layer containing a water-soluble cellulose-based polymer.

Another aspect of the invention is a composition wherein the water-soluble polymer is based on

- 1 045131 cellulose is hydroxypropyl methylcellulose.

In another aspect of the invention, the composition is a sustained release hydrogel composition.

In yet another aspect, the invention is a composition comprising an enteric coating.

In one aspect of the invention, the composition contains from 5 mg to 60 mg of the active ingredient, based on weight, 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one .

The present invention relates to a method of preventing or treating a disease of the central nervous system (CNS), comprising orally administering to a subject a composition for maintaining a blood concentration of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy] -1H-quinolin-2-one at steady state in the range from 15 ng/ml to 400 ng/ml for 1 week.

In another aspect, the present invention relates to a method of preventing or treating a disease of the central nervous system (CNS), comprising administering a composition containing 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy] salt -1H-quinolin-2-one in a dose of 5 mg to 60 mg based on the weight of the free base.

In another aspect, the invention relates to the use of a composition for the prevention or treatment of a disease of the central nervous system (CNS).

In yet another aspect, the invention relates to the use of a composition wherein the CNS disease is selected from the group consisting of schizophrenia; treatment-resistant, refractory or chronic schizophrenia; emotional disorder; psychotic disorder; mood swings; bipolar disorder; depression, endogenous depression; major depression; melancholic and treatment-resistant depression; dysthymic disorder; cyclothymic disorder; anxiety disorder; somatization disorder; factitious disorder; dissociative disorder; sexual disorder; eating disorders; sleep disorders; adaptation disorders; substance use disorder; anhedonia; delirium; cognitive impairment; cognitive impairment associated with neurodegenerative disease; cognitive impairment caused by neurodegenerative disease; cognitive impairment in schizophrenia; cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia; vomiting; seasickness; obesity; migraine; pain; mental retardation; autism spectrum disorders; Tourette's syndrome; tic disorder; attention deficit hyperactivity disorder; behavioral disorders; Down syndrome; impulsive symptoms associated with dementia; and borderline personality disorder.

Beneficial effects of the invention

According to the present description, an agent can be provided for preventing the initial excessive release of an active ingredient (ie, a salt of compound (I)) from a pharmaceutical composition even when the composition is administered in a high dose; and this provides sustained release of a therapeutically effective amount of the active ingredient over an extended period of time. It can maintain a therapeutically effective concentration of the active ingredient in the blood for a long period of time (approximately two weeks at most). Thus, according to the present disclosure, a disease (eg, schizophrenia) treatable with a salt of compound (I) can be treated by less frequent administration than conventional methods, and thus the present invention is effective in improving compliance in patients.

Examples of diseases that are sensitive to compound (I) or its salt include various CNS diseases such as schizophrenia; treatment-resistant, refractory or chronic schizophrenia; emotional disorder; psychotic disorder; mood swings; bipolar disorder (eg, bipolar I disorder and bipolar II disorder); depression; endogenous depression; major depression; melancholic and treatment-resistant depression; dysthymic disorder; cyclothymic disorder; anxiety disorder (eg, panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder and acute stress disorder); somatization disorder (eg, hysteria, somatization disorder, conversion disorder, pain disorder, and hypochondriasis); factitious disorder, dissociative disorder; sexual disorder (eg, sexual dysfunction, libido disorder, sexual arousal disorder and erectile dysfunction); eating disorder (eg, anorexia nervosa and bulimia nervosa); sleep disorder; adjustment disorder; substance use disorder (eg, alcohol abuse, alcohol intoxication and addiction, amphetamine dependence and drug addiction); anhedonia (eg, loss of pleasure, anhedonia, iatrogenic anhedonia, anhedonia of mental or psychological origin, anhedonia associated with depression, anhedonia associated with schizophrenia); rave; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment 2 045131 in schizophrenia; cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia; vomit; seasickness; obesity; migraine; pain; mental retardation; autistic disorder (autism); Tourette's syndrome; tic disorder; attention deficit hyperactivity disorder; behavioral disorders; Down syndrome; impulsive symptoms associated with dementia (eg, agitation associated with Alzheimer's disease); and borderline personality disorder.

Brief description of the figures

In fig. 1a shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 1-1-1-5 (eluate pH: about 4.3).

In fig. 1b shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 1-1-1-5 (eluate pH: about 7).

In fig. 2 shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 2-1-2-4 (eluate pH: about 7).

In fig. 3 shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 3-1-3-9 (eluate pH: about 4.3).

In fig. 4a shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 4-1-4-3 (eluate pH: about 7, with surfactant).

In fig. 4b shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 4-1-4-3 (eluate pH: about 7).

In fig. 5a shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 5-1-5-3 (eluate pH: about 4.3).

In fig. 5b shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 5-1-5-3 (eluate pH: about 7).

In fig. 6a shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 6-1-6-4 (eluate pH: about 7, with surfactant).

In fig. 6b shows the results of the dissolution test of the oral pharmaceutical compositions (osmotic pump compositions) obtained in Examples 6-1-6-4 (eluate pH: about 7).

In fig. 7 shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8a shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8b shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8c shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8d shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8e shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8f shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 8g shows the results of dissolution tests of oral pharmaceutical compositions (osmotic pump formulations) containing various salts of compound (I) and various additives.

In fig. 9a shows the results of dissolution tests of oral pharmaceutical compositions (hydrogel matrix tablets) containing various salts of compound (I) and various additives.

In fig. 9b shows the results of dissolution tests of oral pharmaceutical compositions (hydrogel matrix tablets) containing various salts of compound (I) and various additives.

In fig. 10a shows the results of dissolution tests of oral pharmaceutical compositions (hydrogel matrix tablets) containing various salts of compound (I) and various additives.

In fig. 10b shows the results of dissolution tests of oral pharmaceutical formulations (hydrogel matrix tablets) containing various salts of compound (I) and various additives.

In fig. 11 shows the infrared absorption spectrum of the fumaric acid salt of compound (I).

In fig. 11c shows the infrared absorption spectrum of the citric acid salt of compound (I).

In fig. 11d shows the X-ray powder diffraction pattern of the citric acid salt of compound (I).

In fig. 11e shows the infrared absorption spectrum of the tartaric acid salt of compound (I).

In fig. 11f shows the X-ray powder diffraction pattern of the tartaric acid salt of compound (I).

In Fig. 11g shows the infrared absorption spectrum of the phosphoric acid salt of compound (I).

In fig. 11h shows the X-ray powder diffraction pattern of the phosphoric acid salt of compound (I).

In fig. 11i shows the infrared absorption spectrum of the hydrochloric acid salt of compound (I).

In fig. 11j shows an X-ray powder diffraction pattern of the hydrochloric acid salt of compound (I).

In fig. 11k shows the infrared absorption spectrum of the sulfuric acid salt of compound (I).

In fig. 11l shows the X-ray powder diffraction pattern of the sulfuric acid salt of compound (I).

In fig. 12 shows an example of an osmotic pump composition, which is one embodiment of an oral controlled release pharmaceutical composition.

Description of Embodiments

The present description preferably includes an oral pharmaceutical composition, a method for preparing an oral pharmaceutical composition and the like. However, the description is not limited to them and includes everything that is described in the present invention and that can be understood by a person skilled in the art.

The oral pharmaceutical composition of the present invention includes a salt of compound (I). This oral pharmaceutical composition may be referred to as an oral pharmaceutical composition according to the present description. Compound (I) refers to the compound represented by the following formula (I). Compound (I) or a salt thereof can be prepared by the method described in JP 2006-316052 A (incorporated herein by reference in its entirety) or a similar method.

The salt of compound (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples include various metal salts, inorganic base salts, organic base salts, inorganic acid salts, organic acid salts and the like. Examples of metal salts include alkali metal salts (eg, sodium salts and potassium salts), alkaline earth metal salts (eg, calcium salts and magnesium salts) and the like. Examples of inorganic base salts include ammonium salts and salts of alkali metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate and cesium carbonate), alkali metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide) and similar inorganic bases. Examples of organic base salts include salts of tri(lower)alkylamines (e.g. trimethylamine, triethylamine and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkylmorpholines (e.g. N-methylmorpholine) , 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) and similar organic bases. Examples of inorganic acid salts include hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, sulfuric acid salts, nitric acid salts, phosphoric acid salts and the like. Examples of organic acid salts include formic acid salts, acetic acid salts, propionic acid salts, oxalic acid salts, malonic acid salts, succinic acid salts, fumaric acid salts, maleic acid salts, lactic acid salts, malic acid salts, citric acid salts, tartaric acid, carbonic acid salts, picric acid salts, methanesulfonic acid salts, ethanesulfonic acid salts, p-toluenesulfonic acid salts, glutamic acid salts, benzoic acid salts and the like. Among them, hydrochloric acid salts, sulfuric acid salts, fumaric acid salts, phosphoric acid salts, citric acid salts and tartaric acid salts are preferred. Fumaric acid salts are particularly preferred.

Examples of salts of compound (I) include anhydrides, solvent solvates (eg, hydrate, methanolate, ethanolate and acetonitrile), various crystalline forms of anhydrides and solvates, and mixtures thereof. Compound (I) or a salt thereof also includes isomers such as geometric isomers, stereoisomers and optical isomers.

The salt of compound (I) may be a pharmaceutically acceptable co-crystal salt. As used herein, the term cocrystal or cocrystalline salt means a crystalline material consisting of two or more unique solids at room temperature that differ in physical characteristics (such as structure, melting point, and heat of fusion). Cocrystals and cocrystalline salts can be prepared by known cocrystallization methods.

The oral pharmaceutical composition herein is formulated in a dosage form suitable for releasing the salt of compound (I) at a uniform rate over a long period of time; and preferably formulated in a dosage form suitable for maintaining a constant dissolution concentration even in the lower part of the gastrointestinal tract. More specifically, the oral pharmaceutical composition is formulated as a controlled release oral pharmaceutical composition.

The dissolution rate and sustained release time of the salt of Compound (I) from an oral pharmaceutical composition can be obtained by measuring the dissolution rate and sustained release time of the salt of Compound (I) according to the second method (paddle method) of the dissolution test from Japanese Pharmacopoeia using as an experimental buffer solution with a pH of 5.0 or less, providing sufficient dissolution conditions (specifically, 0.05 mol/L acetate buffer (pH 4.3, acetic acid, sodium acetate)).

The dissolution rate refers to the ratio of the dissolved salt of compound (I) to the total amount of salt of compound (I) contained in the oral pharmaceutical composition. Therefore, the dissolution rate can be expressed as the ratio of the dissolved compound (I) to the total amount of compound (I) contained in the oral pharmaceutical composition. Sustained release time refers to the time from the start of the dissolution test measurement until the final dissolution rate is reached. The final dissolution rate means the rate of dissolution when reaching a plateau in a dissolution test, and the final dissolution rate means the amount of dissolution (eluting) when reaching the final dissolution rate in a dissolution test. In a dissolution test, when the dissolution rate at a certain time point (control time point) is compared with the dissolution rate two hours after the reference time point, and if the dissolution rate two hours after the reference time point falls within the range of the dissolution rate at the reference time point ± 1% (preferably when the dissolution rate more than two hours after the reference time point is compared with the dissolution rate at a specific time point (reference time point), and if the dissolution rate more than two hours after the reference time point falls within the range of the dissolution rate at reference point in time ±1%), it can be considered that the plateau at the control point in time has been reached, that is, the shortest time since the start of the test. However, the dissolution rate at the control time point must be greater than 20% (in other words, when the dissolution rate does not exceed 20%, it is not considered a plateau).

The extended release time is preferably 5 hours or more. The extended release time is preferably 30 hours or less. More preferably, the extended release time is from 5 to 30 hours. The upper or lower limit of the extended release 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 or 29 hours. The extended release time is, for example, even more preferably from 10 to 24 hours, and even more preferably from 15 to 24 hours .

The final dissolution rate of the oral pharmaceutical composition herein is preferably 80% by weight or more of the total amount of salt of compound (I) contained in the oral pharmaceutical composition (generally the oral pharmaceutical composition). More preferably, the final dissolution rate is 81, 82, 83, 84, 84, 85, 85, 86, 87, 88, 89 or 90% by weight or more.

Whether a constant dissolution concentration is maintained in the lower gastrointestinal tract can be assessed by measuring the supersaturation concentration profile of the dissolution salt of compound (I) over the dissolution time using, as the test fluid, a phosphate buffer with a pH of approximately 7, which simulates the lower gastrointestinal tract. intestinal tract, according to the second method (paddle method) of the dissolution test from Japanese Pharmacopoeia.

When sustained release is achieved, an increase in the initial dissolution of the salt of compound (I) from the composition can be achieved immediately after the start of the dissolution test or after a certain time (eg, 1 to 3 hours) after the start of the measurement. However, it is undesirable for it to require more than 5 hours until the dissolution rate becomes 5 wt.% or more of the final dissolution value.

The supersaturated dissolution profile can be assessed by quantification with

- 5 045131 over time, the concentration of the drug is temporarily dissolved at a solubility level higher than that of compound (I) in the dissolution test of the paddle method using the above phosphate buffer solution with a pH of approximately 7 (experimental liquid simulating the lower gastrointestinal - intestinal tract). The preferred supersaturated dissolution profile is one that reaches a peak dissolution rate between 4 and 18 hours after the start of the dissolution test. Additionally, 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, based on compound (I) (free base). Higher supersaturated concentration favors absorption in the lower gastrointestinal tract and is thus expected to increase BA (bioavailability) and decrease PTF (peak-to-trough ratio). This increase in VA or decrease in PTF makes it easier to meet the target PK (pharmacokinetics) range.

The mode 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 methods known in the field of sustained release formulations. Preferred sustained release approaches are, for example, those that use a diffusion controlled composition, a dissolution controlled composition, or an osmotic pump controlled release composition. Among them, more preferred sustained release approaches are, for example, a controlled release osmotic pump composition (especially an osmotic controlled release oral delivery system: OROS) and a hydrogel sustained release composition. Such an oral pharmaceutical composition is preferably an oral solid pharmaceutical composition (especially a solid formulation) from the viewpoint of ease of handling.

The oral pharmaceutical composition according to the present description preferably further contains an additive containing an ion common to a salt of compound (I). For example, when the salt of compound (I) is a fumaric acid salt, examples of additives containing an ion common to the salt include fumaric acid, monosodium fumarate, disodium fumarate and the like. In this case, the ion common to the salt is the fumarate ion. One skilled in the art will be able to understand which ion is common to the salt of Compound (I) according to the type of salt of Compound (I) used, and use an additive containing the ion common to the salt. Examples of such additives include, but are not limited to, inorganic salts, inorganic acids, organic salts and organic acids, each of which contains an ion common to a salt of compound (I). Examples of inorganic salts include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tricotassium 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 hydrosulfite, potassium hydrogensulfite, lithium sulfate, potassium hydrogen phosphate and the like. 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 (sodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, sodium potassium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), hydromaleate sodium, 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. They may be anhydrides or solvates (eg hydrates).

The oral pharmaceutical composition of the present invention preferably contains a water-soluble cellulose-based polymer. The water-soluble cellulose-based polymer is preferably contained in a drug-containing composition. The water-soluble cellulose-based polymer that can be preferably used is, for example, a water-soluble cellulose-based polymer known in the pharmaceutical field. For example, a water-soluble cellulose-based polymer having a structure in which some of the hydrogen atoms of the cellulose OH groups are replaced by methyl groups and/or hydroxypropyl groups is preferred. Specific examples of preferred water-soluble cellulose-based polymers include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose and the like. Such water-soluble cellulose-based polymers can be used alone or in combination of two or more.

Next, the present invention is described below in more detail with reference to a controlled release composition for an osmotic pump, which is a preferred oral solid pharmaceutical composition. A controlled release osmotic pump composition in the form of a formulation may be referred to as an osmotic pump formulation.

The composition for an osmotic pump typically has a structure in which a drug and a substance that creates osmotic pressure when needed (osmotic agent), such as

- 6 045131 salt, surrounded by a semi-permeable membrane; and the semi-permeable membrane has pores through which the drug can be released. Liquid (such as water) flows through the semipermeable membrane according to the osmotic pressure and dissolves the drug and osmotic agent into it, which increases the osmotic pressure gradient across the semipermeable membrane and causes additional liquid to enter the semipermeable membrane, thereby further dissolving and releasing the drug . The osmotic pump composition has the advantage that since the drug release rate is not dependent on the pH of the environment, even if the composition passes through the gastrointestinal tract and encounters an environment with a significantly different pH, the composition can steadily release the drug at a constant rate depending on from osmotic pressure over a long period of time.

For one embodiment of the oral pharmaceutical composition of the present invention, which is an osmotic pump composition, an explanation is provided below with reference to the drawings. In fig. 12, the composition for the osmotic pump 1 (hereinafter sometimes referred to simply as composition 1) includes a wall 2 surrounding an internal compartment 5 in which a composition containing a salt of compound (I) is present. Wall 2 has at least one drug release port 3, which communicates the external environment with the internal compartment. The inner compartment 5 contains a two-layer compressed core consisting of a drug layer 6 and an osmotic agent layer 7. A drug release port 3 is preferably provided in the wall 2 to communicate the inner compartment 5 on the side of the drug layer 6 with the external environment. One or more drug release ports 3 may be provided. For example, the formulation may have two or three drug release ports 3.

Wall 2 is a semi-permeable membrane through which water and external liquids penetrate, but drugs, osmotic agents and the like do not penetrate. The drug layer 6 contains a salt of compound (I) in the form of a mixture with one or more additives. The osmotic agent layer 7 does not contain any salts of compound (I) and contains an osmotic agent and a highly swelling polymer. An osmotic agent refers to a water-soluble ingredient that increases the electrolyte concentration of a pharmaceutical composition, such as an inorganic salt and a saccharide and/or a sugar alcohol. A highly swelling polymer means a polymer that absorbs liquid and swells (preferably a polymer having a relatively high molecular weight). The highly swelling polymer absorbs liquid and swells, causing the salt of compound (I) to be released through port 3 to release the drug. The drug layer 6 and the osmotic agent layer 7 may further contain additives such as a hydrophilic polymer, an osmotic agent, a hydration promoter, a pH regulator, a binding agent, a fluidizer, an antioxidant, a lubricant and a pigment.

In an osmotic pump composition, after oral administration, a liquid such as water penetrates the semi-permeable membrane and is absorbed by the composition. Due to the generated osmotic pressure effect, the salt of compound (I) in the drug layer becomes released, and at the same time the polymer with high swelling ability in the osmotic layer swells. As the body fluid continues to penetrate into the inner compartment, the released salt of compound (I) can be released through the drug release port 3. The release of the salt of compound (I) results in further penetration of body fluid and further swelling of the osmotic layer to achieve sustained release of the salt of compound (I).

Preferably, the semi-permeable membrane used is highly permeable to external liquids such as water and biological fluids, but is substantially impermeable to the salt of compound (I), osmotic agents, highly swelling polymers, etc. Preferably, the semipermeable membrane is substantially non-degradable and non-dissolving in vivo.

Examples of typical polymers used to form the semi-permeable film include semi-permeable monopolymers, semi-permeable copolymers and the like. Examples include cellulose-based polymers such as cellulose ester, cellulose ether, and cellulose ether-ether. Specific examples include cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and trialkanylate, mono-, di- and trialkenylate, cellulose mono-, di- and tri-alloylate and the like. Among them, cellulose acetate is preferred. A semipermeable membrane can be made from such a polymer in a known manner.

In addition to the above, other examples of the semipermeable polymer for forming a semipermeable membrane composition for an osmotic pump include the following: cellulose acetaldehyde dimethyl acetate; cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylaminoacetate; semi-permeable polyurethane; semi-permeable sulfonated polystyrene; cross-linked selectively semi-permeable polymers formed by co-precipitation from an anion and cation, as disclosed in US Patent Nos. 3,173,876, 3,276,586, 3,541,005,

- 7 045131

3,541,006 and 3,546,142; semi-permeable polymers as described in US Pat. No. 3,133,132; semipermeable polystyrene derivatives; semi-permeable poly(sodium styrene sulfonate); semi-permeable poly(vinylbenzyltrimethylammonium chloride); and a semi-permeable polymer exhibiting a liquid permeability of 10 ^-5 to 10 ^-2 (cm ³ ml/cm-h atm) with respect to hydrostatic pressure drop or osmotic pressure drop to the atmosphere upon penetration through the semi-permeable wall.

Such exemplary polymers for use in forming a semipermeable membrane may be used alone or in combination of two or more.

The semipermeable membrane may contain a flow control agent. Flow control agent means a substance added to help control the penetration or volume of fluid through a semipermeable membrane. The flow regulating agent includes a flow increasing substance (hereinafter referred to as a flow increasing agent) or a flow decreasing substance (hereinafter referred to as a flow reducing agent). The flow enhancing agent is substantially hydrophilic, while the flow reducing agent is substantially hydrophobic.

Examples of the flow control agent include polyols, polyalkylene glycols, polyalkylene diols, polyesters of alkylene glycols and the like.

Examples of typical flux enhancing agents include polyethylene glycols (with an average molecular weight of 190 to 9000, such as polyethylene glycol 300, 400, 600, 1500, 3000, 3350, 4000, 6000 or 8000); low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol; polyalkylene diols such as poly(1,3-propanediol), poly(1,4-butanediol) and poly(1,6hexanediol); fatty acids such as 1,3-butylene glycol, 1,4-pentamethylene glycol and 1,4hexamethylene glycol; alkylenetriols such as glycerol, 1,2,3-butanetriol, 1,2,4-hexanetriol and 1,3,6hexanetriol; esters such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate and glycerol acetate esters. Preferred flux enhancing agents include difunctional polyoxyalkylene propylene glycol block copolymer derivatives known as Pluronics (BASF), and the like.

Typical flow reducing agents include phthalates substituted with alkyl or alkoxy, or alkyl and alkoxy groups, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di(2ethylhexyl) phthalate]; aryl phthalates such as triphenyl phthalate and butyl benzyl phthalate; insoluble salts such as calcium sulfate, barium sulfate and calcium phosphate; insoluble oxides such as titanium oxide; polymers in the form of, for example, powder or granules, such as polystyrene, polymethyl methacrylate, polycarbonate and polysulfone; esters, such as citric acid esters esterified with long chain alkyl groups; inert and waterproof fillers; resins compatible with cellulose-based wall-forming materials; and the like.

Such exemplary flow control agents may be used alone or in combination of two or more.

The semipermeable membrane may contain other substances, for example, to impart flexibility and elongation properties to the semipermeable membrane, to make the semipermeable membrane less brittle, or to impart tensile strength to the semipermeable membrane. Examples of materials suitable for this purpose include plasticizers. Specific examples include phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, C6-C11 straight chain phthalates, diisononyl phthalate, diisodecyl phthalate and the like. Other examples of plasticizers include non-phthalates such as triacetin, dioctyl azelate, epoxidized tallate, triisooctyl trimellitate, triisononyl trimellitate, sucrose acetate isobutyrate, and epoxidized soybean oil. When a plasticizer such as those mentioned above is present in the semipermeable membrane, the amount of plasticizer is from about 0.01 to 30% by weight or more, based on the total amount of all components of the semipermeable membrane.

The osmotic agent layer contains a composition for ejecting the salt of compound (I) and is in a multilayer arrangement in contact with the drug layer, for example, as shown in FIG. 5. As described above, the osmotic agent layer contains a highly swelling polymer that absorbs aqueous liquid or biological fluid and swells to force the salt of compound (I) through the port to release the composition. The highly swelling polymer is preferably a swelling hydrophilic polymer that reacts with water or an aqueous biological fluid and swells or expands greatly; and typically demonstrates a 2- to 50-fold increase in volume. The highly swelling polymer may be cross-linked or non-cross-linked. In a preferred embodiment, the polymer is preferably at least cross-linked to create an extended polymer network that is too large to be released from the composition. Accordingly, in a preferred embodiment, the swellable composition is retained in the composition for the duration of its effective action.

Examples of highly swelling polymers include poly(alkylene oxide) with a number average molecular weight of 10,000 to 15,000,000, such as polyethylene oxide, and poly(alkali)

- 8 045131 carboxymethylcellulose) with a number average molecular weight from 500,000 to 3,500,000 (where the alkali is sodium, potassium or lithium). Examples of highly swelling polymers further include polymers containing hydrogel-forming polymers such as Carbopol (registered trademark), acidic carboxypolymers, acrylic polymers cross-linked with polyallyl sucrose (also known as carboxypolymethylene), and carboxyvinyl polymers with molecular weights ranging from 250000 to 4000000; polyacrylamides Cyanamer (registered trademark); cross-linked water-swellable polymers of indenmaleic anhydride; Good-rite polyacrylic acid (registered trademark) with a molecular weight of 80,000 to 200,000; Aqua-Keeps (registered trademark), acrylate polymer polysaccharides consisting of condensed glucose units such as diester cross-linked polyglurane; and the like. The polymers that form hydrogels are described in US Patent Nos. 3,865,108, 4,002,173, 4,207,893, etc.

Such typical high swelling polymers can be used alone or in combination of two or more.

An osmotic agent, sometimes also called an osmotic solute or an osmotically effective agent, may be present in both the drug layer and the osmotic agent layer. The osmotic agent (osmotic pressure regulator) is not particularly limited as long as it exhibits a gradient of osmotic activity across the semi-permeable membrane. Examples thereof include inorganic salts, inorganic acids, organic salts, organic acids, saccharides, sugar alcohols and the like. Examples of inorganic salts include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tricotassium 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 hydrosulfite, potassium hydrogensulfite, lithium sulfate, potassium hydrogen phosphate and the like. Examples of inorganic acids include acids that form the above-mentioned inorganic salts. Examples of organic salts include sodium fumarate (disodium fumarate), sodium hydrofumarate (monosodium fumarate), sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), hydromaleate sodium, 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 saccharides and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose and the like. They may be anhydrides or solvates (eg hydrates). They can be used individually or in combination of two or more.

The drug layer preferably contains an additive containing an ion common to the salt of compound (I). For example, when the salt of compound (I) is fumarate, examples of common ion containing additives include fumaric acid, monosodium fumarate, disodium fumarate and the like. In this case, the common ion is a fumarate ion. When the salt of compound (I) is a phosphate, examples of additives containing a common ion include sodium phosphate (trisodium phosphate), potassium phosphate (tricotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (dipotassium hydrogen phosphate, dipotassium hydrogen phosphate) and similar. In this case, the common ion is the phosphate ion. When the salt of compound (I) is a hydrochloride, examples of additives typically containing the ion include sodium chloride, potassium chloride, lithium chloride, magnesium chloride and the like. In this case, the common ion is a chloride ion. When the salt of compound (I) is a sulfate, examples of additives containing a common ion include magnesium sulfate, potassium sulfate, sodium sulfate, lithium sulfate and the like. In this case, the common ion is a sulfate ion. When the salt of compound (I) is citrate, examples of additives containing the common ion include sodium hydrogen citrate (sodium dihydrogen citrate, disodium hydrogen citrate), sodium citrate (trisodium citrate) and the like. In this case, the common ion is the citrate ion. When the salt of compound (I) is a tartrate, examples of additives containing the common ion include sodium hydrogen tartrate, potassium hydrogen tartrate, sodium tartrate, sodium potassium tartrate and the like. In this case, the common ion is a tartrate ion. One skilled in the art will understand, depending on the type of salt of compound (I) used, which ion is common to the salt of compound (I), and will be able to use an additive containing the common ion. Other examples of additives containing an ion common to the salt of compound (I) that can be used are described above.

Examples of solvents suitable for use in the manufacture of the osmotic pump composition or its components include aqueous or inert organic solvents that do not adversely affect the substances used in the composition. Examples of such solvents include at least one member selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic or heterocyclic solvents, and mixtures thereof.

- 9 045131

Examples of typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, 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, ligroin, 1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvent containing inorganic salt, e.g. sodium chloride or calcium chloride, and mixtures thereof (for example, a mixture of acetone and water, a mixture of acetone and methanol, a mixture of acetone and ethyl alcohol, a mixture of methylene dichloride and methanol, and a mixture of ethylene dichloride and methanol); and the like.

The drug layer contains a therapeutically effective amount of a salt of compound (I) and a carrier. The carrier may contain a hydrophilic polymer. The hydrophilic polymer may provide, for example, hydrophilic polymer particles in the pharmaceutical composition that promote a uniform release rate and controlled release pattern of the salt of compound (I). Examples of such polymers include poly(alkylene oxide) with a number average molecular weight of 100,000 to 750,000, such as poly(ethylene oxide), poly(methylene oxide), poly(butylene oxide) and poly(hexylene oxide); and 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), poly(lithium carboxymethylcellulose) and the like. The pharmaceutical composition may contain hydroxypropyl alkyl cellulose with a number average molecular weight of 9,200 to 125,000, such as hydroxypropyl ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl butyl cellulose and hydroxypropyl pentyl cellulose, to improve the release properties of the composition; and poly(vinylpyrrolidone) having a number average molecular weight of 7,000 to 75,000 to improve the flowability of the composition. Among these polymers, poly(ethylene oxide) having a number average molecular weight of 100,000 to 300,000 is preferred.

Other carriers that may be present in the drug layer include carbohydrates that exhibit sufficient osmotic activity when used alone or with another osmotic agent. These carbohydrates include monosaccharides, disaccharides and polysaccharides. Typical examples include saccharides such as maltodextrin (ie, a polymer of glucose obtained by hydrolysis of corn starch), lactose, glucose, raffinose, sucrose, mannitol and sorbitol. Preferred maltodextrins are those that have a dextrose equivalent (DE) of 20 or less, preferably a DE of about 4 to about 20, and more preferably a DE of 9 to 20. Using a maltodextrin having a DE of 9 to 12 is preferred. Carbohydrates (preferably maltodextrin) are preferred because they can be used in the drug layer without the addition of another osmotic agent and they impart long-term stability to the composition.

The drug layer is, for example, a homogeneous dry composition formed by compression of the carrier and the drug. The drug layer may be formed from ground drug particles and added polymer. Granulation can be carried out using known techniques such as granulation, spray drying, sieving, lyophilization, crushing, grinding, shredding and the like. Such granulation can be carried out using devices such as a high-speed stirred granulator, an extrusion granulator, a fluidized bed granulator and a roller press.

The drug layer may contain one or more surfactants and one or more disintegrating agents. Examples of such surfactants include surfactants having an HLB value of from about 10 to 25 (eg, polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene -20-monolaurate, polyoxyethylene-40-stearate, sodium oleate and the like). Examples of disintegrants include starches, clays, celluloses, algins, gums, cross-linked starches, celluloses, polymers and the like. Preferred disintegrants include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum and the like.

The drug layer may further comprise light anhydrous silicic acid and the like.

The semi-permeable membrane can be formed on the surface of the two-layer compressed core, for example, by panning. More specifically, the semi-permeable membrane can be formed by spraying a semi-permeable membrane-forming composition onto the surface of a compressed bilayer core including a drug layer and an osmotic agent layer tumbled in a turntable. Coating methods other than panning can also be used to coat the compressed core. For example, a semi-permeable membrane can be prepared using an air suspension method. This technique consists of suspending a compressed core in a stream of air and a semi-permeable membrane

- 10 045131 forming the composition and turning it over until a semi-permeable membrane is formed on the core. The air suspension procedure is well suited to independently form a semipermeable membrane. Such a technique for suspending in air is known (eg, US Pat. No. 2,799,241). You can also use a Wurster airborne coating system (registered trademark) or an AeromaticR airborne coating system (registered trademark).

After coating with the semi-permeable membrane, the semi-permeable membrane is dried, for example, in a forced-air oven or in a temperature and humidity controlled oven, thereby removing the solvent. Drying conditions can be selected accordingly based on available equipment, environmental conditions, solvents, coating materials, coating thickness, etc.

The oral pharmaceutical composition according to the present description can be prepared using a known formulation method. For example, the oral pharmaceutical composition can be manufactured using existing wet granulation technologies or dry granulation technologies. More specifically, for example, in the case of wet granulation methods, an organic solvent such as denatured anhydrous alcohol is used as the granulation solution; and the drug and the additive are mixed in a granulator and continuously granulated using a solvent to form granules. The granulating solution is added until a wet mixture is formed and the wet mixture is passed through a pre-set sieve on the oven tray. The mixture is then dried in a forced air oven. Another granulation method is the operation of granulating the powder components of each layer in a fluidized bed granulator. After dry mixing the powder components in the granulator, the granulating liquid is sprayed onto the powder. The coated powder is dried in a granulator. Dry granules obtained by these methods are sieved in a granulator with a crushing mechanism. A lubricant such as magnesium stearate is then added and mixed to form granules using a mixer (eg, a V-type mixer or a portable mixer (hopper type mixer)). The composition thus obtained is layered by compression using, for example, a Manesty press (registered trademark) or a Korsch LCT press. To make a two-layer core, the layer containing the drug is first compressed; and then the wet mixture of the osmotic substance layer, obtained in a similar manner by the wet granulation method, is pressed onto the drug-containing layer. The compressed two-layer core is optionally coated with a water-soluble polymer and then coated with a semi-permeable membrane material as described above. One or more outlet openings (perforations) are provided at the end of the drug layer of the composition. If necessary, a water-soluble protective coating can be applied, where the protective coating can be colored or transparent.

In addition, for example, when dry granulation technology is used as an alternative method, the premixed composition is formed into a layered product using a direct compression roller machine, and the layered product is crushed into granules and sorted by size using a screening mill with a crushing mechanism. A lubricant such as magnesium stearate is added to the sorted granules in the same manner as above, mixed with the granules using a blender and compressed in the same manner as in the production method described above.

The osmotic pump composition is provided with at least one outlet port. The release port is provided during manufacture of the composition or during delivery of the drug by the composition in a liquid medium during use. The expression exhaust port includes the meaning of, for example, passages, openings, openings, and clearances (openings). This expression also includes holes formed by erosion, dissolution or leaching of a substance or polymer from the outer wall. Such a substance or polymer includes, for example, a degradable poly(glycolic acid) or poly(lactic acid) in a semipermeable membrane; gelatin threads; water-removable poly(vinyl alcohol); and leachable compounds, such as liquid-removable hole-forming substances selected from the group consisting of inorganic salts, organic salts, oxides and carbohydrates. The outlet port may be formed, for example, by leaching 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 citrate sodium to produce holes having a pore size suitable for uniform drug release. The release port may be of any shape, such as round, rectangular, square or elliptical, as long as the drug can be released from the composition at a uniform rate. The osmotic pump composition may have one or more outlet ports spaced at regular intervals. The opening size of the release port is not particularly limited as long as the release of the drug can be controlled in interaction with the compressed core. Preferably, the opening size of the outlet port is from 0.1 to 3 mm. For example, a semipermeable membrane drilling method such as mechanical drilling and laser drilling can be used to form an outlet port. Devices for forming such an outlet port are known (eg, US Pat. No.

3,916,899 and US Patent No. 4,088,864).

The amount of salt of Compound (I) in the oral pharmaceutical composition ranges, for example, from less than about 1 mg to about 200 mg or more per dosage form, based on the weight of the free base. For example, the drug layer of the osmotic pump composition described below in the examples contains compound (I) in an amount of 30 mg (based on the free base). The osmotic pump composition has a T ₉₀ of about 10 hours or more. The salt of compound (I) begins to be released at a constant rate approximately 3-4 hours after administration, and the release at the same rate continues for an extended period of at least about 12 hours. Thereafter, drug release continues for several hours until until the dosage form is used up.

Oral pharmaceutical compositions according to the present disclosure preferably release the drug at a relatively uniform release rate over a long period of time. When administered to a patient, the oral pharmaceutical composition of the present disclosure provides plasma drug concentrations in the patient that are less susceptible to fluctuation over an extended period of time than those obtained with conventional pharmaceutical agents (eg, immediate release formulations). When an oral pharmaceutical composition is administered according to the present disclosure, the peak occurs at a time point later than the peak steady state plasma concentration following administration of conventional pharmaceutical agents (eg, immediate release formulations) and the peak is less than the peak observed after administration conventional pharmaceutical agents; accordingly, the composition can provide a therapeutically effective mean steady state concentration in the blood.

The present invention includes a method of treating diseases and conditions treatable with compound (I) by orally administering to a patient an oral pharmaceutical composition as described herein. This method is practiced with a formulation suitable for releasing compound (I) at a uniform release rate over at least about 4 hours, preferably 5 to 30 hours, more preferably 10 to 24 hours, and even more preferably , from 15 to 24 hours.

For the treatment of schizophrenia, the use of the above method in practice is preferable for the purpose of orally administering to a patient an oral pharmaceutical composition as described herein at a frequency of less than once daily. Other diseases 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.

Although not limiting, the oral pharmaceutical composition herein preferably maintains the blood concentration of Compound (I) at a steady state in the range of, for example, 15 ng/ml to 400 ng/ml or 50 ng/ml to 300 ng /ml for 1 week when administered orally to a person (in particular, an adult).

Conventional tablets (non-controlled release formulations) containing compound (I) in the form of 0.5 mg, 1 mg and 2 mg tablets are already commercially available in many countries, including Japan, USA and Europe. Clinical trials have confirmed that conventional tablets are safe and effective for central nervous system diseases such as schizophrenia; and detailed pharmacokinetic analysis was performed. Taking into account such information about conventional tablets, it can be understood that any oral pharmaceutical composition capable of maintaining the concentration of compound (I) in the blood at a steady state in the range of, for example, from 15 ng/ml to 400 ng/ml or from 50 ng/ml ml up to 300 ng/ml when administered to humans, can be used to prevent or treat central nervous system diseases such as schizophrenia in the same way as conventional tablets that are already commercially available.

Accordingly, the oral pharmaceutical composition of the present invention can be administered orally less than once a day; for example, it can be administered orally once a week. The oral pharmaceutical composition of the present disclosure may be administered as one tablet at a time, or two or more tablets at a time; for example, it can be administered as two tablets, three tablets, four tablets, or five tablets at a time. Those skilled in the art will be able to appropriately determine the dose of the oral pharmaceutical composition herein to achieve the above blood concentration based on, for example, pharmacokinetic information on conventional tablets; and estimates based on the single dose administration protocol and the multiple dose administration protocol of the oral pharmaceutical composition of the present disclosure. For example, the strength per dose may be from about 5 to 60 mg, from about 10 to 60 mg, from about 20 to 60 mg, or from about 45 to 60 mg, based on the weight of the free base of compound (I).

As described above, among the oral pharmaceutical compositions herein, one particularly preferred embodiment is an oral solid pharmaceutical composition for an osmotic pump controlled release system. Especially

- 12 045131 preferred embodiments of oral solid pharmaceutical formulations for a controlled release system with an osmotic pump are described in more detail below. Please note that the following description may overlap with the above description. The following description does not preclude the application of the above description.

The oral solid pharmaceutical composition for the osmotic pump controlled release system preferably has a structure in which a core composition formed by laminating a drug layer and an osmotic agent layer is coated with a semi-permeable membrane, and the drug layer contains a salt of compound (I). One embodiment of the composition includes the composition shown in FIG. 12.

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

The weight ratio of the drug layer to the osmotic layer may be, for example, in the range of about 0.8 to 5. The upper limit or lower limit of the weight ratio 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 weight ratio of the drug layer to the osmotic layer may range from about 1 to 4 or about 2 to 3. More specifically, the weight ratio 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.

The salt of compound (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples include the above-mentioned various metal salts, inorganic base salts, organic base salts, inorganic acid salts, organic acid salts and the like. The salt is preferably, for example, a fumaric acid salt, a hydrochloric acid salt, a sulfuric acid salt and the like, and particularly preferably a fumaric acid salt.

Salt includes solvates of salts and may be present in solvate form in a pharmaceutical composition. Examples of solvates include hydrates, methanol solvates, ethanol solvates and the like. The solvate may be a monosolvate, a disolvate, a trisolvate, and the like. For example, the solvate may be a monohydrate, dihydrate, trihydrate and the like. A particularly preferred example of such a salt solvate is, for example, fumarate monohydrate.

The amount of salt of compound (I) in the drug layer may be, for example, in the range of from about 5 to 200 mg, based on the weight of the free base. The upper limit or lower limit of this range is, 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. The amount of salt of compound (I) may, for example, range from about 5 to 60 mg, about 15 to 150 mg, or about 20 to 100 mg, based on the weight of the free base of compound (I).

The amount of salt of compound (I) contained in the drug layer may be, for example, from about 1 to 35% by weight of the drug layer. The upper limit or lower limit of the range is, 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 wt.%. The range may be, for example, from about 2 to 30 wt.%, or from about 5 to 20 wt.%.

In addition to salt, the drug layer may contain additives such as an osmotic agent and a hydrophilic polymer.

The osmotic agent contained in the drug layer is not particularly limited as long as it exhibits an osmotic pressure gradient across the semi-permeable membrane. Examples include inorganic salts, inorganic acids, organic salts, organic acids, saccharides, sugar alcohols and the like. Examples of inorganic salts include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tricotassium 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 hydrosulfite, potassium hydrogensulfite, lithium sulfate, potassium hydrogen phosphate and the like. 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, sodium potassium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), hydromaleate sodium, 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. They may be anhydrides or solvates (eg hydrates). They can be used

- 13 045131 individually or in combination of two or more. The osmotic agent contained in the drug layer preferably contains an ion common to the salt of compound (I). For example, when the salt is a fumarate, examples of the osmotic agent containing an ion common to the fumarate include fumaric acid, monosodium fumarate, disodium fumarate and the like. The osmotic agent can be used alone or in combination of two or more components.

The content of the osmotic agent in the drug layer is, for example, from about 1 to 50 wt.%, based on the weight of the drug layer. The upper limit or lower limit of the range is, 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 wt.%. For example, the range may be from 10 to 38 wt.%, or from 15 to 35 wt.%.

Examples of hydrophilic polymers contained in the drug layer include polyethylene oxide, polyethylene glycol and the like. Preferably, the polyethylene oxide is a low viscosity polyethylene oxide. More specifically, the polyethylene oxide is preferably a polyethylene oxide with an average molecular weight of from about 100,000 to 300,000, and more preferably, a polyoxyethylene oxide with an average molecular weight of from about 150,000 to 250,000 or from 180,000 to 220,000. Preferably, the polyethylene glycol is, for example, one in which polymerizes on average from about 4000 to 8000, preferably from about 4500 to 7500, about 5000 to 7000, or about 5500 to 6500 ethylene oxide units. To inhibit recrystallization of the drug in the formulation, the drug layer may contain as a hydrophilic polymer a water-soluble cellulose-based polymer such as methylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (for example, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose), polyvinyl alcohol, polyvinyl alcohol graft copolymer and polyethylene glycol, polyvinylpyrrolidone, copolyvidone and the like. Hydroxypropyl alkyl cellulose is particularly preferably hydroxypropyl methyl cellulose. Hydroxypropyl methylcellulose preferably has a methoxy content of, for example, about 16 to 30%, and more preferably, about 27 to 30%. Such hydrophilic polymers can be used alone or in combination with two or more types.

As described above, the oral pharmaceutical composition of the present description preferably contains a drug-containing composition containing a water-soluble cellulose polymer. Accordingly, the drug layer preferably contains a water-soluble cellulose-based polymer as a hydrophilic polymer.

The content of hydrophilic polymer in the drug layer is, for example, from about 5 to 94 wt.%, the drug layer. The upper or lower limit of the 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, 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, 81, 82, 83, 84, 84, 85, 86, 87, 88, 89, 90, 91, 92 or 93 wt.%. For example, the range may be from 20 to 90 wt.%.

When the drug-containing composition particularly contains a water-soluble cellulose-based polymer, the content of the water-soluble cellulose-based polymer in the drug layer is, for example, about 5 to 40% by weight, or about 10 to 30% by weight, or from about 10 to 20 wt.%, based on the weight of the drug layer.

When the drug layer particularly contains (i) polyethylene oxide and (ii) at least one member selected from the group consisting of hydroxypropylcellulose, methylcellulose, hydroxypropylalkylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone and copolyvidone, simultaneously with hydrophilic polymers, the content of component (i) may be from 10 to 60% by weight, and the content of component (ii) may be from about 5 to 40% by weight, based on the weight of the drug layer.

The drug layer may also contain other additives. Examples of such additives include lubricants, fluidizers and the like. Examples of preferred lubricants include magnesium stearate. Examples of preferred fluidizers include silica (particularly light anhydrous silicic acid).

The drug layer contains a lubricant (particularly magnesium stearate), for example, in an amount of about 0.1 to 5% by weight, or about 0.2 to 3% by weight, based on the weight of the drug layer. The drug layer may contain a fluidizer (particularly silica) in an amount of, for example, 0.1 to 5% by weight, or about 0.1 to 3% by weight, based on the weight of the drug layer.

The osmotic agent layer also contains a component for extruding the salt of compound (I). Examples of the component include a highly swelling polymer. Examples of highly swelling polymers include polyalkylene oxide and, more particularly, polyethylene oxide. Preferably, the polyethylene oxide contained in the osmotic agent layer is a high viscosity polyethylene oxide; and more particularly, for example, polyethylene oxide having

- 14 045131 average molecular weight, for example from about 3,000,000 to 7,000,000, from about 4,000,000 to

7,000,000 or approximately 4,000,000 to 6,000,000.

The amount of highly swelling polymer in the osmotic layer may vary depending on factors such as the properties and drug content of the drug layer; however, it can be any amount that allows the drug to elute from the drug layer at the desired rate of release by swelling. For example, the content of the highly swelling polymer is 50 to 90 wt%, 50 to 85 wt%, 50 to 80 wt%, 55 to 75 wt%, or about 60 to 70 wt%. %, based on the mass of the osmotic substance layer.

The osmotic layer may also contain other additives. For example, the osmotic agent layer may contain an osmotic agent. Examples of osmotic agents in the osmotic substance layer include inorganic salts, inorganic acids, organic salts, organic acids, saccharides, sugar alcohols and the like. Examples of inorganic salts include sodium chloride, sodium bicarbonate, sodium carbonate, sodium phosphate (trisodium phosphate), potassium phosphate (tricotassium phosphate), sodium hydrogen phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium hydrogen phosphate (dipotassium hydrogen phosphate, dipotassium hydrogen phosphate), potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, sodium hydrogen sulfite, potassium hydrogen sulfite, lithium sulfate, potassium hydrogen phosphate and the like. Examples of inorganic acids include those forming 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, sodium potassium tartrate, sodium malate (disodium malate), sodium hydrogen succinate, sodium succinate (disodium succinate), hydromaleate sodium, 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 forming organic salts described above. Examples of saccharides and sugar alcohols include mannitol, glucose, lactose, fructose, sucrose, sorbitol, xylitol, erythritol, lactose and the like. They may be anhydrides or solvates (eg hydrates).

Preferable examples of the osmotic agent contained in the osmotic agent layer include 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. Sodium bicarbonate is particularly preferred. Such osmotic agents can be used alone or in combination of two or more.

In the osmotic agent layer, the osmotic agent is preferably present in an amount of, for example, 5 to 50 wt%, 15 to 50 wt%, 20 to 50 wt%, 25 to 45 wt%, or about 30 up to 40 wt.%, based on the mass of the layer of osmotic substance.

The osmotic layer may further contain other additives. Examples of such additives include lubricants, fluidizers, pigments and the like. Preferred examples of lubricants include magnesium stearate. Preferred examples of fluidizers include silica (particularly light anhydrous silicic acid). Preferred examples of pigments include iron oxide.

The osmotic agent layer may contain a lubricant (in particular magnesium stearate) in an amount of, for example, from 0.1 to 5 wt.%, based on the weight of the osmotic agent layer. The osmotic agent layer may contain a fluidizer (in particular, silica) in an amount, for example, from about 0.1 to 5 wt.%, or from 0.1 to 3 wt.%, based on the weight of the osmotic agent layer. Also, the layer of osmotic substance may contain a pigment (in particular, iron oxide) in an amount of, for example, from 0.1 to 2 wt.%.

The semipermeable membrane with which the core composition is coated includes, for example, a cellulose-based polymer, preferably cellulose acetate, as described above. The semipermeable membrane may also contain a flow control agent. As described above, the flow control agent is preferably, for example, polyethylene glycol (particularly polyethylene glycol having an average molecular weight of about 2000 to 6000, about 3000 to 5000, or about 3000 to 6000).

The semipermeable membrane may contain cellulose polymer in an amount, for example, from about 70 to 100% by weight, or from 75 to 95% by weight, based on the weight of the semipermeable membrane. The semipermeable membrane may contain a flow control agent in an amount of from about 0.01 to 30% by weight, or from about 5 to 25% by weight, based on the weight of the semipermeable membrane.

The amount of coating of the semipermeable membrane is preferably an amount that provides high permeability to external liquids such as water and body fluids; and which is substantially impermeable to salts of compound (I), highly swelling polymers and the like. The amount of semipermeable membrane can be, for example, from about 5 to 25 parts by weight per 100 parts by weight of the core composition. The upper limit or lower limit of this range is, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,

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16, 17, 18, 19, 20, 21, 22, 23 or 24 parts by mass. The range may be, for example, from about to 25 parts by weight.

A water-soluble polymer coating can be applied between the core composition and the semi-permeable membrane in an oral solid pharmaceutical formulation for a controlled release system with an osmotic pump. In other words, the composition may have a structure in which a water-soluble polymer membrane and a semi-permeable membrane are laminated (preferably coated) in that order onto the core composition.

The water-soluble polymer membrane may contain the above-described hydrophilic polymers as the water-soluble polymer, which may be contained in the drug layer. Among such polymers, for example, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinylpyrrolidone are preferred. Such water-soluble polymers can be used alone or in combination of two or more. If the water-soluble polymer membrane contains, for example, hydroxypropyl methylcellulose, from 60 to 100 wt.%, the water-soluble polymer film may be hydroxypropyl methylcellulose. If the water-soluble polymer membrane contains, for example, polyvinylpyrrolidone, from 0 to 40 wt.%, the water-soluble polymer film may be polyvinylpyrrolidone.

The water-soluble polymer membrane may be present, for example, in an amount of from about 1 to 15 parts by weight per 100 parts by weight of the core composition.

The oral solid pharmaceutical composition of the present disclosure can be used, for example, in the form of uncoated tablets containing the above-mentioned components and not having a color coating. For example, from the viewpoint of imparting distinctiveness or long-term storage stability to the composition and preventing degradation by exposure to light, it is preferable to produce tablets coated with a color coating layer. If necessary, the coating layer may further contain pharmaceutical additives commonly used in coating (film-forming) pharmaceutical products for oral administration, such as a coating agent, a plasticizer, a dispersant and an antifoam. If a color coating layer is provided, the color coating layer is preferably the outermost layer. A known coating agent can be used for the color coating layer. For example, a typical premixed additive such as Opadry can be used as the coating agent. Preferable examples include coating agents containing hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and the like as the base material; and further containing a dye, a lubricant, a plasticizer and the like.

A preferred example of an oral solid pharmaceutical composition for an osmotic pump controlled release system according to the present disclosure is a composition comprising a core composition including a drug layer and an osmotic agent layer, wherein the drug layer includes from 5 to 200 mg of a salt of compound (I) calculated per weight of the free base, from 1 to 50 wt.% of an additive containing an ion common to the salt, based on the weight of the drug layer, from 5 to 94 wt.% of a hydrophilic polymer, based on the weight of the drug layer, from 0.1 up to 5 wt.% lubricant in terms of the weight of the drug layer, and from 0.1 to 5 wt.% fluidizer in terms of the weight of the drug layer, the osmotic substance layer includes from 50 to 90 wt.% of a polymer with high ability to swelling in terms of the weight of the osmotic substance layer, from 5 to 50 wt.% of the osmotic agent in terms of the weight of the osmotic substance layer, from 0.1 to 5 wt.% of the lubricating agent in terms of the weight of the osmotic substance layer, and from 0.1 up to 2 wt.% pigment in terms of the mass of the layer of osmotic substance, the core composition contains from 5 to 25 mass parts of a semi-permeable membrane and from 1 to 15 mass parts of a water-soluble polymer membrane per 100 mass parts of the core composition, the semi-permeable membrane contains from 70 to 100 wt. .% cellulose-based polymer and from 0.01 to 30 wt.% water-soluble permeation control agent, based on the weight of the semi-permeable membrane, and the core composition optionally contains a layer of colored coating.

As described above, another preferred embodiment of the oral pharmaceutical composition herein may be, for example, a sustained release hydrogel composition. More specifically, the sustained-release hydrogel composition (sustained-release hydrogel composition) according to the present description preferably contains a salt of compound (I) as an active ingredient and further an additive containing an ion common to the salt. The sustained release hydrogel composition is preferably, for example, a hydrogel matrix tablet. Hydrogel matrix tablets are a known method in which drug release is controlled by a hydrogel that is formed (in the case of an enteric-coated tablet, by the dissolution of the coating film due to an increase in pH after release from the stomach and then) by the absorption of water in the gastrointestinal tract.

For example, the above-mentioned hydrophilic polymers can be used as the sustained release base (hydrogel forming base) in the hydrogel matrix tablet. Specific examples of bases used include water-soluble cellulose-based polymers, polyalkylene oxide (eg, polyethylene oxide), polyalkylene glycol (eg, polyethylene glycol), polyvinyl alcohol, and the like. As the sustained release base material, the above hydrophilic polymers can be used individually or in combination of two or more. It is particularly preferred that the sustained release base material comprises at least one water-soluble cellulose-based polymer. If a hydrophilic polymer other than water-soluble cellulose-based polymers (eg, polyethylene oxide) is primarily used as a sustained-release base, the hydrophilic polymer is preferably combined with at least one water-soluble cellulose-based polymer.

As the water-soluble cellulose-based polymer, for example, a water-soluble cellulose-based polymer known in the pharmaceutical field can be preferably used. Preferred examples include water-soluble cellulose-based polymers having a structure in which the hydrogen atoms of some of the cellulose OH groups are replaced by methyl and/or hydroxypropyl groups. Specific examples include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose and the like. Water-soluble cellulose-based polymers can be used alone or in combination of two or more.

The water-soluble cellulose-based polymer can be any water-soluble cellulose-based polymer. For example, a water-soluble cellulose polymer having a viscosity of 2.5 to 35,000 mm ² /s, measured as a 2% aqueous solution, can be used. It is particularly preferred to use a water-soluble cellulose-based polymer having a viscosity of from 2.5 to 17.5 mm ² /s, measured in the form of a 2% aqueous solution.

When a water-soluble cellulose-based polymer (eg, hypromellose) is primarily used as a sustained-release base, the water-soluble cellulose-based polymer has a viscosity of 80 to 35,000 mm ² /s, measured as a 2% aqueous solution. The phrase substantially using a hydrophilic polymer here means that the amount of the hydrophilic polymer is 50 wt% or more, such as 80 wt% or more or 90 wt% or more, based on the total weight of the sustained release base .

The core tablet may contain a sustained release base in an amount of, for example, about 30 to 90 weight percent, or about 50 to 80 weight percent, based on the weight of the core tablet.

As the additive containing the ion common to the salt of compound (I) in the hydrogel matrix tablet, the additives described above can be suitably used. The hydrogel matrix tablet may contain an additive in an amount of, for example, about 1 to 50% by weight, or about 10 to 30% by weight, based on the weight of the tablet core.

The hydrogel matrix tablet may additionally contain other additives. Examples of such additives include lubricants, fluidizers and the like.

Examples of preferred lubricants include magnesium stearate and the like. The hydrogel matrix tablet may contain a lubricant in an amount of, for example, 0.1 to 5% by weight, or 0.2 to 3% by weight, based on the weight of the tablet core. Examples of preferred fluidizers include silica (particularly light anhydrous silicic acid). The hydrogel matrix tablet may contain a fluidizer in an amount of, for example, about 0.1 to 5 weight percent, or about 0.1 to 3 weight percent, based on the weight of the tablet core.

The hydrogel matrix tablet more preferably contains an enteric coating. A known enteric coating composition can be used for enteric coating. For example, an enteric coating composition may preferably be used containing an enteric base such as Eudragit, a plasticizer such as triethyl citrate, and a lubricant such as talc. The hydrogel matrix tablet preferably contains an enteric coating in an amount of, for example, from about 1 to 40 parts by weight, or from 10 to 30 parts by weight, per 100 parts by weight of tablet core.

A preferred example of a sustained release hydrogel formulation herein is one containing from 5 to 200 mg of a salt of compound (I) based on the weight of the free base of compound (I); further containing from 1 to 5 wt.%, an additive containing an ion common to the salt of compound (I) based on the weight of the tablet core, from 30 to 90 wt.%, sustained release base material based on the weight of the tablet core, and from

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0.1 to 5 wt.% lubricating agent based on the weight of the tablet core; and additionally contains an enteric coating in an amount of from 1 to 40 parts by weight per 100 parts by weight of the core composition.

As used herein, the term comprising includes consisting essentially of and consisting of.

In addition, the present description includes any and all combinations of the components described herein.

The various characteristics (properties, structures, functions, etc.) described in the above embodiments of the present description may be combined in any manner to define the subject matter of the invention included in the present description. That is, this description includes all objects containing any combination of combinable properties described herein.

Examples

The present invention is described below more specifically with reference to examples, experimental examples, etc. However, the present invention is not limited to these examples. Compound (I) means 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one.

Preparation of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one fumarate

A suspension of 4.22 kg of fumaric acid in 32.5 L of water and 22.16 kg of ethanol is stirred under reflux to dissolve the fumaric acid (boiling point: approximately 82°C). The resulting solution is filtered and washed with 11.86 kg of ethanol to obtain a fumaric acid solution. Suspension of 15.0 kg 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one in 25.96 kg water, 8.32 kg acetic acid and 34.0 L of ethanol are stirred at reflux to dissolve 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1 -yl)-butoxy]-1 H-quinolin-2-one (temperature reflux: approximately 83°C). The resulting solution is added to the fumaric acid solution and then filtered and washed with 11.86 kg of ethanol. The filtrate is stirred at reflux for 15 minutes (reflux temperature: approximately 82°C), then cooled to 30°C or lower and separated into solid and liquid. The resulting 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-ylpiperazin-1 -yl)butoxy]-1H-quinoline fumarate -2-she.

Infrared absorption spectrum.

The IR spectrum of the fumaric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (IRPrestige-21) manufactured by Shimadzu Corporation. As shown in FIG. 11a, the IR spectrum showed absorption at wavenumbers 3657 cm ^-1 , 1711 cm ^-1 , 1643 cm ^-1 , 1416 cm ^-1 , 1227 cm ^-1 and 839 cm ^-1 .

Powder X-ray diffraction

Powder X-ray diffraction of the fumaric acid salt obtained as described above was measured using an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS. In fig. 11b shows an X-ray powder diffraction pattern of a fumaric acid salt. As shown in FIG. 11b, diffraction peaks were observed at 2θ=7.6°, 15.1°, 17.7°, 18.9° and 19.2°. Other 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°.

Water content measurement.

The water content of the resulting fumaric acid salt is measured. In particular, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (Titrando 852) from Metrohm. The results confirmed that the water content of the fumaric acid salt was 3.01 wt%.

Preparation of sustained release drug formulation and evaluation 1

A controlled release composition for an osmotic pump containing a two-layer compressed core containing a drug layer to provide sustained release of the salt of compound (I) and an osmotic agent layer is prepared in accordance with a known conventional manufacturing process. More specifically, a drug layer composition containing a salt of compound (I) and other inert agents and an osmotic agent layer composition containing an osmotic agent and a high-viscosity polymer are separately prepared; each composition is then compressed into a two-layer tablet core using a known core compression method.

The two-layer compressed core is then coated with a composition containing a water-soluble polymer. As a water-soluble polymer composition, hypromellose (hydroxypropyl methylcellulose; TC-5 from Shin-Etsu Chemical Co., Ltd.) and povidone (polyvinylpyrrolidone; Kollidon K30, BASF) (70:30% w/w) were dissolved in water to 8 % solids content for preparing coating solution. This water-soluble polymer coating solution is applied to the two-layer compressed core obtained above using a pan until the coating component constitutes 10 wt.% of the two-layer compressed core.

The resulting water-soluble coating of the two-layer pressed core is then coated with a semi-permeable membrane composition. As a semipermeable membrane composition, ace

- 18 045131 tat cellulose and polyethylene glycol 4000 (85:15% w/w) are dissolved to 5% solids in acetone/water (95:5% w/w) as solvent to produce a coating solution. This coating solution is applied to the water-soluble coated two-layer compressed core prepared above using a pan until the coating component constitutes 10% by weight of the two-layer compressed core. The coated core is removed from the pan and then dried at 40° C. for 24 hours using a rack dryer.

In the thus coated double-layer compressed core, drug release holes having a diameter of 0.8 mm are made on the drug layer side surface using an automated laser to obtain an osmotic pump composition.

In table Figure 1 below shows the components of the composition for an osmotic pump.

Table 1

Compound (mg/unit) Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Components tablet cores Layer medicine Fumaric salt acids compounds (I) 39.27 39.27 39.27 39.27 39.27 Low viscosity polyethylene oxide 89.73 89.73 89.73 89.73 89.73 Fumarovaya acid 30.00 - - - - Monosodium fumarate - 30.00 - - - Sodium hydrogen carbonate - - 30.00 - - D-mannitol - - - 30.00 - Polyethylene glycol - - - - 30.00

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ol 6000 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 Layer of osmotic substance High viscosity polyethyleneoxy 45.40 45.40 45.40 45.40 45.40 Sodium hydrogen carbonate 24.00 24.00 24.00 24.00 24.00 Iron oxide 0.20 0.20 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 0.40 0.40 Intermediate result 230.00 230.00 230.00 230.00 230.00 Components coatings Water soluble polymer HPMC TC-5R 16.10 16.10 16.10 16.10 16.10 Kollidon K30 6.90 6.90 6.90 6.90 6.90 Components semipermeable membrane Acetate cellulose 19.55 19.55 19.55 19.55 19.55 PEG 4000 3.45 3.45 3.45 3.45 3.45 Intermediate result 46.00 46.00 46.00 46.00 46.00 Total 276.00 276.00 276.00 276.00 276.00

The compositions obtained in the examples were subjected to the following Experimental Example 1 and Experimental Example and evaluated.

The low viscosity polyethylene oxide used is POLYOX (trade mark) WSR N-80 (average molecular weight: approximately 200,000, viscosity: 55 to 90 mPa-s (aqueous solution 5% w/v, 25°C). high density polyethylene oxide using POLYOX (registered trademark) WSR Coagulant (average molecular weight: 5000000, viscosity: 5500 to 7500 mPa-s (aqueous solution 1% w/v, 25°C).

Experimental example 1.

The release rate of the formulations prepared in the Examples was assessed by measuring the dissolution rate of each salt of compound (I) at intervals of 30 minutes to 2 hours over a 24 hour period. The dissolution test was carried out in accordance with the ^15th Japanese Pharmacopoeia Dissolution Test Method 2 ( method using a paddle mixer). The test liquid is 900 ml of 0.05 mol/l acetate buffer solution (pH approximately 4.3, acetic acid, sodium acetate), the test is carried out at 37 ° C and a blade speed of 50 rpm. Sampling is carried out after some time, and the amount of compound (I) (free base) in the sampled solution is quantified using a UV sensor (absorbance measurement wavelength: 323 nm and 380 nm). The mass ratio of dissolution (%) of compound (I) (free base) to the total amount (weight) of compound (I) (free base) in the composition, taken as 100%, is defined as the dissolution rate. Since the dissolution rate value is the same as the mass ratio (%) of the dissolved salt of compound (I) to the total amount (weight) of the salt of compound (I) in the composition, taken as 100%, the dissolution rate value can also be used as the dissolution rate of the salt of the compound (I). In fig. Figure 1a shows the results. The term Dissolved (%) in Fig. 1 indicates the dissolution rate.

Experimental example 2.

The release rate of each example was assessed by measuring the dissolution rate of the salt of compound (I) at 1-hour intervals for 24 hours. The dissolution test was carried out in accordance with the ^15th Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). As the experimental liquid, use 900 ml of the second experimental liquid for dissolution (pH approximately 7, potassium dihydrogen phosphate, disodium hydrogen phosphate),

-20045131 specified in Japanese Pharmacopoeia, and the test is carried out at 37°C and a blade speed of 50 rpm. Sampling is carried out after some time, and compound (I) (free base) in the sampled solution is quantified using a UV sensor (absorbance measurement wavelength: 323 nm and 380 nm). The first wavelength (323 nm) is set as the wavelength at which the absorption of the base drug can be detected to a maximum, and the second wavelength (380 nm) is set as the wavelength at which the absorption of the base drug is not detected. In fig. Figure 1b shows the results. In the figure, dissolved (µg/ml) means the concentration of compound (I) eluted (dissolved) (free base).

In Experimental Example 1, the eluate had a pH of approximately 4.3. The evaluation result in the dissolution test in the experimental example is an indication of the degree of dissolution of the salt of compound (I) throughout the gastrointestinal tract after oral administration of the oral pharmaceutical composition. The sustained release time of the oral pharmaceutical composition can be estimated from the resulting profile.

On the other hand, in Test Example 2, the pH of the eluate is approximately 7. The results of the dissolution test evaluation in Test Example 2 indicate to what level the salt of compound (I) elutes in the lower gastrointestinal tract after oral administration of the oral pharmaceutical composition and passage it through the stomach. In Experimental Example 1, the following phenomenon is observed: since the solubility of the salt of compound (I) is higher than the solubility of compound (I), the dissolution concentration of the salt of compound (I) of the composition temporarily exceeds the solubility of compound (I), showing a supersaturated concentration, and then the dissolution concentration decreases upon recrystallization of compound (I). The profile obtained at this time is defined as the supersaturated dissolution profile and can be assessed as an indicator of absorption in the lower part of the gastrointestinal tract.

The results presented above confirm that formulations, in particular containing fumaric acid or monosodium fumarate as an osmotic agent in the drug layer, showed excellent dissolution supersaturation profiles (Fig. 1(b)) and were particularly preferred.

Preparation of sustained release drug formulation and evaluation 2

Oral pharmaceutical compositions (osmotic pump compositions) shown in table. 2 was prepared in the same manner as in the method described above in the section Preparation of sustained-release drug and evaluation 1, except that the types and amounts of tablet core components and coating components were changed as shown in Table. 2. The compositions obtained in the examples shown in table. 2 are evaluated in the same way as in experimental example 2. In table. 2 presents the results.

table 2 Composition (mg/unit) Example 2-1 Example 2-2 Example 2-3 Example 2-4 Tablet core components Layer medicine Fumaric acid salt of compound (I) 39.27 39.27 39.27 39.27 Low viscosity polyethylene oxide 89.73 69.73 69.73 69.73 Monosodium fumarate 30.00 30.00 30.00 30.00 Hypromellose TC-5R - 20.00 - - Low-substituted hydroxypropylcellose - - 20.00 - Polyethylene glycol 6000 - - - 20.00 Magnesium stearate 1.00 1.00 1.00 1.00

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Layer of osmotic substances High viscosity polyethylene oxide 45.40 45.40 45.40 45.40 Sodium bicarbonate 24.00 24.00 24.00 24.00 Iron oxide 0.20 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 0.40 Subtotal 230.00 230.00 230.00 230.00 Coating components Water soluble polymer HPMC TC-5R 16.10 16.10 16.10 16.10 Kollidon K30 6.90 6.90 6.90 6.90 Components semi-permeable my membrane Cellulose acetate 31.05 31.05 31.05 31.05 PEG 4000 3.45 3.45 3.45 3.45 Subtotal 57.50 57.50 57.50 57.50 Total 287.50 287.50 287.50 287.50

The above results confirmed that formulations, particularly those containing hypromellose (hydroxypropyl methylcellulose) as a carrier (particularly a hydrophilic polymer), have an excellent supersaturation concentration profile upon dissolution and were found to be superior.

Preparation of sustained release drug formulation and evaluation 3

Oral pharmaceutical compositions (osmotic pump compositions) shown in table. 3 was prepared in the same manner as in the method described above in the section Preparation of sustained-release drug and evaluation 1, except that the types and amounts of tablet core components and coating components were changed as shown in table. 3. Compositions obtained in the examples shown in table. 3 are evaluated in the same way as in Experimental Example 1. In FIG. Figure 3 shows the results.

Table 3 Composition (mg/unit) Example 3-1 Example 3-2 Example Example 3-4 Example 3-5 Example 3-6 Example 3-7 Example 3-8 Example 3-9 Components tablet cores Layer medicine Fumaric acid salt of compound (I) 39.27 39.27 39.27 39.27 39.27 39.27 39.27 39.27 39.27 Low viscosity polyethylene oxide 87.73 87.73 87.73 87.73 87.73 87.73 87.73 87.73 87.73 Crospovidon Kollidon CL 16.00 16.00 16.00 16.00 16.00 16.00 16.00 16.00 16.00 Povidone Kollidon KZO 16.00 16.00 16.00 16.00 16.00 16.00 16.00 16.00 16.00 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Layer of osmotic substance Polyethyleneoxy high viscosity 45.40 45.40 45.40 45.40 45.40 45.40 45.40 45.40 45.40 Sodium chloride 24.00 - - - - - - - - D-mannitol - 24.00 - - - - - - - Fructose - - 24.00 - - - - - - Sucrose - - - 24.00 - - - - - Sorbitol - - - - 24.00 - - - - Sodium bicarbonate - - - - - 24.00 - - -

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Disodium carbonate - - - - - - 24.00 - - Sodium dihydrogen phosphate - - - - - - - 24.00 - Disodium hydrogen phosphate - - - - - - - - 24.00 Iron oxide 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 Subtotal 230.00 230.00 230.00 230.00 230.00 230.00 230.00 230.00 230.00 Coating Component Water soluble polymer HPMC TC-5R 16.10 16.10 16.10 16.10 16.10 16.10 16.10 16.10 16.10 Kollidon KZO 6.90 6.90 6.90 6.90 6.90 6.90 6.90 6.90 6.90 Components semipermeable membrane Cellulose acetate 19.55 19.55 19.55 19.55 19.55 19.55 19.55 19.55 19.55 PEG 4000 3.45 3.45 3.45 3.45 3.45 3.45 3.45 3.45 3.45 Subtotal 46.00 46.00 46.00 46.00 46.00 46.00 46.00 46.00 46.00 Total 276.00 276.00 276.00 276.00 276.00 276.00 276.00 276.00 276.00

The above results confirmed that the formulations obtained in all examples exhibited excellent sustained release properties (FIG. 3). It was further found that when using sodium bicarbonate or sodium chloride as the osmotic agent in the osmotic agent layer, the slope of the dissolution rate plot in FIG. 3 is more constant (i.e., the dissolution of the salt of compound (I) continues at a constant rate) and is preferred from this point of view. It was also found that when sodium chloride was used, the resulting final dissolution rate was slightly lower than when other osmotic agents were used. Based on the above results, it has been found that the use of sodium bicarbonate is particularly preferable because a high final dissolution rate is achieved and dissolution continues at a constant rate.

Preparation of extended release drug formulation and evaluation 4.

Oral pharmaceutical compositions (osmotic pump compositions) shown in table. 4 was prepared in the same manner as in the method described above in the section Preparation of Sustained Release Drug Formulation and Evaluation 1, except that the types and amounts of tablet core components and coating components were changed as shown in Table. 4. Compositions obtained in the examples shown in table. 4 were evaluated in the same manner as in Experimental Examples 1 and 2. However, when evaluated in Experimental Example 1, the liquid obtained by adding a surfactant (cetyltrimethylammonium bromide: CTAB) at a final concentration of 0.5% w/w. , to the test liquid used in Experimental Example 2 was used as the test liquid. This test liquid was prepared in such a way that the surfactant added to it increases the solubility of compound (I) at pH around 7 and ensures 100% dissolution of the drug from the formulation. This test solution is used because it is considered more suitable for assessing the release of the formulation under pH conditions throughout the gastrointestinal tract.

In fig. 4a and 4b show the results.

Table 4

Medicinal layer

Composition (mg/unit) Example 4-1 Example 4-2 Example 4- Tablet core components Fumaric acid salt of compound (I) 39.27 39.27 39.27

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facilities Low viscosity polyethylene oxide 59.73 59.73 59.73 Monosodium fumarate 40.00 40.00 40.00 Hypromellose TC-5R 20.00 20.00 20.00 Magnesium stearate 1.00 1.00 1.00 Osmotic layer High viscosity polyethylene oxide 45.40 45.40 45.40 D-mannitol 24.00 - - Sodium bicarbonate - 24.00 - Fructose - - 24.00 Iron oxide 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 Subtotal 230.00 230.00 230.00 Coating components Water soluble polymer HPMC TC-5R 16.10 16.10 16.10 Kollidon KZO 6.90 6.90 6.90 Components semipermeable membrane Cellulose acetate 36.80 36.80 36.80 PEG 4000 9.20 9.20 9.20 Subtotal 69.00 69.00 69.00 Total 299.00 299.00 299.00

Preparation of sustained release drug formulation and evaluation 5

Oral pharmaceutical compositions (osmotic pump compositions) shown in table. 5 was prepared in the same manner as in the method described above in the section Preparation of sustained-release drug and evaluation 1, except that the types and amounts of tablet core components and coating components were changed as shown in Table. 5. Compositions obtained in the examples shown in table. 5 are evaluated in the same way as in Experimental Examples 1 and 2. In FIG. 5a and 5b show the results.

Table 5

Composition (mg/unit) Example 5- 1 Example 5-2 Example 5-3 Tablet core components

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Layer Fumaric acid salt 39.27 39.27 39.27 medicinal compounds (I) facilities Low polyethylene oxide 69.73 69.73 69.73 viscosity Monosodium fumarate 30.00 30.00 30.00 Hypromellose TC-5R 20.00 20.00 20.00 Magnesium stearate 1.00 1.00 1.00 Layer Polyethylene oxide 45.40 45.40 45.40 osmotic high viscosity substances Sodium bicarbonate 24.00 24.00 24.00 Iron oxide 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 Subtotal 230.00 230.00 230.00 Coating components B odosoluble HPMC TC-5R 16.10 16.10 16.10 polymer Kollidon KZO 6.90 6.90 6.90 Components Cellulose acetate 20.70 31.05 41.40 semi-permeable PEG 4000 2.30 3.45 4.60 membranes Subtotal 46.00 57.50 69.00 Total 276.00 287.50 299.00 These results confirmed that the formulations obtained in all examples showed excellent sustained release properties (Fig. 5(a)). It was also confirmed that the extended release time can be controlled by changing the amount of film component (semi-permeable component). Even when hypromellose having a different aqueous solution viscosity is used in the drug layer (more specifically, when hypromellose TC-5E having a viscosity of about 3 mPa-s measured at 20°C is used in the form of a 2% aqueous solution instead of hypromellose TC5R having viscosity is about 6 mPa-s, measured at 20°C in the form of a 2% aqueous solution), the difference in viscosity does not have much significance in the effect of delayed release and maintenance of re-

saturation.

Preparation of sustained release drug formulation and evaluation 6.

Oral pharmaceutical compositions (osmotic pump compositions) shown in table. 6 was prepared in the same manner as in the method described above in the section Preparation of sustained-release drug and evaluation 1, except that the types and amounts of tablet core components and coating components were changed as shown in Table. 6. Compositions obtained in the examples shown in table. 6 were evaluated in the same manner as in Experimental Examples 1 and 2. However, when evaluated in Experimental Example 1, the liquid obtained by adding a surfactant (cetyltrimethylammonium bromide: CTAB) at a final concentration of 0.5% w/w. , to the test liquid used in Experimental Example 2 was used as the test liquid. In fig. 6a and 6b show the results.

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Table 6

Compound (mg/unit) Example 6-1 Example 6- 2 Example 6-3 Example 6- 4 Components tablet cores Layer medicinal facilities Fumaric salt acids compounds (I) 39.27 39.27 39.27 39.27 Low viscosity polyethylene oxide 87.73 67.73 57.73 47.73 Monosodium fumarate 10.00 30.00 40.00 50.00 Hypromellose TC5R 20.00 20.00 20.00 20.00 Light anhydrous silicic acid Aerosil 200 2.00 2.00 2.00 2.00 Magnesium stearate 1.00 1.00 1.00 1.00 Osmotic layer High viscosity polyethylene oxide 45.40 45.40 45.40 45.40 Sodium hydrogen carbonate 24.00 24.00 24.00 24.00 Iron oxide (pigment) 0.20 0.20 0.20 0.20 Magnesium stearate 0.40 0.40 0.40 0.40 Intermediate 230.00 230.00 230.00 230.00 result Components coatings Water soluble polymer HPMC TC-5R 16.10 16.10 16.10 16.10 Kollidon KZO 6.90 6.90 6.90 6.90 Components semipermeable membrane Cellulose acetate 31.05 31.05 31.05 31.05 PEG 4000 3.45 3.45 3.45 3.45 Intermediate result 57.50 57.50 57.50 57.50 Total 287.50 287.50 287.50 287.50

These results confirmed that the formulations obtained in all examples showed excellent sustained release properties (Fig. 6(a)). It has also been found that when the drug layer contains sodium fumarate as an osmotic agent in an amount of about 20 wt.% or more based on the total weight of the drug layer, optimal properties for maintaining sustained release and supersaturation can be obtained.

Preparation of sustained release drug formulation and evaluation 7.

Preparation of citric acid salt 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H

- 26 045131 quinolin-2-one.

g 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, 280 ml of ethanol and 52.5 ml of acetic acid are placed in a Kolben flask; and stir at reflux to dissolve 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin2-one (reflux temperature: about 83° WITH). After cooling to reflux, 16.62 g of citric acid is added to the flask. After washing with 70 ml of ethanol, the mixture is heated with stirring to reflux temperature (reflux temperature: approximately 82°C). After refluxing, the mixture is cooled to 5°C or lower and separated into solid and liquid. The resulting solid was washed with ethanol and dried at 60° C. to obtain 50.32 g of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinoline-2 citric acid salt -ona (unmilled product).

Infrared absorption spectrum.

The IR spectrum of the citric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (FT-IR IR Affinity-1S) manufactured by Shimadzu Corporation. As shown in FIG. 11c, the IR spectrum showed absorption at wavenumbers 2959 cm ^-1 , 1713 cm ^-1 , 1626 cm ^-1 , 1416 cm ^-1 , 1227 cm ^-1 and 754 cm ^-1 .

Powder X-ray diffraction.

Powder X-ray diffraction of the citric acid salt obtained as described above was measured using an X-ray diffractometer (D8 Advance) manufactured by Bruker AXS. In fig. 11d shows a powder X-ray diffraction pattern of citric acid salt. As shown in FIG. 11d, diffraction peaks were observed at 2θ=14.1°, 16.2°, 17.3°, 22.2° and 24.8°. Other diffraction peaks were observed at 2θ=7.1°, 11.1°, 11.9°, 12.5°, 13.0°, 17.7°, 19.4°, 19.9°, 20.9 °, 23.5°, 24.0°, 25.9° and 28.4°.

Water content measurement.

The water content in the resulting citric acid salt is measured. Specifically, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (CA-200) manufactured by Mitsubishi Chemical Analytech. The results confirmed that the water content of the citric acid salt was 0.76 wt%.

Preparation of the tartaric acid salt of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1Hquinolin-2-one.

g 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, 280 ml of ethanol and 52.5 ml of acetic acid are placed in a Kolben flask; and stir at reflux to dissolve 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin2-one (reflux temperature: about 83° WITH). After cooling to reflux, 12.72 g of tartaric acid is added to the flask. After washing with 70 ml of ethanol, the mixture is heated with stirring to reflux temperature (reflux temperature: approximately 83°C). After refluxing, the mixture is cooled to 5°C or lower and separated into solid and liquid. The resulting solid was washed with ethanol and dried at 60° C. to obtain 46.53 g of tartaric acid salt 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinoline-2 -ona (unmilled product).

Infrared absorption spectrum.

The IR spectrum of the tartaric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (FT-IR IR Affinity-1S) manufactured by Shimadzu Corporation. As shown in FIG. 11e, the IR spectrum showed absorption at wavenumbers 3321 cm ^-1 , 1717 cm ^-1 , 1661 cm ^-1 , 1414 cm ^-1 , 1240 cm ^-1 and 754 cm ^-1 .

Powder X-ray diffraction.

Powder X-ray diffraction of the tartaric acid salt obtained as described above was measured using an X-ray diffractometer (D8 Advance) manufactured by Bruker AXS. In fig. 11f shows an X-ray powder diffraction pattern of a tartaric acid salt. As shown in FIG. 11f, diffraction peaks were observed at 2θ=15.5°, 15.9°, 21.6°, 23.7° and 24.7°. Other diffraction peaks were observed at 2θ=10.9°, 11.6°, 12.2°, 13.2°, 16.3°, 16.7°, 17.2°, 18.3°, 18.9 °, 19.3°, 20.5°, 22.2°, 25.4°, 26.0°, 26.8°, 27.8°, 32.8°, 34.6°, 35.7 ° and 38.7°.

Water content measurement.

The water content in the resulting tartaric acid salt is measured. Specifically, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (CA-200) manufactured by Mitsubishi Chemical Analytech. The results confirmed that the water content of the tartaric acid salt was 0.42 wt%.

Preparation of the phosphoric acid salt of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1Hquinolin-2-one.

g 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, 350 ml of ethanol and 52.5 ml of acetic acid are placed in a Kolben flask; and stirred at reflux to dissolve 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinoline

- 27 045131

2-ona (reflux temperature: about 82°C). After cooling to reflux, 5.78 ml of phosphoric acid is added to the flask. After washing with 70 ml of ethanol, the mixture is heated with stirring to reflux temperature (reflux temperature: approximately 82°C). After refluxing, the mixture is cooled to 5°C or lower and separated into solid and liquid. The resulting solid was washed with ethanol and dried at 60° C. to obtain 41.96 g of the phosphoric acid salt 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-III-quinoline-2 -ona (unmilled product).

Infrared absorption spectrum.

The IR spectrum of the phosphoric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (FT-IR IR Affinity-1S) manufactured by Shimadzu Corporation. As shown in FIG. 11g, the IR spectrum showed absorption at wavenumbers 2951 cm ^-1 , 1651 cm ^-1 , 1416 cm ^-1 , 1223 cm ^-1 , 1072 cm ^-1 and 741 cm ^-1 .

Powder X-ray diffraction.

Powder X-ray diffraction of the phosphoric acid salt obtained by the above method is measured using an X-ray diffractometer (D8 Advance) manufactured by Bruker AXS. In fig. 11h shows an X-ray powder diffraction pattern of a phosphoric acid salt. As shown in FIG. 11h, diffraction peaks were observed at 2θ=4.7°, 13.8°, 16.6°, 17.4° and 22.8°. Other diffraction peaks were observed at 2θ=11.0°, 11.7°, 12.1°, 14.3°, 15.3°, 18.1°, 19.1°, 19.8°, 21.0 °, 21.8°, 22.4°, 23.5°, 24.4°, 24.7°, 25.8°, 27.0°, 27.8°, 28.5°, 30.2 °, 30.8°, 33.8° and 34.2°.

Water content measurement.

The water content in the resulting phosphoric acid salt is measured. Specifically, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (CA-200) manufactured by Mitsubishi Chemical Analytech. The results confirmed that the water content of the phosphoric acid salt was 0.37 wt%.

Preparation of the hydrochloric acid salt of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1yl)butoxy]-1 H-quinolin-2-one.

g 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-III-quinolin-2-one, 210 ml of ethanol, 70 ml of water and 52.5 ml of acetic acid are placed in Kolben flask; and stir at reflux to dissolve 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1Hquinolin-2-one (reflux temperature: about 82° WITH). After cooling to reflux, 7.27 ml of 36% hydrochloric acid is added to the flask. After washing with 70 ml of ethanol, the resulting mixture is cooled until crystals precipitate. After the crystals have precipitated, the resulting mixture is heated with stirring to reflux temperature (reflux temperature: approximately 81°C). After stirring under reflux, the mixture is cooled to 5°C or below and stirred at 5°C or below and then separated into solid and liquid. The resulting solid was washed with ethanol and air-dried to obtain 36.62 g of 7-[4-(4benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloric acid salt (unground product).

Infrared absorption spectrum.

The IR spectrum of the hydrochloric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (FT-IR IR Affinity-1S) manufactured by Shimadzu Corporation. As shown in FIG. 11i, the IR spectrum showed absorption at wavenumbers 3102 cm ^-1 , 2951 cm ^-1 , 1670 cm ^-1 , 1416 cm ^-1 , 1221 cm ^-1 and 745 cm ^-1 .

Powder X-ray diffraction.

Powder X-ray diffraction of the hydrochloric acid salt obtained as described above was measured using an X-ray diffractometer (D8 Advance) manufactured by Bruker AXS. In fig. Figure 11j shows an X-ray powder diffraction pattern of a hydrochloric acid salt. As shown in FIG. 11j, diffraction peaks were observed at 2θ=16.0°, 20.4°, 20.6°, 23.8° and 24.5°. Other diffraction peaks were observed at 2θ=5.3°, 6.0°, 7.8°, 9.2°, 10.5°, 12.6°, 13.4°, 14.6°, 15.4 °, 17.2°, 17.6°, 17.8°, 18.4°, 19.5°, 21.8°, 25.2°, 25.9°, 26.8°, 27.3 °, 28.4°, 29.2°, 29.7° and 30.7°.

Water content measurement.

The water content in the resulting hydrochloric acid salt is measured. Specifically, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (CA-200) manufactured by Mitsubishi Chemical Analytech. The results confirmed that the water content of the hydrochloric acid salt was 3.84 wt%.

Preparation of the sulfuric acid salt of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1Hquinolin-2-one.

g 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-III-quinolin-2-one, 210 ml of acetonitrile and 70 ml of water are placed in a Kolben flask; and stirred at room temperature in a suspended state. After adding 4.71 ml of sulfuric acid and 70 ml of acetonitrile to the flask and stirring

- 28 045131 at room temperature, the resulting mixture is heated to reflux temperature (reflux temperature: approximately 78°C). After refluxing, the mixture is cooled to 5°C or lower. After stirring at 5°C or less, the mixture is separated into solid and liquid phases. The resulting solid was washed with acetonitrile and dried at 60° C. to obtain 42.45 g of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin1-yl)butoxy]-1H-quinolin-2-one sulfuric acid salt (unmilled product).

Infrared absorption spectrum.

The IR spectrum of the sulfuric acid salt obtained by the above method was measured by the KBr pellet pressing method using a Fourier transform infrared spectrophotometer (FT-IR IR Affinity-1S) manufactured by Shimadzu Corporation. As shown in FIG. 11k, IR spectrum showed absorption at wavenumbers 2961 cm ^-1 , 1630 cm ^-1 , 1229 cm ^-1 , 1155 cm ^-1 , 1034 cm ^-1 and 756 cm ^-1 .

Powder X-ray diffraction.

Powder X-ray diffraction of the hydrochloric acid salt obtained as described above was measured using an X-ray diffractometer (D8 Advance) manufactured by Bruker AXS. In fig. 11l shows a powder X-ray diffraction pattern of a hydrochloric acid salt. As shown in FIG. 11l, diffraction peaks were observed at 2θ=12.1°, 17.6°, 20.5°, 22.8° and 24.1°. Other diffraction peaks were observed at 2θ=4.3°, 11.5°, 12.7°, 12.9°, 13.5°, 14.1°, 14.6°, 15.4°, 15.6 °, 17.2°, 18.7°, 19.1°, 19.7°, 22.3°, 25.0°, 26.8°, 27.2°, 28.6°, 29.3 °, 29.9°, 32.8°, 34.1°, 34.8° and 37.8°.

Water content measurement.

The water content in the resulting hydrochloric acid salt is measured. Specifically, the water content is measured by the Karl Fischer method (coulometric titration method) using a water content measuring device (CA-200) manufactured by Mitsubishi Chemical Analytech. The results confirmed that the water content of the hydrochloric acid salt was 0.41 wt%.

The osmotic pump formulations were prepared using substantially the same composition as the osmotic pump formulation of Example 6-3, except that the drug layer was formed using a different salt of compound (I) instead of the fumaric acid salt of compound (I), and using a different component instead of monosodium fumarate.

More specifically, the osmotic pump compositions are prepared in the same manner as above, using the same types and amounts of components as in Example 6-3; however, to form the drug layer, the components shown in table. 7a, are used in the quantities indicated in table. 7a, as a carrier (instead of hypromellose (HPMC) TC-5R used in Example 6-3), and the components shown in table. 7a, are used in the quantities indicated in table. 7a, as water-soluble polymers (instead of HPMC TC-5R and Kollidon K30 used in example 6-3). In table 7a Metolose SM-4 is methylcellulose, HPC-SL is hydroxypropylcellulose, and Kollicoat IR is a polyvinyl alcohol-polyethylene glycol graft copolymer.

In addition, the compositions for the osmotic pump are prepared in the same manner as above, using the same types and quantities of components as in Example 6-3; however, various types of salts are used to form the drug layer, shown in the table. 7b, in the quantities indicated in table. 7b, as salts of compound (I) (instead of fumaric acid used in Example 6-3), various components shown in table. 7b is used in the quantities indicated in table. 7b as osmotic agents (instead of monosodium fumarate used in Example 6-3), and the amount of low viscosity polyethylene oxide used was changed to the amount shown in Table. 7a; and no carriers (instead of using hypromellose (HPMC) TC-5R in Example 6-3). In addition, to form the coating layer, the components listed in table. 7b are used in the quantities indicated in table. 7b, the coating component water-soluble polymers (instead of HPMC TC-5R and Kollidon K30 used in Example 6-3), and the amounts of coating component semipermeable membrane components were changed to 19.55 mg/unit cellulose acetate and 3.45 mg/unit cellulose acetate. unit of PEG 4000. In table. 7b Kollicoat IR is a graft copolymer of polyvinyl alcohol and polyethylene glycol.

____________________________________________________________________Table 7a

Composition (mg/unit) Example 7a-1 Example 7a-2 Example 7a-3 Example 7a-4 Example 7a-5 Carrier HPMS TS- 5R 20 - - - - Metolose SM-4 - 20 - - - HPC-SL - - 20 - - PVP - - - 20 -

- 29 045131

Kollidon 25 Kollicoat IR - - - - 20 Water soluble polymer Kollicoat IR 6.9 6.9 6.9 6.9 6.9

Table 7b

Composition (mg/unit) Example Example Example Example Example Example Example Example Example Example Example Example 7b-1 7b-2 7b-3 7b-4 7b-5 7b-6 7b-7 7b-8 7b-9 7b-10 7b-11 7b-12 Compound salt® Fumaric acid salt 39.27 - - - - - - - - - - - Sulfuric acid salt - 36.79 - - - - - 36.79 - - - - Salt hydrochloric acids 33.77 33.77 Phosphoric acid salt - - - 36.78 - - - - - 36.78 - - Citrate - - - - 43.29 - - - - - 43.29 - Tartaric acid salt - - - - - 40.39 - - - - - 40.39 Free base - - - - - - thirty - - - - - Low viscosity polyethylene oxide 77.73 80.21 83.23 80.22 73.71 76.61 87 80.21 83.23 80.22 73.71 76.61 Osmotic agent Sodium hydrofumarate 40 40 40 40 40 40 40 - - - - - Sodium hydrosulfite - - - - - - - 40 - - - - Sodium chloride - - - - - - - - 40 - - - Sodium dihydrogen phosphate - - - - - - - - - 40 - - Sodium dihydrogen citrate - - - - - - - - - - 40 - Monosodium maleate trihydrate - - - - - - - - - - - - (±) Monohydrate - - - - - - - - - - - 40 sodium hydrogen tartrate Hydrocarbon resin HPMC TC-5R 16.1 16.1 16.1 16.1 16.1 16.1 16.1 16.1 16.1 16.1 16.1 16.1 Kollicoat IR 6.9 6.9 6.9 6.9 6.9 6.9 6.9 6.9 6.9 6.9 6.9 6.9

The release rate of the osmotic pump compositions obtained in the examples was evaluated in the same manner as in Experimental Example 1 and Experimental Example 2 above. In fig. 7 and 8g show the results of evaluating the release rate in the same way as in Experimental Example 1. FIG. 8a-8f show the results of evaluating the release rate in the same way as in Experimental Example 2.

Preparation of sustained release drug formulation and evaluation 8.

Sustained release hydrogel formulations (hydrogel matrix tablets) are prepared according to the formulations shown in Table. 8 by the usual known method of preparation. More specifically, the components are mixed and compressed into tablets using a known core compression method to produce a hydrogel matrix tablet (uncoated tablet). Hydrogel matrix tablets are a known method in which drug release is controlled by a hydrogel that is formed (in the case of enteric-coated tablets, by the dissolution of the coating film due to the increase in pH after gastric release and then) by the absorption of water in the gastrointestinal tract. tract. In the composition shown in table. 8, hypromellose is used as a sustained release base (hydrogel forming base).

-30045131

Table 8

Pharmaceutical composition (mg/unit) Example 8A-1 Example 8A-2 Fumaric acid salt of compound (I) 39.27 39.27 Hypromellose 90SH-4000SR 89.73 119.73 Sodium hydrofumarate 30.00 - Magnesium stearate 1.00 1.00 Total 160.00 160.00

In addition, uncoated tablets may preferably be enteric coated. A known enteric coating composition can be used for enteric coating. For example, an enteric coating composition containing Eudragit may preferably be used.

The resulting hydrogel matrix tablets (uncoated tablets) were evaluated for release rate in the same manner as Experimental Example 1 and Experimental Example 2 above. Hydrogel matrix tablets prepared without using the fumaric acid salt of compound (I) were also evaluated in the same manner. In fig. 9a shows the results of evaluating the release rate in the same way as in Experimental Example 1. FIG. 9b shows the results of evaluating the release rate in the same way as in Experimental Example 2.

Hydrogel matrix tablets (uncoated tablets) are prepared in the same manner as above, using the same compositions as shown in table. 8, except that instead of hypromellose, hypromellose TC5R and polyethylene oxide (MW: 7000K) are used as the sustained release base (Table 9). The resulting hydrogel matrix tablets were evaluated for release rate in the same manner as Experimental Example 1 and Experimental Example 2 above. In addition, hydrogel matrix tablets prepared without the use of sodium hydrofumarate and tablets prepared without the use of hypromellose were evaluated in the same manner. In fig. 10a shows the results of evaluating the release rate in the same way as in Experimental Example 1. FIG. 10b shows the results of evaluating the release rate in the same way as in Experimental Example 2.

Table 9

Pharmaceutical composition (mg/unit) Example 8B-1 Example 8B-2 Example 8B-3 Example 8B-4 Fumaric acid salt of compound (I) 39.27 39.27 39.27 39.27 Polyethylene oxide 69.73 89.73 99.73 119.73 Sodium hydrofumarate 30.00 30.00 - - Hyprommeloza TC-5R 20.00 - 20.00 - Magnesium stearate 1.00 1.00 1.00 1.00 Total 160.00 160.00 160.00 160.00

An example of the composition of compounds for an osmotic pump.

In table 10 shows composition examples of osmotic pump formulations containing the oral pharmaceutical compositions disclosed herein. In table 10, the amounts of components of the drug layer and the osmotic agent layer are indicated in parts by weight, while the amounts of components of the coating layer are indicated in parts by weight per 100 parts by weight of the hydrochloride core part. As referred to herein, the core portion means a portion containing a combination of a drug layer and an osmotic agent layer.

-31 045131

Table 10

Form. Etc. 1 Form. Etc. 2 Form. Etc. 3 Form. Etc. 4 Form. Etc. 5 Form. Etc. 6 Form. Etc. 7 Form. Etc. 8 Form. Etc. 9 Form. Etc. 10 Form. Etc. AND Form. Etc. 12 Form. Etc. 13 Form. Etc. 14 Form. Etc. 15 Form. Etc. 16 Layer medicinal product Fumaric acid salt of compound (I) 7.9 9.8 10.5 I,4 12.3 13.1 13.1 13.1 15.1 17.9 17.9 17.9 23.8 24.5 24.6 24.6 Polyethylene oxide (MM: 200K) 40.0 50.1 37.4 31.8 54.6 31.7 34.6 34.8 28.4 43.2 52.2 52.2 25.6 41.6 29.8 54.8 Sodium hydrogen fumarate 31.7 25.0 31.7 31.9 18.8 31.2 31.7 31.7 42.5 18.2 18.2 9.1 18.8 25.0 31.3 6.3 Hypromellose 16.7 12.5 16.7 20.9 12.5 20.0 16.7 16.7 10.0 18.2 9.1 18.2 31.3 6.3 12.5 12.5 Silica 2.0 0.6 2.0 2.0 1.3 2.0 2.0 2.0 2.0 0.6 0.6 0.6 - 0.6 1.3 1.3 Magnesium stearate 1.8 2.0 1.8 2.0 0.6 2.0 2.0 1.8 2.0 2.0 2.0 2.0 0.6 2.0 0.6 0.6 Total layer medicine 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Layer Polyethylene 64.3 64.4 64.3 64.3 64.9 64.3 64.3 64.3 64.3 64.4 64.4 64.4 64.9 64.4 64.9 64.9 osmotic Wow substances oxide (MM: 5000K) Sodium hydrogen carbonate 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 34.3 One and a half iron oxide 0.4 o, s 0.4 0.4 o, s 0.4 0.4 0.4 0.4 o, s o, s o, s o, s o, s o, s o, s Magnesium stearate 1.0 1.0 1.0 1.0 0.6 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.6 1.0 0.6 0.6 Total layer of osmotic substance 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Water soluble polymer (1 coating) Copolymer PVA- PEG/core part h,o h,o h,o 5.0 2.4 5.0 h,o h,o 5.0 5.0 5.0 5.0 - 5.0 h,o h,o Hypromellose/ core - 7.0 - - 5.6 - - - - - - - - - 7.0 7.0 Component semi-permeable membranes (2 Cellulose acetate/ core 6.3 13.5 6.3 9.0 10.8 9.0 4.8 6.3 7.2 9.0 9.0 9.0 18.0 9.0 13.5 13.5 PEG 4000/ 0.7 1.5 0.7 1.0 1.2 1.0 o, s 0.7 0.8 1.0 1.0 1.0 2.0 1.0 1.5 1.5 coating) core Part

Note: Form. Etc. means example composition

Estimation of the concentration of compound (I) in the blood after oral administration to humans.

The blood concentration of Compound (I) at steady state after oral administration of the oral pharmaceutical composition herein to a human is assessed based on the following single dose administration protocol and multiple dose administration protocol. The composition (experimental composition) used in this evaluation is an osmotic pump composition prepared as described herein, which contains the fumaric acid salt of compound (I) as an active ingredient. The doses and contents of the tablets shown in the table below are given in terms of free base, i.e. per mass of compound (I). In a single dose protocol, 24 mg of the test drug (one 24 mg tablet) is administered once on an empty stomach. Then, after a washout period, 48 mg of the test composition (two 24 mg tablets) is administered once on an empty stomach.

Claims (15)

on an empty stomach. In a multi-dose protocol, the test formulation is re-administered on an empty stomach using any of the following routes of administration 1-5. In each protocol, the PK parameter of the compound (I) is analyzed. The observation shows that the formulation maintains the desired stable blood concentration of compound (I) as a drug for once weekly administration (eg, 15 ng/ml to 400 ng/ml). Table 11 Date of introduction First day Day 8, Day 15, Day 22 and Day 29 Method of administration Dose Tablet ka Number of tablets Dose Tablet ka Number of tablets 1 24 mg 24 mg 1 tablet 48 mg 24 mg 2 tablets 2 18 mg 18 mg 1 tablet 36 mg 18 mg 2 tablets 3 24 mg 24 mg 1 tablet 42 mg 18 mg 24 mg 1 tablet each 4 30 mg 30 mg 1 tablet 54 mg 24 mg 30 mg 1 tablet each 5 30 mg 30 mg 1 tablet 60 mg 30 mg 2 tablets CLAIM 1. A controlled-release oral solid pharmaceutical composition containing 7-[4-(4-benzo[b]thiophen-4-ylniperazin-1-yl)butoxy]-1H-quinolin-2-one salt as an active ingredient and additionally containing an additive containing an ion common to salt. 2. The composition according to claim 1, where the active ingredient is a fumaric acid salt, a phosphoric acid salt, a hydrochloric acid salt, a sulfuric acid salt, a citric acid salt or a tartaric acid salt 7-[4-(4-benzo[b]thiophene- 4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one. 3. The composition according to claim 1, where the active ingredient is a fumaric acid salt of 7-[4(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, and an additive containing an ion common to the salt is at least one compound selected from the group consisting of fumaric acid, monosodium fumarate and disodium fumarate. 4. The composition according to any one of claims 1-3, additionally containing a water-soluble cellulose-based polymer. 5. The composition of claim 4, wherein the water-soluble cellulose-based polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose and methylcellulose. 6. The composition according to any one of claims 1 to 5, which is a composition for an osmotic pump. 7. The composition according to claim 6, wherein the osmotic pump composition comprises a drug layer containing a water-soluble cellulose-based polymer. 8. The composition according to claim 7, wherein the water-soluble cellulose-based polymer is hydroxypropyl methylcellulose. 9. The composition according to any one of claims 1 to 5, which is a hydrogel composition with prolonged release. 10. The composition according to claim 9, containing an enteric coating. 11. Composition according to any one of claims 1 to 10, containing from 5 to 60 mg of the active ingredient, based on weight, 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H -quinoline-2-one. 12. A method for preventing or treating a disease of the central nervous system (CNS), comprising orally administering to a subject a composition according to any one of claims 1 to 11 to maintain blood concentrations of 7-[4-(4-benzo[b]thiophen-4-ylpiperazine -1-yl)butoxy]-1H-quinolin-2-one at steady state in the range of 15 to 400 ng/ml for 1 week. 13. A method for preventing or treating a disease of the central nervous system (CNS), including administering a composition according to any one of claims 1 to 11, containing 7-[4-(4-benzo[b]thiophen-4ylpiperazin-1-yl)butoxy] salt -1H-quinolin-2-one in a dose of 5 to 60 mg based on the weight of the free base. 14. Use of a composition according to any one of claims 1 to 11 for the prevention or treatment of a disease of the central nervous system (CNS). 15. Use according to claim 14, where the CNS disease is selected from the group consisting of schizophrenia; treatment-resistant, refractory or chronic schizophrenia; emotional disorder; psychotic disorder; mood swings; bipolar disorder; depression, endogenous depression; major depression; melancholic and treatment-resistant depression; dysthymic disorder; -