OA17035A

OA17035A - Tablet Comprising 7-[4-(4-benzo[b]thiophen4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

Info

Publication number: OA17035A
Application number: OA1201400155
Authority: OA
Inventors: Yoshiharu Inoue
Original assignee: Otsuka Pharmaceutical Co.
Priority date: 2011-10-14
Filing date: 2012-10-12
Publication date: 2016-03-04

Abstract

Provided is a tablet containing the active ingredient of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-1H-quinolin-2-one or a salt thereof, the tablet having excellent disintegration, favorable storage stability, and high light stability; in particular, provided is a tablet obtained by coating, with a coating layer containing hypromellose, talc, titanium oxide, and a colorant or the like, a plain tablet which contains 7-[4-(4benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-1Hquinolin-2-one or a salt thereof as an active ingredient, and also contains: lactose, corn starch, crystalline cellulose, or another excipient; lowsubstituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, or another disintegrating agent; hydroxypropyl cellulose or another binder; and stearic acid salt or another lubricant.

Description

Title of Invention:

Tablet comprising 7-[4-(4benzo[b]thiophen-4-yl-pipera2in-1-yl)butoxy]-1H-quinolin-2-one or a sait thereof

Technical Field

The présent invention relates to a tablet comprising 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1 -yl)butoxy]-1 H-quinolin-2-one or a sait thereof as an active Ingrédient.

BaekgroundArt

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1 H-quinolin-2-one (hereunder referred to as Compound (I)) or a sait thereof is known to ad as a dopamine 1¾ reœptor partial agonist, a serotonin 5-ΗΤςα reœptor antagonist, and an a, adrenergic reœptor antagonist, as well as a serotonin uptake inhibitor (or a serotonin reuptake inhïbitor) (Patent Literature 1 ), and to possess a wide therapeutic spectrum in the treatment of central nervous System diseases (in particular, schizophrenia).

Citation List

Patent Literature

PTL1: Japanese Unexamined Patent Publication No. 2006-316052

Summary of Invention

Technical Problem

An objed of the présent invention is to provide a tablet comprising Compound (I) or a sait thereof as an active ingrédient and having excellent disintegration ability, storage stabiiity, and high photostability.

Solution to Problem

The présent inventors conducted intensive research to achieve the above objed

- 2 and found that a tablet comprising Compound (I) or a sait thereof as an active ingrédient and further comprising lactose, com starch, microcrystalline cellulose or like excipient; low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch or like disintegrant; and hydroxypropyl cellulose or like binderexhibits excellent disintegration abtlity and storage stability. The présent Inventera further found that higher photostability can be attained by applying a coating layer containing a colorant The présent invention was completed through further studies based on this finding, and provides the following items.

Item 1. A tablet comprising 7-{4-(4-benzo[b]thiophen-4-yl-piperaan-1-yl)butoxy]-1Hquinolin-2-one or a sait thereof as an active ingrédient

Item 2. The tablet according to Item 1, further comprising: an excipient (a), a binder (b), a disintegrant (c) and a lubricant (d), wherein the excipient (a) is at least one member selected from the group consisting of sugars, sugaralcohols, starches, and celluloses;

the binder (b) is a cellulose dérivative;

the disintegrant (c) is at least one member selected from the group consisting of cellulose dérivatives and starch dérivatives; and the lubricant (d) Is a stéarate.

Item. 3

The tablet according to Item 2, wherein the excipient (a) is at least one member selected from the group consisting of lactose, com starch, and microcrystailine cellulose;

the binder (b) is hydroxypropyl cellulose;

the disintegrant (c) is at least one member selected from the group consisting of lowsubstituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; and the lubricant (d) is magnésium stéarate.

Item 4. The tablet according to Item 2 or 3, wherein the tablet is an uncoated tablet comprising:

0.05 to 25% by weight of 7-{4-(4-benzo[b]thiophen-4-yl-piperaar>-1-yl)butoxy]-1 Hquinoün-2-one or a sait thereof;

to 98.5% by weight of the excipient (a);

0.1 to 20% by weight of the binder (b);

- 3 1 to 25% by weight of the dislntegrant (c); and

0.1 to 10% by weight of the lubricant (d), with respect to the weight of the uncoated tablet

Item 5. The tablet according to any one of Items 2 to 4, wherein per 1 part by weight of 7-[4-(4-benzo[b]thiophen-4-yl-piperazn-1-yl)butoxy]-1H-quinolin-2-one or a sait thereof, the tablet comprises:

to 2000 parts by weight of the excipient (a);

0.01 to 100 parts by weight of the binder (b);

0.1 to 500 parts by weight of the disintegrant (c): and

0.01 to 50 parts by weight of the lubricant (d).

Item 6. The tablet according to any one of Items 1 to 5, which further comprises a coating layer on the surfaoe thereof.

Item 7. The tablet according to Item 6, which further comprises the colorant (e) In the coating layer, wherein the colorant (e) contains an iron oxide, and the tablet contains 0.1 to 50% by weight of the colorant (e) with respect to the weight of the coating layer.

Item 8. The tablet according to any one of Items 1 to 7, which is obtained by forming, Into a tablet, a granulated substance obtained through wet granulation.

Item 9. The tablet according to any one of Items 1 to 8, wherein the tablet does not contain povidone or crospovidone.

Item 10. A method for produdng a tablet the method comprising the steps of:

(1) granulating a mixture containing 7-[4-(4-benzo[b]thiopherh4-yI-piperazin-1yl)butoxy]-1 H-quino!in-2-one or a sait thereof, an excipient (a), a binder (b), and a disintegrant (c), and further mixing thereto a lubricant (d); and (2) forming the obtained mixture into a tablet, wherein the excipient (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

the binder (b) is a cellulose dérivative;

- 4 the disintegrant (c) Is at least one member selected from the group consisting of cellulose dérivatives and starch dérivatives; and the lubricant (d) is a stéarate.

Item 11. The method for produdng the tablet according to Item 10, further comprising the step of:

(3) mixing a coating agent, a colorant (e), and a liquid medium to obtain a mixture, and coating the surface of the tablet using the mixture.

Advantageous Effects of Invention

The tablet of the présent invention exhibits excellent disintegration ability, storage stability, and high photostability, so that it can be effectively used In the medical field.

Brief Description of Drawings

Fig. 1 is a graph showing dissolution test results of tablets obtained in Examples 1-1 to 1 -3, and Examples 2-1 to 2-3.

Description of Embodiments

The tablet of the présent Invention comprises Compound (I) or a sait thereof as an active Ingrédient

Hère, the tablet of the présent invention may be an uncoated tablet having no coating layer applied thereon or a ooated tablet having a coating layer on the surface thereof. Furthermore, the tablet of the présent invention may be used as an orally disintegrating tablet

Compound (I) or a sait thereof can be produced by a known method, for example, that disclosed In Japanese Unexamlned Patent Publication No. 2006-316052 or a method based thereon.

Salts of Compound (i) are not particulariy limited as long as they are pharmacologically acceptable. Préférable exampies thereof Indude: métal salts such as alkali meta) salts (e.g., sodium salts and potassium salts), alkaline earth meta) salts (e.g., caldum salts and magnésium salts), salts of inorganic bases such as ammonium salts, alkali métal carbonates (e.g.,

- 5 lithium carbonate, potassium carbonate, sodium carbonate, and césium carbonate), alkali métal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), and alkali métal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and césium hydroxide); salts of organic bases such as tri(lower)alkylamines (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, qulnoline, piperidine, Imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., Nmethylmorpholine), 1,5-diazabÎcydo[4.3.0]non-5-ene(DBN), 1,8-diazabicydo[5.4.0]undeo-7-ene (DBU), 1,4-diazabicydo[2.2.2]octane (DABCO); salts of inorganic acids such as hydrochloride, hydrobromate, sulfate, nitrate, and phosphate; salts of organic acids such as formate, acetate, propionate, oxalate, mabnate, sucdnate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfbnate, ethanesulfonate, p-toluenesulfonate, and glutamate; and the like.

Compound (I) or a sait thereof ln the above forms may be used singly or ln a combination of two or more.

The content of Compound (I) or a sait thereof is preferably about 0.05 to 25% by weight, and more preferably about 0.1 to 15% by weight with respect to the weight of the tablet (the weight of an uncoated tablet before applying a coating when the tablet is a coated tablet).

The tablet of the présent invention preferably comprises additives such as an excipient (a), a binder (b), a disintegrant (c), and a lubricant (d).

Examples of excipients (a) Include, for example, sugar such as fructose, white soft sugar, sucrose, powdered sucrose, lactose, powdered hydrogenated maltose starch syrup, and maltose; sugar alcohois such as D-mannitol, D-sorbitol, xylitol, erythritol, maltitol; starch such as wheat starch, corn starch, and potato starch; starch dérivatives such as dextrin, beta-cydodextrin; cellulose or a dérivative thereof such as microcrystalline cellulose, powdered cellulose, ethyl cellulose, carboxymethyl cellulose (carmellose). sodium carboxymethyl cellulose (carmellose sodium), and mierocrystalline cellulose/carmellose sodium; silidc aad or a sait thereof such as light anhydrous silidc add, hydrated silicon dioxide, silicon dioxide, caldum silicate, magnésium silicate, and magnésium aluminometasilicate; kaolin; titanium oxide; magnésium oxide; talc; predpitated caldum carbonate; anhydrous dibasfc caldum phosphate.

These exdpients (a) may be used singly or ln a combination of two or more.

- 6 Among these, sugar, a sugar alcohol, starch, and cellulose are préférable, and lactose, microcrystalline cellulose and oom starch are more préférable.

The excipient (a) content is not particularty limited, and is preferably about 10 to 98.5% by weight with respect to the weight of the tablet (when the tablet is coated, the weight of the uncoated tablet), more preferably about 20 to 95%, and still more preferably about 30 to 90% by weight

The excipient (a) amount is not particularty limited, and is preferably about 1 to 2000 parts by weight per 1 part by weight of Compound (I) or a sait thereof, and more preferably about 3 to 1800 parts by weight

By setting the content and the amount of the excipient (a) as described above, the productivity can be improved.

Examples of the binder (b) indude sucrose; white soft sugar; pregelatinized starch; partialty pregelatinized starch; cellulose or a dérivative thereof such as microcrystalline cellulose, methyl cellulose, ethyi cellulose, sodium carboxymethyl cellulose (carmellose sodium), hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, kw-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromelloses such as hypromellose 2208, hypromellose 2906, and hypromellose 2910),; other polysaccharides such as acacia, powdered acacia, agar, powdered agar, guar gum, tragacanth, powdered tragacanth, pullulan, and pectin; aaylic add based polymer such as methacrytic add copolymer L, methacrytic add copolymer LD, methacrytic add copolymer S, ethyi acrylate-methyl méthacrylate copolymer dispersion, aminoalkyl méthacrylate copolymer E, and aminoalkyl méthacrylate copolymer RS; sodium alglnate; purified gelatin; hydrolyzed gelatin powder; carboxyvinyl polymer; copdyvidone; povidone; polyvinyl alcohol These binders (b) may be used singly or in a combination of two or more. Among these, a cellulose dérivative is préférable, and hydroxypropyl cellulose is more préférable. It should be noted that when povidone is contained as a binder (b), the obtaîned tablet tends to hâve reduced photostability and storage stability. Therefore, it is more préférable if this component is substantially not contained.

The binder (b) content is not particularty limited, and is preferably about 0.1 to 20% by weight with respect to the weight of the tablet (when the tablet is coated, the weight of the uncoated tablet), and more preferably about 0.5 to 5% by weight

- 7 The binder (b) amount Is not particulariy limited, and Is preferably about 0,01 to 100 parts by weight per 1 part by weight of Compound (I) or a sait thereof, and more preferably about 0.1 to 50 parts by weight By setting the content and amount of the binder (b) as described above, the productivity and désintégration ability can be Improved.

Examples of disintegrants (c) include starch or a dérivative thereof such as wheat starch, com starch, potato starch, partially pregelatinized starch, sodium carboxymethyl starch, and hydroxypropyl starch; cellulose or a dérivative thereof such as microcrystalline cellulose, carboxymethyl cellulose (carmellose), calcium carboxymethyl cellulose (carmellose calcium), croscarmellose sodium, and low-substituted hydroxypropyl cellulose; crospovidone; alginicadd; and bentonite. These disintegrants (c) may be used singly or in a combination of two or more. Among these, starch or a dérivative thereof, and cellulose or a dérivative thereof are préférable, and sodium carboxymethyl starch, carmellose calcium, croscarmellose sodium and low-substituted hydroxypropyl cellulose are more préférable, It should be noted that, when crospovidone is contained, the obtalned tablet tends to hâve reduced photostabllity and storage stability. Therefore, it is more préférable if this component Is substantially not contained.

Hère, in the présent spécification, “low-substituted hydroxypropyl cellulose is a dérivative of cellulose induding hydroxypropoxyl groups by about 5 to 16%. The amount of the hydroxypropoxyl groups in the low-substituted hydroxypropyl cellulose may be measured by a method listed In, for example, the Japanese Pharmacopeia. The low-substituted hydroxypropyl cellulose may be produced by a method known in the art, or a commerdally available product thereof may also be used. Examples of commerdally available products of the low-substituted hydroxypropyl cellulose include, but are not limited to, LH sériés and 'NBD sériés manufactured by Shin-Etsu Chemical Co., Ud.

Furthermore, in the présent spécification, hydroxypropyl cellulose’ is a dérivative of cellulose induding hydroxypropoxyl groups by about 50 to 85%. The amount of the hydroxypropoxyl groups in the hydroxypropyl cellulose may be measured by a method listed in, for example, the Japanese Pharmacopeia. The hydroxypropyl cellulose may be produced by a method known in the art, or a commerdally available product thereof may also be used. Examples of commerdally available products of the hydroxypropyl cellulose indude, but are not limited to, HPC sériés manufactured by Nippon Soda Co., Ltd.; and ’KJuœi sériés manufactured by Hercules Inc.

- 8 In the présent spécification, “sodium carboxymethyl starch is a dérivative of starch Including sodium about 6 to 11%.

The désintégrant (c) content is not particulariy limrted, and is preferably about 1 to 25% by welght with respect to the weight of the tablet (when the tablet is coated, the weight of the uncoated tablet), more preferably about 2 to 20% by weight, and still more preferably about 3 to 15% by weight

Furthermore, the disintegrant (c) amount Is not particulariy limited, and is preferably about 0.1 to 500 parts by weight per 1 part byweightof Compound (I) or a sait thereof, more preferably about 1 to 500 parts by weight and still more preferably about 1 to 250 parts by weight By setting the content and amount of the disintegrant (c) as described above, the disintegration ability can be improved.

Examples of lubricants (d) Include stearic add or a sait thereof such as stearic acid, aluminum stéarate, calcium stéarate, and magnésium stéarate; camauba wax; glycerol ester of fatty add; hydrogenated oil; yellow beeswax; white beeswax; talc; sodium steary! tumarate; and polyethylene glycol (macrogols such as macrogd 400, macrogol 600, macrogol 1500, macrogol 4000, and macrogol 6000). These lubricants (d) may be used singly or In a combination of two or more. Among these, stéarate, sucrose ester of fatty add, and hydrogenated oil are préférable, and magnésium stéarate Is more préférable.

The lubricant (d) content Is not particulariy limited, and is preferably about 0.1 to 10% by weig ht with respect to the weight of the tablet (when the tablet Is coated, the weight of the uncoated tablet), more preferably about 0.2 to 8% by weight, and still more preferably about 0.3 to 7% by weight

The lubricant (d) amount Is not particulariy limited, and is preferably about 0.01 to 50 parts by weight per 1 part by weight of Compound (I) or a sait thereof, and more preferably about 0.02 to 30 parts by weight By setting the content and amount of the lubricant (d) as described above, the tabletab'lity can be improved.

The tablet of the présent invention may comprise other components In addition to the exapient (a), the binder (b), the disintegrant (c), and the lubricant (d). Examples of other components include various additives applicable to tablets, such as colorants, pH adjusters,

- 9 preservatives, absorbefadents, faste enhancers, antioxidants, buffers, chelating agents, abrasives, solvents, hardening agents, surfactants, sweeteners, fluidizers, brightening agents, and flavors. Those components may be used in an amount that does not adversely affect the présent invention.

The tablet of the présent invention may be used as an uncoated tablet that comprises the above described components but does not hâve a coating layer provided thereon. A coated tablet (film-coated tablet) provided with a coating layer is préférable to achieve tong-term storage stabüity and prevent dégradation due to light or the like.

The coating layer may comprise pharmaceutical additives, such as a coating agent, plastidzer, dispersant, defoaming agent, and the like, usually used for coating (for providing a coat to) orally administrable pharmaceutical préparations.

Examples of additives include celluloses such as microcrystalline cellulose, methyl cellulose, ethyl cellulose, carmellose sodium, hydraxypropyl cellulose, and hydraxypropyl methyl cellulose (hypromeüose) and dérivatives thereof; polyethylene glycol (macrogol); polyvinyl aloohol; titanium oxide; and talc. These additives may be used singly or in a combination of two or more.

Among these, a combination of hydraxypropyl methy! cellulose (hypromeüose), talc, and titanium oxide, which are components for coating agent, is préférable. It should be noted that, when polyethylene glycol (macrogol) existe in the coating layer, the obtained tablet tends to hâve reduced photostability and storage sfability. Therefore, it is more préférable if polyethylene glycol (macrogol) is substantially not contained.

Furthermore, with regard to the coated tablet, by coloring the coating layer, photostability can be supplied to the ooated tablet Therefore, a colorant (e) Is preferably added to the coating agent for coating the tablet

Examples of ooforants (e) include: Iran oxides such as red ferrie oxide, yellow ferrie oxide, and black Iran oxide; titanium oxide; beta-caratene; food blue No. 2; food blue No. 2 aluminium lake; and riboflavin.

Among these, containing an iron oxide fc more préférable from a standpoint of not only adding a color to the tablet but also further improving photostability of the tablet

- 10 The colorant (e) may be suitably selected, or used In combination, depending on the color of the coated tablet prepared. For example, to obtain a white coated tablet, titanium oxide is used; to obtain a red coated tablet, a combination of titanium oxide and red ferrie oxide is used; to obtain a yellow coated tablet, a combination of titanium oxide and yellow ferrie oxide Is used; to obtain a blue coated tablet, a combination of titanium oxide and food blue No. 2 aluminium lake is used; to obtain an orange coated tablet, a combination of titanium oxide, red ferrie oxide, and yellow ferrie oxide is used; to obtain a green coated tablet, a combination of titanium oxide, yellow ferrie oxide, and black Iran oxide, or a combination of titanium oxide, yellow ferrie oxide and food blue No. 2 aluminium lake is used; and to obtain a purpie coated tablet, a combination of titanium oxide, red ferrie oxide and black iron oxide, or a combination of titanium oxide, red femc oxide and food blue No. 2 aluminium lake is used. As described above, a coated tablet may be made into various cotors.

The colorant (e) content is preferably about 0.1 to 3% by weight with respect to the total weight of the coated tablet, and about 5 to 50% by weight with respect to the weight of the coating layer of the coated tablet

The amount of a coating layer in tablet that is coated using the coating agent and a colorant (e) that is contained if necessary is preferably about 1 to 10 parts by weight per 100 parts by weight of a tablet (uncoated tablet) before having a coating provided thereon.

Spécifie préférable examples of the additives contained in the tablet of the présent Invention indude:

as an excipient (a), at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

as a binder (b), cellulose dérivatives;

as a disintegrant (c), at least one member selected from the group consisting of cellulose dérivatives and starch dérivatives; and, as a lubricant (d), stéarates.

From a standpoint of productwty and disintegration abilîty, these additives are preferably used In a combination of: as an excipient (a), at least one member selected from the group consisting of lactose, corn starch, and microcrystalline cellulose; as a binder (b), hydroxypropyl cellulose; as a disintegrant (c), at least one member selected from the group consisting of lowsubstituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; and, as a lubricant (d), magnésium stéarate.

The tablet ofthe présent invention preferably contains each ofthe components In the content and amount shown below.

Content of each of the Components In the Tablet

Compound (I) or a sait thereof:

0.05 to 20% by weight

Sugar and/or sugar alcohol: 20 to 80% by weight Starch: 5 to 50% by weight

Cellulose: 1 to 30% by weight

Hydroxypropyl cellulose: 0.1 to 20% by weight

At least one member selected from the group consisting of bw-substituted hydroxypropyl cellulose, cnoscaimellose sodium, and starch dérivatives:

to25% by weight

0.1 to 10% by weight

Stéarate:

to 1000 parts by weight to 400 parts by weight

0.1 to 200 parts by weight

0.01 to 100 parts by weight

Amount of each of the Components In the Tablet per 1 part by weight of Compound (I) or a Sait thereof

Sugar and/or sugar alcohol:

Starch:

Cellulose:

Hydroxypropyl cellulose:

At least one member selected from the group consisting of bw-substituted hydroxypropyl cellulose, croscarmellose sodium, and starch dérivatives:

0.1 to 500 parts by weight

0.01 to 50 parts by weight

Stéarate:

The content and amount of each ofthe components in a further préférable mode of the tablet ofthe présent invention are shown below.

Content of each ofthe Components in the Tablet Compound (I) or a sait thereof·.

Lactose:

0.1 to 15% by weight 30 to 60% by weight

10to 30% by weight 5to20% by weight 0.5 to 10% by weight

Comstarch:

Microcrystalline cellulose: Hydroxypropyi cellulose:

At least one member selected from the group consisting of low-substituted hydroxypropyi cellulose, croscarmellose sodium, and sodium carboxymethyl starch:

2to 15% by weight

0.1 to 10% by weight

Magnésium stéarate:

to 500 parts by weight to 200 parts by weight

0.5 to 100 parts by weight

0.05 to 50 parts by weight

Amount of each of the Components in the Tablet per 1 Part by Weight of Compound (i) or a Sait Thereof Lactose: Comstarch: Microcrystalline cellulose: Hydroxypropyi cellulose:

to 250 parts by weight

0.05 to 30 parts by weight

Magnésium stéarate:

When the tablet of the présent Invention is a coated tablet, préférable examples of the additives contained in the coated tablet include, as the components for an uncoated tablet before coating:

as a binder (b),cellulose dérivatives;

as a disintegrant (c), at least one member selected from the group consisting of cellulose dérivatives and starch dérivatives; and as a lubricant (d), stéarates, and as components for the coating layer cellulose dérivatives, talc, titanium oxides and iron oxides as colorant (e).

Furthermore, when the tablet of the présent invention is a coated tabiet, a more préférable combination is a formulation obtained by applying a coating layer on an uncoated tablet in which, the uncoated tablet contains Compound (I) or a sait thereof, lactose, com starch, microcrystalline cellulose, low-substituted hydraxypropyl cellulose, hydraxypropyl cellulose, and

- 13 magnésium stéarate, and the coating layer contains hypromellose, talc, titanium oxide, and at least one colorant (e) (iron oxide) selected from the group consisting of red ferrie oxide, yellow ferrie oxide, and black iron oxide.

The préférable content and amount of each of the components, and further préférable content and amount of each of the components in a préférable mode of the coated tabiet are shown bebw.

Content of each of the Components in the Uncoated Tabiet

Compound (I) or a sait thereof.	0.05 to 20% by weight
Sugar and/or sugar aloohol:	20 to 80% by weight
Starch:	5 to 50% by weight
Cellulose:	1 to 30% by weight
Hydroxypropyl cellulose:	0.1 to 20% by weight

At least one member selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, and starch dérivatives:

	1 to 25% by weight
Stéarate:	0.1 to 10% by weight

Content of each of the Components in the Coating Layer (per entire coated tabiet)

Cellulose dérivative:	1 to 6% by weight
Talc:	0.1 to 1% by weight
Titanium oxide:	0.1 to 2% by weight
Iron oxide:	0.01 to 1% by weight

Amount of each of the Components in the Coated Tabiet per 1 part by weight of Compound (I) or a Sait thereof

Lactose:	1 to 1000 parts by weight
Starch:	1 to 400 parts by weight
Cellulose:	0.1 to 200 parts by weight
Hydroxypropyl cellulose:	0.01 to 100 parts by weight

0.1 to 500 parts by weight

Stéarate: Hypromellose: Talc:

Titanium oxide:

Iran oxide:

- 14 0.01 to 50 parts by weight

0.1 to 50 parts by weight

0.01 to 10 parts by weight

0.01 to 20 parts by weight

0.0005 to 5 parts by weight

The content and amount of each of the components in a further préférable mode of the coated tablet are shown below.

Content of each of the Components ln the Unooated Tablet

Compound (I) or a sait thereof:

Lactose:

Comstanch:

Microaystalllne cellulose:

Hydroxypropyl cellulose:

0.1 to 15% by weight 30to60% by weight 10to 30% by weight 5to20%byweight

0.5 to 10% by weight

At least one member selected from the group consisting of (ow-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl stanch:

2to15%byweight

Magnésium stéarate:

0.1 to 10% by weight

Content of each of the Components ln the Coating Layer (per entire coated tablet) Hypromellose: 1.5 to 4% by weight

5 Talc: 0.2 to 0.5% by weight

Titanium oxide: 0.2 to 1% by weight

Iran oxide: 0.02 to 0.5% by weight

Amount of each of the Components ln the Coated Tablet per 1 part by weight of Compound (I) or a Sait thereof

Lactose:

Comstanch: Microcrystalline cellulose: Hydroxypropyl cellulose:

to 500 parts by weight to 200 parts by weight

0.5 to 100 parts by weight

0.05 to 50 parts by weight

At least one member selected from the group consisting of bw-substituted hydroxypropyl

- 15 cellulose, croscarmenose sodium, and sodium carboxymethyl starch:

Magnésium stéarate: Hypromellose: Talc:

Titanium oxide:

Iran oxide:

to 250 parts by weight

0.05 to 30 parts by weight

0.2 to 40 parts by weight

0.02 to 8 parts by weight

0.02 to 15 parts by weight

0.001 to 2.5 parts by weight

The method for produdng the tablet of the présent invention is not particularty limited; for example, the tablet of the présent invention can be produced by a step of forming into a tablet a mixture containing Compound (I) or a sait thereof, and components other than Compound (I) or a sait thereof necessary to form a tablet (Le., an excipient (a), a binder (b), a disintegrant (c), a lubricant (d) and the like). Altematively, the tablet of the présent invention can be produced by the method comprising: granulating a mixture containing Compound (I) or a sait thereof, an excipient (a), a binder (b), and a disintegrant (c), and further mixing thereto a lubricant (d); and forming the obtained mixture into a tablet

The granulation method used for forming the granulated substance into a tablet is not particulariy limited. Examples thereof indude dry granulation methods and wet granulation methods (e.g., a fluidized-bed granulation method, and a knead-granulation method). Among these, wet granulation methods are preferably used for the production, from a standpoint of being able to unifbrmly mix the active Ingrédient and other components in the tablet, and being able to obtain a tablet whose components are uniformly distributed therein.

Examples of the tablet forming methods indude tableting, such as direct compression tableting, dry tableting, wet tableting, and extemal lubrication tableting.

The coated tablet of the présent Invention can be produced by mixing a coating agent, a colorant (e), and a liquid medium; spraying the obtained liquid mixture on the surface of the uncoated tablet obtained by the method described above; and successively drying it

Examples of the liquid medium (e.g., a dispersion medium) used in the above described step Indude: water; methanol, éthanol, Isopropanol, and like lower alcohols; acetone, methyl ethyl ketone, and like ketones; dichloromethane, dichloroethane, chloroform, carbon

- 16 tetrachloride and like halogenated hydrocarbons; and mixtures of these solvents.

The tablet of the présent invention preferably comprises Compound (I), which is an active Ingrédient, or a sait thereof In an amount of about 0.05 to 25 mg calculated as Compound (I).

The dose of the tablet of the présent invention is suitably selected according to the Intended use; the patients âge, sex, and other conditions; the severity of the disease; and the like. The dose is preferably selected so that the amount of Compound (I) (Le., the active Ingrédient) or a sait thereof taken is about 0.05 to 6 mg per day calculated as Compound (I).

Examples

The présent invention is explained In detail below with référencé to Examples. However, the scope of the présent Invention is not limited to these Examples. Note that In all of the Examples described below, Compound (I) was “7-{4-(4-benzo[b]thiophen-4-yLpÎperazin-1-yl)butoxy]1H-quinolin-2-one.

Example 1

Uncoated tablets (a tablet not provided with a ooating layer) of Compound (I) were produced using the components and amounts shown in Table 1, by foilowing the procedures described below.

Example 1-1

Compound (I), lactose, com starch, microcrystalline cellulose (CEOLUS PH-301), and low-substituted hydroxypropyfcellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxyprepoxyl groups content 10.0 to 12.9%) were weighed and mixed. A separately prepared aqueous solution of hydroxypropylcellulose was added to the powder mixture, followed by wet kneading granulation. After drying and stang the resuit, magnésium stéarate was added thereto and mixed. The resulting mixture was compressed using a single tableting machine equipped with a punch of diameter 6.5 mm in such a manner that the weight of the tablet bécarre 100 mg, obtaining uncoated tablets containing 10 mg of Compound (I) per tablet

Example 1-2

Compound (I), lactose, com starch, microcrystalline cellulose, and croscarmellose sodium were weighed and mixed. A separately prepared aqueous solution of

- 17 hydroxypropylcellulose was added to the powder mixture, followed by wet kneading granulation. After drying and sizîng the resuit, magnésium stéarate was added thereto and mixed. The resulting mixture was compressed using a single tableting machine equipped with a punch of diameter 6.5 mm in such a mannerthat the weight of the tablet became 100 mg, obtaining uncoated tablets containing 10 mg of Compound (I) per tablet

Example 1-3

Compound (I), lactose, com starch, microcrystalline cellulose, and sodium carboxymethyl starch were weighed and mixed. A separately prepared aqueous solution of hydroxypropylcellulose was added to the powder mixture, followed by wet kneading granulation. After drying and sizing the resuit magnésium stéarate was added thereto and mixed. The resulting mixture was compressed using a single tableting machine equipped with a punch of diameter 6.5 mm in such a manner that the weight of the tablet became 100 mg, obtaining uncoated tablets containing 10 mg of Compound (I) per tablet

Table 1

Components (mg)	Example 1-1	Example 1-2	Example 1-3
Compound (I)	10.0	10.0	10.0
Lactose	48.2	53.2	53.2
Com starch	20.0	20.0	20.0
Microcrystalline cellulose	10.0	10.0	10.0
Low-substituted hydroxypropylcellulose	10.0	-	-
Croscarmellose sodium	-	5.0	-
Sodium carboxymethyl starch	-	-	5.0
Hydroxypropylcellulose	1.0	1.0	1.0
Magnésium stéarate	0.8	0.8	0.8
Weight of uncoated tablet (mg)	100.0	100.0	100.0

Table 2 shows the tablet properties of uncoated tablets obtained in Examples 1-1 to 13.

- 18 Table 2

Tablet properties	Example 1-1	Example 1-2	Example 1-3
Hardness (Kp, n=3)	5.4	5.6	4.7
Thickness (mm, n=3)	2.78	2.77	2.82
Disintegration time (mm:ss, n=6)	1:18-1:36	2:00-2:16	1:09-1:35

The measurementof disintegration time (disintegration test) results show the measurement results of six tablets of each Example. The test was performed using water as a test 5 Iiquid according to the disintegration test of the Japanese Pharmacopeia (without an auxiliary disk).

Examples 2-1 to2-3

The uncoated tablets produced in Examples 1-1 to 1-3 each having a weight of 100 mg and containing 10 mg of Compound (I) were subjected to coating by spraying a coating Iiquid 10 comprising the coating layer components whose amounts are shown in Table 3 thereby obtaining coated tablets.

Table 3

Components (mg)	Example 2-1	Example 2-2	Example 2-3
Uncoated tablet	Example 1-1	Example 1-2	Example 1-3
Weight of uncoated tablet (mg)	100.0	100.0	100.0
Coating layer (mg)
Hypromellose	2.07	2.07	2.07
Macrogol 6000	0.30	0.30	0.30
Talc	0.30	0.30	0.30
Titanium oxide	0.30	0.30	0.30
Yellow ferrie oxide	0.03	0.03	0.03
Weight of coating layer (mg)	3.0	3.0	3.0
Weight of coated tablet (mg)	103.0	103.0	103.0

- 19 Measurements of disintegration time (disintegration tests) were performed for the coated tablets produced in Examples 2-1 to 2-3 in the same manner as in Example 1-1. Table 4 shows the resufts. No delay in disintegration time due to coating was observed in the coated tablets produced h Examples 2-1 to 2-3.

Table 4

	Example 2-1	Example 2-2	Example 2-3
Disintegration time (mm:ss, n=6)	1:35-1:50	2:22-2:40	1:26-1:44

Dissolution tests were performed for the uncoated tablets produced In Examples 1-1 to 1-3. and the coated tablets produced in Examples 2-1 to 2-3. Fig. 1 shows the results.

The dissolution test results show the average values of the measurement resufts of two tablets of each Example. The dissolution test was performed in accordance with the dissolution test method (paddle method; 50 rpm) of the Japanese Pharmacopoeia, using a disodium hydrogenphosphate-citric acid buffer solution (900 mL) with pH 4.5 as a test liquid.

The dissolution test results confimn excellent dissolution profiles of the uncoated tablets produced h Examples 1-1 to 1-3 and the coated tablets produced in Examples 2-1 to 2-3.

Furthermore, a stability test was performed for the uncoated tablets produced in Examples 1-1 to 1-3 and the coated tablets produced in Examples 2-1 to 2-3 under the storage conditions of fight irradiation (visible light total illuminance of 1.8 x 10⁶ lux hr, ultraviolet light total intensityof300 W· hr/m²) and a dosed system at 40°C (sealed in bottles forone month orthree months). The contents of Compound (I) and Impurity after the storage in each condition were measured. Table 5 shows the results.

Note that after the storage under the above fight irradiation conditions, yellow coloring was observed in the uncoated tabiets produced in Exampies 1-1 to 1-3.

- 20 Tables

Example No.	1-1	1-2	1-3	2-1	2-2	2-3
	Contents of Compound (I) (%, n=3)
Initial	98.1	99.4	99.7	99.6	101.5	101.9
Ught Irradiation	98.3	99.3	99.8	100.0	101.7	102.3
4O’C-1 month	99.6	101.4	100.8	102.2	103.5	103.4
40^eC-3 months	98.0	100.5	100.0	100.1	102.8	103.5
	Content of impurity (%, n=1 )
Initial	0.365	0.362	0.371	0.373	0.367	0.374
Ught Irradiation	0.662	0.634	0.592	0.477	0.500	0.463
40^eC-1 month	0.354	0.378	0.376	0.370	0.393	0.411
40^eC—3 months	0.409	0.373	0.401	0.385	0.409	0.419

Example 3-1

Using the components and amounts shown In Table 6, uncoated tablets containing

0.25 mg of Compound (I) per tablet were produced In the same manner as In Example 1-1, except that a rotary tableting machine equipped with a punch of diameter 6.0 mm was used to obtain uncoated tablets each having a weight of 90 mg.

Table6

Components (mg)	Example 3-1
Compound (I)	0.25
Lactose	48.15
Com starch	20.0
Microcrystalline cellulose	10.0
Low-substituted hydroxypropylcellulose	10.0
Hydroxypropylcellulose	1.0
Magnésium stéarate	0.6
Weight of uncoated tablet (mg)	90.0

Examples 3-2 to 3-9

- 21 The uncoated ta blets produced In Example 3-1 each having a weight of 90 mg and containing 0.25 mg of Compound (1) were subjected to coating by spraying a coating liquid comprising the coating layer components whose amounts are shown in Table 7 thereby obtaining coated tablets.

Table 7

Example No.	3-2	3-3	3-4	3-5	3-6	3-7	3-8	3-9
Uncoated tablet	Example 3-1
Weight of uncoated tablet (mg)	90.0
Coating layer (mg)
Hypromellose	1.8	2.1	1.8	2.1	1.8	2.1	1.8	2.1
Macrogd6000	0.3	-	0.3	-	0.3	-	0.3	-
Talc	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3
Titanium oxide	0.6	0.6	0.54	0.54	0.54	0.54	0.54	0.54
red ferrie oxide	-	-	0.06	0.06	-	-	-	-
Yellcw ferrie oxide	-	-	-	-	0.06	0.06	-	-
Food blue No. 2
Aluminium lake (3-5%)	-	•	*	*	*	•	0.06	0.06
Weight of coating layer (mg)	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
Weight of coated tablet (mg)	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0

Furthermore, a stability test was performed for the uncoated tablets produced in Example 3-1 and the coated tablets produced in Examples 3-2 to 3-9 under the storage conditions of 10 light irradiation (visible fight total illuminance of 1.8 x 10^e lux hr; ultraviolet îight total intensîty of 300 W-hr/m²) and an open system at 40’C/75% RH (three months, six months), i.e., conditions as or more severe as those of Examples 1-1 to 1-3 and Examples 2-1 to 2-3. The contents of impurity after the storage in each condition were measured. Table 8 shows the results.

No increase in impurity was observed in the tablets of Examples 3-5 and 3-7, even after the light irradiation.

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- 23 Examples 4-1 to4-13

Coated tablets of Compound (I) of Examples 4-1 to 4-13 that comprise the components and amounts shown ln Table 9 were produced ln the same manner as ln Example 3-2.

Table 9

Components (mg)	Example No.
4-1	4-2	4-3	4-4	4-5	4-6	4-7	4-8	4-9	4-10	4-11	4-12	4-13
Compound (!)	0.05	0.25	0.5	1.0	2.0	3.0	4.0	5.0	6.0	0.25	0.25	0.25	1.0
Lactose	48.35	48.15	47.9	47.4	46.4	45.4	44.4	43.4	42.4	48.15	48.15	48.15	47.4
Corn starch	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0	20.0
Microcrystalline cellulose	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0
Low-substituted hydroxypropylcellulose	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	10.0	. 10.0
Hydroxypropylcellulose	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0
Magnésium stéarate	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6
Weight of uncoated tablet (mg)	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0	90.0
Hypromellose	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1	2.1
Talc	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3
Titanium oxide	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.54	0.57
Red ferrie oxide	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06	-	-	0.02	0.01
Yellow ferrie oxide	-	-	-	-	-	-	-	-	-	-	0.04	-	-
Black iron oxide	-	-	-	-	-	-	-	-	-	0.06	0.02	0.04	0.02
Weight of coating layer (mg)	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
Weight of coated tablet ima)	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93.0	93. 0

- 25 Industrial Applicabîlity

The tablet of the présent Invention comprising benzothiophen compound (I) or a sait thereof has excellent désintégration abilîty, storage stability, and photostabillty. Therefore, the tablet of the présent Invention is hîghly usable in the medical field.

Claims

[Claim 1]

A tabiet comprising 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1yl)butoxy]-1H-quinolin-2-one or a sait thereof as an active Ingrédient.
[Claim 2]

The tabiet according to claim 1, further comprising:

an excipient (a), a binder (b), a disintegrant (c) and a lubricant (d), wherein the excipient (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

the binder (b) is a cellulose dérivative;

the disintegrant (c) is at least one member selected from the group consisting of cellulose dérivatives and starch dérivatives; and the lubricant (d) is a stéarate.

[Ciaim 3]

The tabiet according to claim 2, wherein the excipient (a) is at least one member selected from the group consisting of lactose, com starch, and microcrystalline cellulose;

the binder (b) is hydroxypropyl cellulose;

the disintegrant (c) is at least one member selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; and the lubricant (d) is magnésium stéarate.

[Claim 4]

The tabiet according to claim 2 or 3, wherein the tabiet is an uncoated tabiet comprising:

0.05 to 25% by weight of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1yl)butoxy]-1H-quinolin-2-one or a sait thereof;

10 to 98.5% by weight of the excipient (a);

0.1 to 20% by weight of the binder (b);

1 to 25% by weight of the disintegrant (c); and

0.1 to 10% by weight of the lubricant (d), with respect to the weight of the uncoated tabiet.

- 27 [Claim 5]

The tablet according to any one of daims 2 to 4, wherein per 1 part by weight of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a sait thereof, the tablet comprises:

1 to 2000 parts by weight of the excipient (a);

0.01 to 100 parts by weight of the binder (b);

0.1 to 500 parts by weight of the disintegrant (c); and

0.01 to 50 parts by weight of the lubricant (d).

[Claim 6]

The tablet according to any one of clalms 1 lo3, which further comprises a coating layer on the surface thereof.

[Claim 7]

The tablet according to claim 6, which further comprises the colorant (e) in the coating layer, wherein the colorant (e) contains an Iron oxide, and the tablet contains 0.1 to 50% by weight of the colorant (e) with respect to the weight of the coating layer.

[Claim 8]

The tablet according to any one of clalms 1 to 7, which is obtained by forming, into a tablet, a granulated substance obtained through wet granulation.

[Claim 9]

The tablet according to any one of claims 1 to 8, wherein the tablet does not contaln povidone or crospovidone.

[Claim 10]

A method for producing a tablet, the method comprising the steps of:

(1) granulating a mixture containing 7-[4-(4-benzo[bIthiophen-4-y1· ρΐρβΓ3ζίη-1-νΙ)ϋυΙοχγ]-1Η·ςυίποΙΐη-2-οηθ or a sait thereof, an excipient (a), a binder (b), and a disintegrant (c), and further mixing thereto a lubricant (d); and (2) forming the obtained mixture into a tablet,

- 28 wherein the excipient (a) is at least one member selected from the group consisting of sugars, sugar alcohols, starches, and celluloses;

the binder (b) is a cellulose dérivative;

the disintegrant (c) is at least one member selected from the group 5 consisting of cellulose dérivatives and starch dérivatives; and the lubricant (d) Is a stéarate.

[Claim 11]

The method for producing the tablet according to claim 10, further

10 comprising the step of:

(3) mixing a coating agent, a colorant (e), and a liquid medium to obtain a coating mixture, and coating the surface of the tablet using the coating mixture.