TABLET

Provided is a tablet showing improved hygroscopicity, which contains, as a pharmaceutically active ingredient, a compound showing deliquescence at a relative humidity of not less than 80% at 25 degrees C. A tablet containing a compound showing deliquescence at a relative humidity of not less than 80% at 25 degrees C. and an additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25 degrees C. of not less than 7 wt % relative to its dry weight.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a tablet comprising a compound showing deliquescence at a relative humidity of not less than 80% at 25° C. and an additive showing an equilibrium moisture absorption rate at a relative humidity of 75% at 25° C. of not less than 7 wt % relative to its dry weight.

BACKGROUND OF THE INVENTION

Patent document 1 (WO2009/154300) describes 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide and a salt thereof, which have a renin inhibitory action and are useful as prophylactic or therapeutic agents for hypertension or various organ disorders caused by hypertension and the like.

Patent document 2 (WO2011/158880) improves hygroscopicity of 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride by crystallizing the compound.

Patent document 3 (WO2010/013823) improves stability of a nonpeptidic compound having a primary or secondary amino group, which is contained as a pharmaceutically active ingredient in a tablet, by adding an acidic compound such as organic acid and the like.

Patent document 4 (JP-A-2008-94845) improves the shelf-life stability and resistance to degradation of a tablet containing a purine compound as a pharmaceutically active ingredient by adding, as excipients, a ductile filler and/or a brittle filler and a disintegrant, and forming a light-protective layer on the tablet.

Patent document 5 (JP-A-H11-243907) improves hardness and hygroscopicity of a tablet containing xylitol, by directly compressing a xylitol powder coated with a lipid, which lipid is solid at room temperature, and producing the tablet.

DOCUMENT LIST

Patent Documents

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

When a “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is used as a pharmaceutically active ingredient, a tablet which is easily produced and handled, and can be preserved for a long term can be provided once the hygroscopicity of the compound is improved or reduced.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that addition of “an additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” to a tablet containing “a compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” as a pharmaceutically active ingredient improves (reduces) hygroscopicity of the compound, which resulted in the completion of the present invention.

Accordingly, the present invention relates to

[1] a tablet comprising a compound showing deliquescence at a relative humidity of not less than 80% at 25° C. and an additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight;
[2] the tablet of the above-mentioned [1], wherein the compound has a secondary amine;
[3] the tablet of the above-mentioned [1], wherein the compound is represented by the formula (I):

wherein
R1is a hydrogen atom, an alkyl group optionally having substituent(s), an alkenyl group optionally having substituent(s), or a cycloalkyl group optionally having substituent(s);
X is absent, or a hydrogen atom, an alkyl group optionally having substituent(s) or a cycloalkyl group optionally having substituent(s);
ring A is a heterocycle optionally having substituent(s); ring B is a 5- to 7-membered, nitrogen-containing heterocycle optionally having substituent(s); and
n is 0, 1 or 2 (hereinafter sometimes to be abbreviated as “Compound (I)” which includes compound (A) to be described later),
or a salt thereof;
[4] the tablet of the above-mentioned [1], wherein the compound is 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide (hereinafter sometimes to be abbreviated as “compound (A)”) or a salt thereof;
[5] the tablet of the above-mentioned [4], wherein the 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide or a salt thereof is 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride;
[6] the tablet of the above-mentioned [1], wherein the additive comprises crystalline cellulose and low-substituted hydroxypropylcellulose;
[7] the tablet of the above-mentioned [6], wherein the content of the crystalline cellulose is 30 wt % or more of one tablet;
[8] the tablet of the above-mentioned [6], wherein the content of the low-substituted hydroxypropylcellulose is 5 wt % or more of one tablet;
[9] the preparation of the above-mentioned [1], wherein the content of the additive is 35 wt % or more of one tablet;
[10] the tablet of the above-mentioned [6], wherein the content of the crystalline cellulose is 30 wt % or more of one tablet, and the content of the low-substituted hydroxypropylcellulose is 5 wt % or more of one tablet;
[11] a tablet comprising the following (i)-(iii):
(i) 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide or a salt thereof,
(ii) not less than 30 wt % of crystalline cellulose in the tablet (of the weight of one tablet), and
(iii) not less than 5 wt % of low-substituted hydroxypropylcellulose in the tablet (of the weight of one tablet);
[12] the tablet of the above-mentioned [11], wherein 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide or a salt thereof is 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride;
and the like.

Effect of the Invention

According to the present invention, a tablet containing a compound showing deliquescence at a relative humidity of not less than 80% at 25° C. as a pharmaceutically active ingredient, which shows improved (reduced) hygroscopicity of the compound, can be easily produced and handled, and can be stably preserved for a long term, can be provided.

According to the present invention, a tablet containing a compound showing deliquescence at a relative humidity of not less than 80% at 25° C. as a pharmaceutically active ingredient, which is stable and shows no change in the dissolution property even under high humidity, can be provided.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, the “relative humidity” is a ratio in percentage of water vapor pressure at a given temperature to saturated water vapor pressure at said temperature.

In the present specification, the “equilibrium moisture absorption rate” is a ratio in percentage of an increase in the weight of a sample when it absorbed moisture at a given relative humidity at a given temperature and reached equilibrium, to the weight of the sample when dried completely (dry weight).

In the present specification, the “deliquescence” means the property of a solid to be a liquid as a result of dissolution into the absorbed water vapor in the air.

In the present specification, “high humidity” means relative humidity of not less than 75%.

In the present specification, the “dissolution property” means the property of a pharmaceutically active ingredient to dissolve from the preparation into a solution. The dissolution property can be evaluated by, for example, the Dissolution Test Method (e.g., rotating basket method, Paddle Method) described in the Japanese Pharmacopoeia 16th Ed.

Examples of the “halogen atom” in the present specification include fluorine, chlorine, bromine and iodine.

Examples of the “C1-4alkylenedioxy group” in the present specification include methylenedioxy, ethylenedioxy, trimethylenedioxy and the like.

Examples of the “cycloalkyl” moiety of the “cycloalkyloxy group” in the present specification include those similar to the above-mentioned “cycloalkyl group”.

Examples of the “C1-6alkoxy-carbonyl group” in the present specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.

Examples of the “C1-6alkyl-carbonyl group” in the present specification include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like.

The “optionally halogenated” in the present specification means being optionally substituted by 1 to 5, preferably 1 to 3 halogen atoms.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” in the present specification include an alkyl group, an alkenyl group, an alkynyl group, an alkylidene group, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group, an aryl group, an aralkyl group, an arylalkenyl group, a cycloalkylalkyl group and the like. Preferable examples include a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-3alkylidene group, a C3-10cycloalkyl group, a C3-10cycloalkenyl group, a C4-10cycloalkadienyl group, a C6-14aryl group, a C7-16aralkyl group, a C8-13arylalkenyl group, a C3-10cycloalkyl-C1-6alkyl group and the like. The above-mentioned C3-10cycloalkyl group, C3-10cycloalkenyl group and C4-10cycloalkadienyl group may be each condensed with a benzene ring.

Examples of the “C1-3alkylidene group” in the present specification include methylidene, ethylidene, propylidene, isopropylidene and the like.

Examples of the “C3-10cycloalkyl group” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like. Among these, a C3-6cycloalkyl group is preferable. The above-mentioned C3-10cycloalkyl may be condensed with a benzene ring, and examples of the fused group include indanyl, tetrahydronaphthyl, fluorenyl and the like.

Examples of the “C3-10cycloalkenyl group” in the present specification include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. The above-mentioned C3-10cycloalkenyl may be condensed with a benzene ring, and examples of the fused group include indenyl and the like.

Examples of the “C4-10cycloalkadienyl group” in the present specification include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. The above-mentioned C4-10cycloalkadienyl may be condensed with a benzene ring.

Examples of the “C6-14aryl group” in the present specification include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, a C6-10aryl group is preferable, and phenyl is more preferable. The above-mentioned C6-14aryl may be condensed with C3-10cycloalkane (examples of the C3-10cycloalkane include a ring corresponding to the above-mentioned C3-10cycloalkyl group), and examples of the fused group include tetrahydronaphthyl, indanyl and the like.

Examples of the “C7-16aralkyl group” in the present specification include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.

Examples of the “C8-13arylalkenyl group” in the present specification include styryl and the like.

Examples of the “C3-10cycloalkyl-C1-6alkyl group” in the present specification include cyclopropylmethyl, cyclohexylmethyl and the like.

The “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is two or more, respective substituents may be the same or different.

Examples of the “substituent” of the “hydrocarbon group optionally having substituent(s)” include the following substituents (hereinafter to be referred to as substituent group A).

Examples of the “3- to 10-membered cyclic hydrocarbon group” of the “3- to 10-membered cyclic hydrocarbon group optionally having substituent(s)” for substituent group A include C3-10cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkadienyl group, C6-10aryl group and the like. Examples of the C3-10cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkadienyl group and C6-10aryl group include those similar to the C3-10cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkadienyl group and C6-10aryl group exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)”.

Examples of the “3- to 10-membered heterocyclic group” of the “3- to 10-membered heterocyclic group optionally having substituent(s)” for substituent group A include a 3- to 10-membered ring from the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” to be mentioned later.

Examples of the “substituent” of the “alkyl group optionally having substituent(s)” and “alkoxy group optionally having substituent(s)”, “3- to 10-membered cyclic hydrocarbon group optionally having substituent(s)” and “3- to 10-membered heterocyclic group optionally having substituent(s)” for substituent group A include 1 to 5, preferably 1 to 3 selected from the following substituents (hereinafter to be referred to as substituent group B). When the number of the substituents is two or more, the respective substituents may be the same or different.

Examples of the “substituent” of the “amino group optionally having substituent(s)” for substituent group A include 1 or 2 selected from substituent group B. When the number of the substituents is two, the respective substituents may be the same or different.

Examples of the “substituent” of the “mercapto group optionally having a substituent” for substituent group A include substituent group B. The mercapto group may be oxidized by 1 or 2 oxygens.

Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” in the present specification include an aromatic heterocyclic group and a nonaromatic heterocyclic group.

Examples of the “aromatic heterocyclic group” include a 4- to 10-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 10-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.

Examples of the “non-aromatic heterocyclic group” include a 3- to 10-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group. Examples of the fused non-aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 3- to 10-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, a 5-membered heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.

The above-mentioned “heterocyclic group” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is two or more, the respective substituents may be the same or different.

Examples of the “substituent” of the “heterocyclic group optionally having substituent(s)” include the groups exemplified as the aforementioned substituent group A and the like.

Examples of the “acyl group” in the present specification include groups represented by the formulas: —CORA, —CO—ORA, —SO2RA, —SORA, —CO—NR′R′, —CS—NR′R″ wherein RAis a hydrogen atom, a hydroxy group, a hydrocarbon group optionally having substituent(s), an amino group optionally having substituent(s) or a heterocyclic group optionally having substituent(s). R′ and R″ are each a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), or R′ and R″ form, together with the nitrogen atom bonded thereto, a nitrogen-containing heterocycle optionally having substituent(s), and the like.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” for RA, R′ or R″ include those similar to the “hydrocarbon group” of the aforementioned “hydrocarbon group optionally having substituent(s)”.

Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” for RA, R′ or R″ include those similar to the “heterocyclic group” of the aforementioned “heterocyclic group optionally having substituent(s)”.

Examples of the “amino group optionally having substituent(s)” for RAinclude those similar to the “amino group optionally having substituent(s)” of the aforementioned substituent group A.

Examples of the substituent of the “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” for RA, R′ or R″ each include 1 to 5, preferably 1 to 3, selected from the aforementioned substituent group A. When the number of the substituents is two or more, the respective substituents may be the same or different.

Examples of the “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent(s)” formed by R′ and R″ together with the nitrogen atom bonded thereto include a 4- to 7-membered nonaromatic nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atom, one nitrogen atom, and optionally further containing 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. The nonaromatic nitrogen-containing heterocycle may be condensed with a benzene ring.

The “nitrogen-containing heterocycle” optionally has (preferably 1 to 3, more preferably 1 or 2) substituent(s) at substitutable position(s). Examples of the substituent include substituent group B and the like. When the number of the substituents is two or more, the respective substituents may be the same or different.

Preferable examples of the “acyl” include

(1) a formyl group;
(2) a carboxy group;
(3) a C1-6alkyl-carbonyl group;
(4) a C1-6alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3 substituents selected from the substituent group B;
(5) a group represented by the formula: —CO—NR′R″ wherein R′ and R″ are each a hydrogen atom, a hydrocarbon group optionally having 1 to 3 substituents selected from the aforementioned substituent group B or a heterocyclic group optionally having 1 to 3 substituents selected from the aforementioned substituent group B, or R′ and R″ optionally form, together with the nitrogen atom bonded thereto, a nitrogen-containing heterocycle optionally having 1 to 3 substituents selected from the aforementioned substituent group B, and the like.

Examples of the “aryl group” in the present specification include C6-14aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, C6-10aryl is preferable and phenyl is more preferable. The above-mentioned aryl may be condensed with C3-10cycloalkane (examples of the C3-10cycloalkane include a ring corresponding to the above-mentioned C3-10cycloalkyl), and examples of the fused group include tetrahydronaphthyl, indanyl and the like.

Examples of the “aryl” moiety of the “aryloxy group” in the present specification include those similar to the above-mentioned “aryl group”.

Examples of the “heteroaryl group” in the present specification include a monocyclic aromatic heterocyclic group and a fused aromatic heterocyclic group from the “heterocyclic group” of the aforementioned “heterocycle optionally having substituent(s)”.

Examples of the “heterocycle” in the present specification include monocyclic heterocycle and fused heterocycle.

Examples of the “monocyclic aromatic heterocycle” include a 4- to 10-membered (preferably 5- or 6-membered) monocyclic aromatic heterocycle containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.

Examples of the “monocyclic non-aromatic heterocycle” include a 3- to 10-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.

Examples of the “fused heterocycle” include fused aromatic heterocycle and fused non-aromatic heterocycle.

Examples of the “fused aromatic heterocycle” include a ring wherein a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocycle containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed and the like.

Examples of the “fused non-aromatic heterocycle” include a ring wherein a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.

Examples of the “5- to 7-membered nitrogen-containing heterocycle” in the present specification include pyrrolidine, piperidine and homopiperidine.

While the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is not particularly limited as long as it shows deliquescence at a relative humidity of not less than 80% at 25° C. Examples thereof include a low-molecular nonpeptidic compound having a molecular weight of not more than about 1000, preferably not more than about 500, and showing deliquescence at a relative humidity of not less than 80% at 25° C.

While the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is preferably “a compound showing deliquescence at a relative humidity of 80%-90% at 25° C.” and is not particularly limited as long as it shows deliquescence at a relative humidity of 80%-90% at 25° C. Examples thereof include a low-molecular nonpeptidic compound having a molecular weight of not more than about 1000, preferably not more than about 500, and showing deliquescence at a relative humidity of 80%-90% at 25° C.

Preferred as the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is a low-molecular nonpeptidic compound having a secondary amine in the structure and a molecular weight of not more than about 1000, preferably not more than about 500.

More preferred as the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide (compound (A)) or a salt thereof.

Other preferable examples of the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” include

a compound represented by the formula (I):

wherein
R1is a hydrogen atom, an alkyl group optionally having substituent(s), an alkenyl group optionally having substituent(s), or a cycloalkyl group optionally having substituent (s);
X is absent, or a hydrogen atom, an alkyl group optionally having substituent(s) or a cycloalkyl group optionally having substituent(s);
ring A is heterocycle optionally having substituent(s);
ring B is a 5- to 7-membered, nitrogen-containing heterocycle optionally having substituent(s); and
n is 0, 1 or 2,
or a salt thereof.

Each symbol in the formula (I) is defined in detail in the following.

In the formula (I), R1is a hydrogen atom, an alkyl group optionally having substituent(s), an alkenyl group optionally having substituent(s) or a cycloalkyl group optionally having substituent(s).

Examples of the substituent of the “alkyl group optionally having substituent(s)”, “alkenyl group optionally having substituent(s)” and “cycloalkyl group optionally having substituent(s)” for R1each include 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A. When the number of the substituents is two or more, the respective substituents may be the same or different.

In the formula (I), X is absent or a hydrogen atom, an alkyl group optionally having substituent(s) or a cycloalkyl group optionally having substituent(s).

The “alkyl group” of the “alkyl group optionally having substituent(s)” for X optionally has (e.g., 1 to 5, preferably 1 to 3) substituent(s) at substitutable position(s). When the number of the substituents is two or more, the respective substituents may be the same or different. Examples of the substituent include a halogen atom, a hydroxy group, an alkenyl group optionally having substituent(s), an alkynyl group optionally having substituent(s), a cycloalkyl group optionally having substituent(s), a cycloalkyloxy group optionally having substituent(s), an alkylthio group optionally having substituent(s), an alkylsulfinyl group optionally having substituent(s), an alkylsulfonyl group optionally having substituent(s), an alkoxy group optionally having substituent(s), an aryl group optionally having substituent(s), a heteroaryl group optionally having substituent(s), an aryloxy group optionally having substituent(s), and an acyl group.

Examples of the substituent of the “alkenyl group optionally having substituent(s)”, “alkynyl group optionally having substituent(s)”, “cycloalkyl group optionally having substituent(s)”, “cycloalkyloxy group optionally having substituent(s)”, “alkylthio group optionally having substituent(s)”, “alkylsulfinyl group optionally having substituent(s)”, “alkylsulfonyl group optionally having substituent(s)”, “alkoxy group optionally having substituent(s)”, “aryl group optionally having substituent(s)”, “heteroaryl group optionally having substituent(s)” and “aryloxy group optionally having substituent(s)”, which are exemplified as the “substituent” of the “alkyl group optionally having substituent(s)” for X, each include 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A. When the number of the substituents is two or more, the respective substituents may be the same or different.

Examples of the substituent of the “cycloalkyl group optionally having substituent(s)” for X include 1 to 5, preferably 1 to 3, substituent selected from the aforementioned substituent group A. When the number of the substituents is two or more, the respective substituents may be the same or different.

X is preferably

Ring A

In the formula (I), ring A is a heterocycle optionally having substituent(s).

Ring A is preferably

Ring B

In the formula (I), ring B is a 5- to 7-membered nitrogen-containing heterocycle optionally having substituent(s), n is 0, 1 or 2 and NH constituting ring B is unsubstituted.

Examples of the substituent of the “5- to 7-membered nitrogen-containing heterocycle optionally having substituent(s)” for ring B include 1 to 5, preferably 1 to 3, selected from the aforementioned substituent group A or two substituents bonded to the carbon atoms adjacent to ring B may be bonded to form C3-10cycloalkane (e.g., cyclopentane, cyclohexane) to be condensed with ring B. When the number of the substituents is two or more, the respective substituents may be the same or different.

Ring B is preferably

More preferable ring B is a ring represented by

wherein R4is as defined above.

R4is preferably a group represented by the formula: —CO—NR′R″ wherein R′ and R″ are as defined above, more preferably morpholin-4-ylcarbonyl.

Further preferable examples of compound (I) or a salt thereof include the following.

A compound represented by the formula (I) wherein ring A is a ring represented by the formula

ring B is a ring represented by

Preferable compound (I) or a salt thereof is compound (A) or a salt thereof.

Compound (I) or a salt thereof can be produced according to a method known per se, for example, the production method described in WO2009/154300 or a method analogous thereto.

Examples of the salts of compound (I) and compound (A) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.

Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine or the like.

Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid (e.g., monohydrochloride, dihydrochloride), hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like.

Preferable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine or the like.

Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid or the like.

Preferable compound (A) is hydrochloride, and monohydrochloride is particularly preferable.

In the tablet of the present invention, the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.” is used at a content of preferably about 1-about 40 wt %, more preferably about 1.5-about 25 wt %, of one tablet of the present invention.

In one preferable embodiment of the tablet of the present invention wherein compound (I) (particularly, compound (A)) or a salt thereof is used as the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.”, compound (I) (particularly compound (A)) or a salt thereof is used at a content of preferably about 1-about 40 wt %, more preferably about 1.5-about 25 wt %, as compound (I) (particularly compound (A)), of one tablet of the present invention.

In another preferable embodiment of the tablet of the present invention wherein compound (A) or a salt thereof is used as the “compound showing deliquescence at a relative humidity of not less than 80% at 25° C.”, compound (A) or a salt thereof is used at a content of preferably about 3-about 40 wt %, more preferably about 3-about 20 wt %, as compound (A), of one tablet of the present invention.

Examples of the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” to be used in the present invention include crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, croscarmellose sodium, carmellose calcium and the like.

When the tablet of the present invention is a core tablet or a film-coated tablet, the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” may be contained in any of the film coating layer and the core tablet. For example, hydroxypropylcellulose and hydroxypropylmethylcellulose (e.g., Hypromellose 2910 (Shin-Etsu Chemical Co., Ltd.)) may be used as a binder, a disintegrant, a water-soluble film coating base and the like in amounts within the contents to be described later.

The “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” to be used in the present invention may be a combination of one or more kinds of the above-mentioned additives.

In the tablet of the present invention, one or more kinds of the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” is(are) used at a (total) content of 35 wt % or more of one tablet of the present invention.

While the crystalline cellulose to be used in the present invention is not particularly limited as long as it is used as an additive for pharmaceutical products, crystalline cellulose, crystalline cellulose (granule), crystalline cellulose (fine particle) and the like may be used alone or two or more kinds thereof may be mixed and used.

In the tablet of the present invention, when crystalline cellulose alone is used as the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight”, it is used at a content of not less than about 35 wt % of one tablet of the present invention. When crystalline cellulose is used in combination with other additive mentioned above, it is used at a content of not less than about 30 wt %, preferably about 30-about 50 wt %, more preferably about 30-about 40 wt %, of one tablet of the present invention.

The low-substituted hydroxypropylcellulose to be used in the present invention is not particularly limited as long as it is used as a pharmaceutical additive. It may be used alone or two or more kinds thereof may be mixed and used.

In the present specification, low substitution rate means that 5.0%-16.0% of a hydroxypropoxyl group is contained after drying.

In the tablet of the present invention, when low-substituted hydroxypropylcellulose alone is used as the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight”, it is used at a content of not less than about 35 wt % of one tablet of the present invention. When low-substituted hydroxypropylcellulose is used in combination with other additive mentioned above, it is used at a content of not less than about 5 wt %, preferably about 5-about 20 wt %, more preferably about 7-about 9 wt %, of one tablet of the present invention.

The “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” is preferably crystalline cellulose.

In the tablet of the present invention, when crystalline cellulose is used as the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight”, crystalline cellulose is preferably used at a content of not less than about 30 wt %, of one tablet of the present invention. More preferably, crystalline cellulose is used at a content of about 30-about 50 wt %, of one tablet of the present invention. Further preferably, crystalline cellulose is used at a content of about 30-about 40 wt %, of one tablet of the present invention.

The “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” is preferably low-substituted hydroxypropylcellulose.

In the tablet of the present invention, when low-substituted hydroxypropylcellulose is used as the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight”, low-substituted hydroxypropylcellulose is used at a content of not less than about 5 wt %, of one tablet of the present invention. More preferably, low-substituted hydroxypropylcellulose is used at a content of about 5-about 20 wt %, of one tablet of the present invention. Further preferably, low-substituted hydroxypropylcellulose is used at a content of about 7-about 9 wt %, of one tablet of the present invention.

The “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight” is more preferably crystalline cellulose and low-substituted hydroxypropylcellulose used in combination.

In the tablet of the present invention, when crystalline cellulose and low-substituted hydroxypropylcellulose are used as the “additive showing an equilibrium moisture absorption rate at relative humidity 75% at 25° C. of not less than 7 wt % relative to its dry weight”, crystalline cellulose is preferably used at a content of not less than about 30 wt % and low-substituted hydroxypropylcellulose is used at a content of not less than about 5 wt %, each of one tablet of the present invention. More preferably, crystalline cellulose is used at a content of about 30-about 50 wt % and low-substituted hydroxypropylcellulose is used at a content of about 5-about 20 wt %, each of one tablet of the present invention. Further preferably, crystalline cellulose is used at a content of about 30-about 40 wt % and low-substituted hydroxypropylcellulose is used at a content of about 7-about 9 wt %, each of one tablet of the present invention.

The tablet of the present invention may further contain an additive conventionally used in the field of pharmaceutical preparation. Examples of the additive include excipients, binder, disintegrant, colorant, pH adjuster, surfactant, stabilizer, acidulant, flavor, fluidizer, lubricant, coating base, coating additive and the like. Unless particularly indicated, these additives are used in an amount conventionally employed in the field of pharmaceutical preparation.

Preferable examples of the excipient include mannitol; starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, perforated starch and the like; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate and the like. Among these, mannitol is preferable.

In the tablet of the present invention, an excipient is used at a content of preferably about 20-about 60 wt %, more preferably about 30-about 50 wt %, of one tablet of the present invention.

Preferable examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone (povidone), gum arabic and the like.

Preferable examples of the colorant include food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, food lake colors, red ferric oxide, yellow ferric oxide, titanium oxide and the like.

Preferable examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like.

Preferable examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene(160)polyoxypropylene(30)glycol and the like.

Preferable examples of the stabilizer include tocopherol, tetrasodium edetate, nicotinic acid amide, cyclodextrins and the like.

Preferable examples of the acidulant include ascorbic acid, citric acid, tartaric acid, malic acid and the like.

Preferable examples of the flavor include menthol, peppermint oil, lemon oil, vanillin and the like.

Preferable examples of the fluidizer include light anhydrous silicic acid, hydrated silicon dioxide, talc and the like. Among these, light anhydrous silicic acid is preferable.

The fluidizer is used at a content of preferably about 0.1-about 1 wt %, more preferably about 0.2-about 0.5 wt %, of one tablet of the present invention.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate and the like. Among these, magnesium stearate is preferable.

The lubricant is used at a content of preferably about 0.1-about 5 wt %, more preferably about 1-about 3 wt %, of one tablet of the present invention.

Preferable examples of the coating base include sugar coating base, aqueous film coating base, enteric film coating base, sustained-release film coating base and the like.

As the sugar coating base, sucrose can be used. Furthermore, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

Examples of the aqueous film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose (e.g., Hypromellose 2910 (Shin-Etsu Chemical Co., Ltd.), hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E (e.g., Eudragit E (trade name)), polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like, and the like.

Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L (e.g., Eudragit L (trade name)), methacrylic acid copolymer LD (e.g., Eudragit L-30D55 (trade name)), methacrylic acid copolymer S (e.g., Eudragit S (trade name)) and the like; naturally occurring substances such as shellac and the like; and the like.

Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS (e.g., Eudragit RS (trade name)), ethyl acrylate-methyl methacrylate copolymer suspension (e.g., Eudragit NE (trade name)) and the like; and the like.

Preferable examples of the coating additive include light shielding agents such as titanium dioxide and the like, fluidizers such as talc and the like; colorants such as red ferric oxide, yellow ferric oxide and the like; plasticizers such as polyethylene glycol (e.g., macrogol 6000), triethyl citrate, castor oil, polysorbates and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; and the like.

Two or more kinds of the above-mentioned additives may be mixed at an appropriate ratio and used.

Specific preferable examples of the tablet of the present invention include the following: (tablet A)

A tablet containing the following (i)-(iii):

(i) compound (A) (preferably hydrochloride of compound (A), more preferably monohydrochloride of compound (A)),
(ii) not less than 30 wt % of crystalline cellulose in the tablet (of the weight of one tablet), and
(iii) not less than 5 wt % of low-substituted hydroxypropylcellulose in the tablet (of the weight of one tablet).
(tablet B)

A tablet containing the following (i)-(iii):

(i) compound (A) (preferably hydrochloride of compound (A), more preferably monohydrochloride of compound (A)),
(ii) 30-50 wt % of crystalline cellulose in the tablet (of the weight of one tablet), and
(iii) 5-20 wt % of low-substituted hydroxypropylcellulose in the tablet (of the weight of one tablet).
(tablet C)

A tablet containing the following (i)-(iii):

(i) 1.5-25 wt % of compound (A) (preferably hydrochloride of compound (A), more preferably monohydrochloride of compound (A)), (of the weight of one tablet),
(ii) 30-50 wt % of crystalline cellulose in the tablet (of the weight of one tablet), and
(iii) 5-20 wt % of low-substituted hydroxypropylcellulose in the tablet (of the weight of one tablet).
(tablet D)

A tablet containing the following (i)-(iii):

(i) 1.5-25 wt % of compound (A) (preferably hydrochloride of compound (A), more preferably monohydrochloride of compound (A)), (of the weight of one tablet),
(ii) 30-40 wt % of crystalline cellulose in the tablet (of the weight of one tablet), and
(iii) 7-9 wt % of low-substituted hydroxypropylcellulose in the tablet (of the weight of one tablet).

The tablet of the present invention may be film-coated from the aspects of dosability, strength of preparation and the like. Preferable examples of the coating base and coating additive used for film coating include those similar to the coating base and coating additive used for the aforementioned tablet of the present invention.

When the tablet of the present invention is film-coated, a film coating layer is generally formed in the proportion of 1-10 parts by weight, preferably 2-6 parts by weight, per 100 parts by weight of the tablet of the present invention (core tablet) before coating.

The tablet of the present invention can be produced by granulating and mixing compound (I) or a salt thereof, crystalline cellulose, low-substituted hydroxypropylcellulose and, where necessary, other additive, and tableting the mixture.

In the production process of the tablet of the present invention, operations of granulation, mixing, tableting, coating and the like can be performed by a method conventionally used in the formulation technical field.

Granulation is performed using, for example, a granulator such as high speed mixer granulator, fluid bed dryer granulator, extrusion granulator, roller compacter and the like. Mixing is performed using, for example, a mixer such as V-type mixer, tumbler mixer and the like.

Tableting (punching) is performed using, for example, a single punch tableting machine, a rotary tableting machine and the like.

When a single punch tableting machine, a rotary tableting machine or the like is used, generally, a tableting pressure of 1-45 kN/cm2(preferably 5-40 kN/cm2) is preferably adopted, and further, a tapered die is preferably used for the purpose of preventing capping.

The coating is performed by, for example, using a film coating apparatus and the like.

The tablet of the present invention preferably has a hardness of about 50-about 200 N.

The tablet of the present invention may be film-coated from the aspects of dosability, strength of preparation and the like. In addition, the above-mentioned tablet may be filled in a capsule (e.g., gelatin capsule) to give a capsule.

In addition, the tablet of the present invention may be printed with stamps or letters for discrimination, or have a separating line for dividing the tablet.

The tablet of the present invention can be safely administered orally to a mammal (e.g., mouse, rat, rabbit, cat, dog, bovine, horse, monkey, human).

In the present invention, a tablet containing compound (I) as a pharmaceutically active ingredient is useful as a safe prophylactic or therapeutic agent for various diseases caused by the renin-angiotensin system (RA system).

The various diseases caused by RA system also include circulatory diseases, various organ disorders caused by hypertension and the like.

The various organ disorders caused by hypertension include cardiac disease, encephalopathy, renal diseases, multiple organ failure and the like.

Specifically, for example, the effective amount of compound (I) as its free form is generally 0.01-1000 mg/day, preferably 1-500 mg/day, more preferably 5-250 mg/day, further preferably 5-100 mg/day, per an adult (body weight 60 kg). The administration frequency of the tablet, containing compound (I) as a pharmaceutically active ingredient, to the aforementioned mammal per day is preferably 1-3 times.

Particularly preferable examples of the tablet containing compound (I) as pharmaceutically active ingredient include

The tablet of the present invention can be used in combination with one or more kinds of other drugs (hereinafter sometimes to be abbreviated as concomitant drug).

Specific examples of the combination drug include the following:

(3) Therapeutic Agent for Diabetes

(4) Therapeutic Agents for Diabetic Complications

Besides the above, they can be used in combination with other pharmaceutical ingredients including therapeutic drugs for bone diseases, myocardial protective drugs, therapeutic drugs for coronary heart diseases, therapeutic drugs for chronic cardiac failure, therapeutic drugs for hypothyroidism, therapeutic drugs for nephrosis syndrome, therapeutic drugs for chronic renal failure, therapeutic agents for renal anemia (e.g., erythropoietin preparation, peginesatide), therapeutic drugs for gynecologic diseases and therapeutic drugs for infections.

Furthermore, the drug to be used in combination may be an antibody drug or a nucleic acid drug.

Moreover, the preparation of the present invention can also be used along with a gene therapy.

When the tablet of the present invention and a concomitant drug are used in combination, the administration time of these is not limited, and they can be administered simultaneously to an administration subject, or may be administered in a staggered manner.

In addition, the tablet of the present invention and the concomitant drug may be administered as separate preparations or as a single preparation containing the tablet of the present invention and the concomitant drug, to an administration subject.

The dose of the concomitant drug can be appropriately determined based on the clinically employed dose of each drug. In addition, the mixing ratio of the tablet of the present invention and the concomitant drug can be appropriately determined according to the administration subject, administration route, target disease, condition, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the tablet of the present invention.

Use of the concomitant drug in this way provides superior effects such as 1) enhanced action of the tablet of the present invention or the concomitant drug (synergistic effect of the actions of the medicaments), 2) reduced dose of the tablet of the present invention or the combination drug (effect of reduction of dose of medicaments as compared to single drug administration), 3) reduced secondary action of the tablet of the present invention or the concomitant drug, and the like.

The present invention is explained in more detail in the following by referring to Examples and Experimental Examples, which are not to be construed as limitative.

As additives for pharmaceutical preparations in the following Examples, the Japanese Pharmacopoeia 16th edition, the Japanese Pharmacopoeia Japanese Pharmaceutical Codex or Japanese Pharmaceutical Excipients 2003 compatible products were used.

EXAMPLES

According to the formulation of Table 1, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose (1), low-substituted hydroxypropylcellulose, magnesium stearate (1) and light anhydrous silicic acid were uniformly mixed in a mixing machine (vertical granulator 50 L, POWREX CORPORATION), and granulated using a roller compacter (Alexanderwerk). The obtained flakes were sieved using a sieving mill (Power Mill P-3, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give a sized powder. To the sized powder were added crystalline cellulose (2) and magnesium stearate (2), and the mixture was mixed in a mixing machine (tumbler 60 L, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give granules for tableting. The granules were tableted by a rotary tableting machine (AQUARIOUS 08242L2JI, Kikusui Seisakusho Ltd.) using a 6.5 mm punch to give core tablets (weight 110 mg per tablet). On the other hand, titanium oxide, red ferric oxide, yellow ferric oxide and talc were dispersed in an aqueous hydroxypropylmethylcellulose (hypromellose) solution to prepare a film coating solution. The film coating solution was sprayed on the above-mentioned core tablets in a film coating machine (Dria Coater DRC650, POWREX CORPORATION) to give film-coated tablets containing 5 mg (94000 tablets) and 20 mg (86000 tablets) of compound (A) (free form) per tablet.

According to the formulation of Table 2, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose (1), low-substituted hydroxypropylcellulose, magnesium stearate (1) and light anhydrous silicic acid were uniformly mixed in a mixing machine (vertical granulator 10 L, POWREX CORPORATION), and granulated using a roller compacter (Alexanderwerk). The obtained flakes were sieved using a sieving mill (Power Mill P-3, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give a sized powder. To the sized powder were added crystalline cellulose (2) and magnesium stearate (2), and the mixture was mixed in a mixing machine (tumbler 5 L, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give granules for tableting. The granules were tableted by a rotary tableting machine (Correct 19K, Kikusui Seisakusho Ltd.) using a 11×6 mm punch to give a core tablet (weight 220 mg). On the other hand, titanium oxide, red ferric oxide, yellow ferric oxide and talc were dispersed in an aqueous hydroxypropylmethylcellulose (hypromellose) solution to prepare a film coating solution. The film coating solution was sprayed on the above-mentioned core tablets in a film coating machine (HI-COATER LABO, Freund Corporation) to give film-coated tablets containing 40 mg of compound (A) (free form) per tablet.

According to the formulation of Table 3, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose (1), low-substituted hydroxypropylcellulose, magnesium stearate (1) and light anhydrous silicic acid were uniformly mixed in a mixing machine (vertical granulator 10 L, POWREX CORPORATION), and granulated using a roller compacter (Alexanderwerk). The obtained flakes were sieved using a sieving mill (Power Mill P-3, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give a sized powder. To the sized powder were added crystalline cellulose (2) and magnesium stearate (2), and the mixture was mixed in a mixing machine (tumbler 5 L, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give granules for tableting. The granules were tableted by a rotary tableting machine (Correct 19K, Kikusui Seisakusho Ltd.) using a 8 mm punch to give a core tablet (weight 220 mg) containing 10 mg of compound (A) (free form) per tablet.

According to the formulation of Table 4, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose (1), low-substituted hydroxypropylcellulose, magnesium stearate (1) and light anhydrous silicic acid were uniformly mixed in a mixing machine (vertical granulator 10 L, POWREX CORPORATION), and granulated using a roller compacter (Alexanderwerk). The obtained flakes were sieved using a sieving mill (Power Mill P-3, SHOWA KAGAKU KIKAI KOUSAKUSHO CO., LTD.) to give a sized powder. To the sized powder were added crystalline cellulose (2) and magnesium stearate (2), and the mixture was mixed in a bag to give granules for tableting. The granules were tableted by a rotary tableting machine (Correct 19K, Kikusui Seisakusho Ltd.) using a 9 mm punch to give core tablets (weight 300 mg per tablet). On the other hand, titanium oxide, red ferric oxide, yellow ferric oxide and talc were dispersed in an aqueous hydroxypropylmethylcellulose (hypromellose) solution to prepare a film coating solution. The film coating solution was sprayed on the above-mentioned core tablets in a film coating machine (HI-COATER LABO, Freund Corporation) to give film-coated tablets containing 10 mg and 50 mg of compound (A) (free form) per tablet.

According to the formulation of Table 5, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, magnesium stearate and light anhydrous silicic acid were uniformly mixed in a mortar, and tableted by Autograph (AG-1, Shimadzu Corporation) using a 9 mm punch to give a core tablet (weight 300 mg)

Experimental Example 1

The equilibrium moisture absorption rate of hydrochloride (monohydrochloride) of compound (A) at various relative humidities at 25° C. was measured by a vapor sorption analyzer (SGA-CX, VTI Corporation). The results are shown inFIG. 1.

Experimental Example 2

The equilibrium moisture absorption rate of crystalline cellulose (CEOLUS PH-302 (Asahi Kasei Chemicals Corporation) at various relative humidities at 25° C. was measured by a vapor sorption analyzer (SGA-CX, VTI Corporation). The results are shown inFIG. 2.

Experimental Example 3

The equilibrium moisture absorption rate of low-substituted hydroxypropylcellulose (LH-21 (Shin-Etsu Chemical Co., Ltd.)) at various relative humidities at 25° C. was measured by a vapor sorption analyzer (SGA-CX, VTI Corporation). The results are shown inFIG. 3.

According to the formulation of Table 6, hydrochloride (monohydrochloride) of compound (A), mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, magnesium stearate and light anhydrous silicic acid were uniformly mixed in a mortar, and the mixture was tableted by a desktop tableting machine (HANDTAB, ICHIHASHI-SEIKI CO., LTD.) using a 6.5 mm punch to give a core tablet (weight 110 mg).

Comparative Example 1

According to the formulation of Table 7, hydrochloride (monohydrochloride) of compound (A), mannitol, magnesium stearate and light anhydrous silicic acid were uniformly mixed in a mortar, and the mixture was tableted by a desktop tableting machine (HANDTAB, ICHIHASHI-SEIKI CO., LTD.) using a 6.5 mm punch to give a core tablet (weight 110 mg).

Experimental Example 4

The equilibrium moisture absorption rate of xylitol (reagent special grade xylitol (Wako Pure Chemical Industries, Ltd.)) at various relative humidities at 25° C. was measured by a moisture adsorption and desorption measuring apparatus (SGA-CX, VTI Corporation). The results are shown inFIG. 4.

Experimental Example 5

The tablets of Example 6 and Comparative Example 1 were preserved under the conditions of 25° C. and relative humidity of 93%, and the weight loss of drying was measured under the conditions of 105° C. and 3 hr. The results are shown in Table 8.

Experimental Example 6

The tablets of Example 6 and Comparative Example 1 were preserved under the conditions of 25° C. and relative humidity of 93%, and the dissolution property of compound (A) was measured according to the Japanese Pharmacopoeia Paddle Method (rotation number 50 rpm, 37° C., 0.1N hydrochloric acid test solution 900 mL, n=3). The results are shown in Table 9. The values in the Table each show an average dissolution ratio of 3 tablets.

As shown in Table 9, the tablet of Comparative Example 1 showed delayed dissolution of compound (A) after preservation. In contrast, the tablet of Example 6 did not show remarkable delay in the dissolution property of compound (A) after preservation, thus confirming stability of the tablet.

INDUSTRIAL APPLICABILITY

The present invention can provide a tablet containing a compound showing deliquescence at a relative humidity of not less than 80% at 25° C. as a pharmaceutically active ingredient, which shows improved (reduced) hygroscopicity, can be easily produced and handled, and can be stably preserved for a long term.

This application is based on a patent application No. 2012-030987 filed in Japan, the contents of which are incorporated in full herein.