JP2005145894A - Solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation containing one or more kinds of nonsteroidal antiinflammatory drugs (NSAID), and useful as an antipyretic, antalgic and antiinflammatory agent having a suppressing or reducing effect on the manifestation of gastrointestinal injury by the NSAID. <P>SOLUTION: This solid preparation comprises a combination of a granules, grain or a tablet containing a proton pump inhibitor (PPI), with granules or grains containing one or more kinds of the nonsteroid antiinflammatory drugs (NSAID). Preferably, the solid preparation is a capsule filled with both thereof. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention contains a nonsteroidal anti-inflammatory agent (NSAID) and a proton pump inhibitor (PPI) useful as a therapeutic agent for rheumatoid arthritis, a therapeutic agent for osteoarthritis, an anti-inflammatory agent, an antipyretic analgesic agent, and the like. Relates to solid formulations.

The following preparations have been reported as preparations containing an acid labile proton pump inhibitor (PPI) and a non-steroidal anti-inflammatory agent (NSAID).
1) A multiple unit tablet in which PPI is dispersed in a tablet containing at least one NSAID as a pellet coated with an enteric coating (see Patent Document 1).
2) Tablets coated with PPI on the surface of tablets containing NSAID and further coated with an enteric coating, or solid preparations filled with capsules containing NSAID-containing tablets and enteric coating (see Patent Document 2) ).

US Pat. No. 6,365,184 International Publication No. WO02 / 22108

  INDUSTRIAL APPLICABILITY The present invention is useful as a therapeutic agent for rheumatoid arthritis, osteoarthritis agent, anti-inflammatory agent, antipyretic analgesic agent, etc., and is excellent in treatment and prevention of gastrointestinal disorders caused by NSAID and 1 It is an object to provide a solid preparation containing seeds or more NSAIDs. It is desirable to develop a solid dosage form that is less affected by pharmacokinetics such as absorbability of each drug depending on the presence or absence of meals, has excellent stability and compounding properties, and has the same pharmacokinetics for each drug compared to concomitant administration. ing.

〔式中、環Ａは置換基を有していてもよいベンゼン環、Ｒ^１は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ同一または異なって、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基、およびＹは窒素原子またはＣＨを示す〕で表される化合物もしくはその光学活性体またはその塩である前記（２）記載の固形製剤、
（４）ベンツイミダゾール系化合物が、ランソプラゾール、オメプラゾール、ラベプラゾール、パントプラゾールもしくはその光学活性体またはその塩である前記（２）記載の固形製剤、
（５）ＰＰＩがイミダゾピリジン系化合物である前記（１）記載の固形製剤、
（６）イミダゾピリジン系化合物がテナトプラゾールもしくはその光学活性体またはその塩である前記（５）記載の固形製剤、
（７）ＰＰＩを含有する顆粒、細粒または錠剤が腸溶性被覆を施されている前記（１）記載の固形製剤、
（８）ＮＳＡＩＤを含有する顆粒または細粒が持続性顆粒または細粒である前記（１）記載の固形製剤、
（９）ＰＰＩを含有する顆粒、細粒または錠剤と１種またはそれ以上のＮＳＡＩＤを含有する顆粒または細粒の組合せが１つのユニットに充填された前記（１）記載の固形製剤、
（１０）１つのユニットがカプセルである前記（９）記載の固形製剤、
（１１）ＮＳＡＩＤがフェニル酢酸系化合物、プロピオン酸系化合物、サリチル酸系化合物、インドール酢酸系化合物、アントラニル酸系化合物、オキシカム系化合物またはそれらの塩である前記（１）記載の固形製剤、
（１２）ＮＳＡＩＤがＣＯＸ−２阻害剤である前記（１）記載の固形製剤、
（１３）ランソプラゾール、オメプラゾール、ラベプラゾール、パントプラゾールおよびテナトプラゾール、それらの光学活性体並びにそれらの塩から選ばれるＰＰＩを含有する腸溶性被覆顆粒とジクロフェナックナトリウム、イブプロフェン、ケトプロフェン、ナプロキセン、ロキソプロフェンナトリウム、アスピリン、インドメタシン、メフェナム酸、ピロキシカム、ロフェコキシブ、セレコキシブおよびバルデコキシブから選ばれる１種またはそれ以上のＮＳＡＩＤを含有する顆粒がカプセルに充填された前記（９）記載の固形製剤、
（１４）ＰＰＩと１種またはそれ以上のＮＳＡＩＤを３対１ないし１対３００の重量比で含有する前記（１）記載の固形製剤、
（１５）ランソプラゾールとジクロフェナックナトリウムを１対１ないし１対２０の重量比で含有する前記（１４）記載の固形製剤、
（１６）ランソプラゾールとピロキシカムを２対１ないし１対２の重量比で含有する前記（１４）記載の固形製剤、
（１７）ＮＳＡＩＤによる胃腸障害の予防、治療、軽減効果を有する解熱・鎮痛・抗炎症剤である前記（１）記載の固形製剤等に関する。 When producing a compounded solid preparation containing NSAID and acid-labile PPI, the present inventors fill one unit with an appropriate amount of two or more kinds of solid preparations such as granules containing each component. Is a therapeutic agent for rheumatoid arthritis, deformable joint, which is excellent in the treatment and prevention of gastrointestinal disorders by NSAID, hardly affected by diet, excellent in stability and compounding, and the pharmacokinetics of each drug is the same as in combined administration The present inventors have found that solid preparations useful as treatments for infectious diseases, anti-inflammatory drugs, antipyretic analgesics and the like can be obtained. As a result of further research based on this finding, the present inventors have completed the present invention.
That is, the present invention
(1) a solid formulation comprising a combination of granules, granules or tablets containing a proton pump inhibitor (PPI) and granules or granules containing one or more non-steroidal anti-inflammatory agents (NSAIDs),
(2) The solid preparation according to the above (1), wherein PPI is a benzimidazole compound,
(3) The benzimidazole compound is represented by the formula (I):

[Wherein, ring A is an optionally substituted benzene ring, R ¹ is a hydrogen atom, an optionally substituted aralkyl group, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ is the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent or an amino group which may have a substituent, and Y Represents a nitrogen atom or CH], or a solid preparation according to the above (2), which is a compound represented by
(4) The solid preparation according to the above (2), wherein the benzimidazole compound is lansoprazole, omeprazole, rabeprazole, pantoprazole, an optically active substance thereof, or a salt thereof,
(5) The solid preparation according to (1), wherein the PPI is an imidazopyridine compound,
(6) The solid preparation according to the above (5), wherein the imidazopyridine compound is tenatoprazole or an optically active substance thereof or a salt thereof,
(7) The solid preparation according to (1), wherein the granules, fine granules or tablets containing PPI are enteric-coated,
(8) The solid preparation according to the above (1), wherein the NSAID-containing granule or fine particle is a persistent granule or fine particle,
(9) The solid preparation according to (1), wherein a combination of granules, fine granules or tablets containing PPI and granules or fine granules containing one or more NSAIDs is filled in one unit;
(10) The solid preparation according to (9), wherein one unit is a capsule,
(11) The solid preparation according to (1), wherein the NSAID is a phenylacetic acid compound, a propionic acid compound, a salicylic acid compound, an indoleacetic acid compound, an anthranilic acid compound, an oxicam compound, or a salt thereof,
(12) The solid preparation according to the above (1), wherein the NSAID is a COX-2 inhibitor,
(13) Enteric-coated granules and diclofenac sodium, ibuprofen, ketoprofen, naproxen, loxoprofen sodium, aspirin containing PPI selected from lansoprazole, omeprazole, rabeprazole, pantoprazole and tenatoprazole, optically active forms thereof and salts thereof The solid preparation according to (9), wherein a granule containing one or more NSAIDs selected from indomethacin, mefenamic acid, piroxicam, rofecoxib, celecoxib and valdecoxib is filled in a capsule;
(14) The solid preparation according to (1) above, containing PPI and one or more NSAIDs in a weight ratio of 3: 1 to 1: 300,
(15) The solid preparation according to the above (14), which contains lansoprazole and diclofenac sodium in a weight ratio of 1: 1 to 1:20,
(16) The solid preparation according to the above (14), which contains lansoprazole and piroxicam in a weight ratio of 2: 1 to 1: 2.
(17) The present invention relates to the solid preparation according to the above (1), which is an antipyretic / analgesic / anti-inflammatory agent having an effect of preventing, treating, and reducing gastrointestinal disorders by NSAID.

The solid preparation of the present invention is useful as a therapeutic agent for rheumatoid arthritis, a therapeutic agent for osteoarthritis, an anti-inflammatory agent, an antipyretic / analgesic agent, etc. . In addition, it is a dosage form in which the pharmacokinetics such as PPI or NSAID absorbability are hardly affected by the presence or absence of meals, and it is excellent in stability and compounding, and the pharmacokinetics of each drug is the same as when administered in combination. is there.
Furthermore, the solid preparation of the present invention can be easily produced by a simple method.

〔式中、環Ａは置換基を有していてもよいベンゼン環、Ｒ^１は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ同一または異なって、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基、およびＹは窒素原子またはＣＨを示す〕で表される化合物またはその塩が挙げられる。
好ましい化合物は、式（Ｉ）において、環Ａが、ハロゲン原子、ハロゲン化されていてもよいＣ_1-4アルキル基、ハロゲン化されていてもよいＣ_1-4アルコキシ基および５または６員複素環基から選ばれた置換基を有していてもよいベンゼン環であり、Ｒ^１が水素原子であり、Ｒ^２がＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルコキシ−Ｃ_１−６アルコキシ基またはジ−Ｃ_１−６アルキルアミノ基であり、Ｒ^３が水素原子、Ｃ_１−６アルコキシ−Ｃ_１−６アルコキシ基またはハロゲン化されていてもよいＣ_１−６アルコキシ基であり、Ｒ^４が水素原子またはＣ_１−６アルキル基であり、Ｙが窒素原子である化合物である。
特に好ましくは、式（Ｉａ）：

〔式中、Ｒ^１は水素原子、Ｒ^２はＣ_１−３アルキル基またはＣ_１−３アルコキシ基、Ｒ^３はハロゲン化されているかまたはＣ_１−３アルコキシ基で置換されていてもよいＣ_１−３アルコキシ基、Ｒ^４は水素原子またはＣ_１−３アルキル基、Ｒ^５は、水素原子、ハロゲン化されていてもよいＣ_１−３アルコキシ基またはピロリル基（例えば、１−，２−または３−ピロリル基）を示す〕で表される化合物である。
式（Ｉａ）において、Ｒ^１が水素原子、Ｒ^２がＣ_１−３アルキル基、Ｒ^３がハロゲン化されていてもよいＣ_１−３アルコキシ基、Ｒ^４が水素原子、Ｒ^５が水素原子またはハロゲン化されていてもよいＣ_１−３アルコキシ基である化合物が特に好ましい。 The NSAID used in the present invention may be any drug that is useful as a therapeutic agent for rheumatoid arthritis, a therapeutic agent for osteoarthritis, an anti-inflammatory agent, an antipyretic analgesic, and the like. Specific examples of the NSAID include, for example, phenylacetic acid compounds (eg, diclofenac, fenbufen), propionic acid compounds (eg, ibuprofen, ketoprofen, naproxen, loxoprofen, pranoprofen), salicylic acid compounds (eg, aspirin), Examples thereof include indole acetic acid compounds (eg, indomethacin, sulindac), anthranilic acid compounds (eg, mefenamic acid), oxicam compounds (eg, piroxicam, meloxicam) or salts thereof. NSAIDs such as COX-2 inhibitors (eg, rofecoxib, celecoxib, valdecoxib) are also applicable to the present invention.
In this invention, NSAID may be used individually by 1 type, or may be used combining 2 or more types in a suitable ratio. The PPI used in the present invention may be any drug that has the effect of treating and preventing gastrointestinal disorders caused by NSAID and can alleviate such disorders.
Specific examples of PPI include, for example, a benzimidazole compound (eg, lansoprazole, omeprazole, rabeprazole, pantoprazole, or an optically active form thereof), an imidazopyridine compound (eg, tenatoprazole or an optically active form thereof) or a salt thereof. Is mentioned.
The benzimidazole compound which is a PPI used in the present invention includes a compound represented by the formula (I):

[Wherein, ring A is an optionally substituted benzene ring, R ¹ is a hydrogen atom, an optionally substituted aralkyl group, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ is the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent or an amino group which may have a substituent, and Y Represents a nitrogen atom or CH] or a salt thereof.
Preferred compounds are those in the formula (I) wherein ring A is a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and a 5- or 6-membered heterocycle. A benzene ring which may have a substituent selected from a cyclic group, R ¹ is a hydrogen atom, R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy -C _1-6 alkoxy group or di-C _1-6 alkylamino group, and R ³ is a hydrogen atom, C _1-6 alkoxy-C _1-6 alkoxy group or optionally halogenated C _1-6. A compound which is an alkoxy group, R ⁴ is a hydrogen atom or a C _1-6 alkyl group, and Y is a nitrogen atom.
Particularly preferably, formula (Ia):

[Wherein, R ¹ is a hydrogen atom, R ² is a C _1-3 alkyl group or a C _1-3 alkoxy group, R ³ is halogenated or optionally substituted by a C _1-3 alkoxy group. _1-3 alkoxy group, R ⁴ is a hydrogen atom or a C _1-3 alkyl group, R ⁵ is a hydrogen atom, an optionally halogenated C _1-3 alkoxy group or a pyrrolyl group (for example, 1-, 2- Or a 3-pyrrolyl group).
In the formula (Ia), R ¹ is a hydrogen atom, R ² is a C _1-3 alkyl group, R ³ is a halogenated C _1-3 alkoxy group, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom. Or the compound which is the _C1-3 alkoxy group which may be halogenated is especially preferable.

In the compound represented by the above formula (I) [hereinafter referred to as compound (I)], the “substituent” of the “benzene ring optionally having substituent (s)” represented by ring A is, for example, Halogen atom, cyano group, nitro group, optionally substituted alkyl group, hydroxy group, optionally substituted alkoxy group, aryl group, aryloxy group, carboxy group, acyl group, acyloxy Group, a 5- to 10-membered heterocyclic group, and the like. These substituents may be substituted by 1 to 3 on the benzene ring. When the number of substituents is 2 or more, each substituent may be the same or different. Of these substituents, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, and the like are preferable.
Examples of the halogen atom include fluorine, chlorine, bromine atom and the like. Of these, fluorine is preferred.
As the “alkyl group” of the “optionally substituted alkyl group”, for example, a C _1-7 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, hexyl, heptyl group, etc.). Examples of the “substituent” of the “optionally substituted alkyl group” include a halogen atom, a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₁ Examples thereof include a _-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), a carbamoyl group, etc. The number of these substituents may be about 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
Examples of the “alkoxy group” in the “optionally substituted alkoxy group” include a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, etc.) and the like. Can be mentioned. Examples of the “substituent” of the “alkoxy group optionally having substituent (s)” include those similar to the “substituent” of the above-mentioned “alkyl group optionally having substituent (s)”. The number of substitutions is the same.
Examples of the “aryl group” include C _6-14 aryl groups (for example, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl group, etc.) and the like.
Examples of the “aryloxy group” include C _6-14 aryloxy groups (eg, phenyloxy, 1-naphthyloxy, 2-naphthyloxy groups, etc.).
Examples of the “acyl group” include formyl, alkylcarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylsulfinyl, alkylsulfonyl group and the like.
Examples of the “alkylcarbonyl group” include a C _1-6 alkyl-carbonyl group (for example, acetyl, propionyl group, etc.) and the like.
Examples of the “alkoxycarbonyl group” include a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and the like.
The “alkylcarbamoyl group” includes N—C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.), N, N-diC _1-6 alkyl-carbamoyl group (eg, N, N— Dimethylcarbamoyl, N, N-diethylcarbamoyl group, etc.).
Examples of the “alkylsulfinyl group” include C _1-7 alkylsulfinyl groups (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl groups, etc.) and the like.
Examples of the “alkylsulfonyl group” include a C _1-7 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl group, etc.) and the like.
Examples of the “acyloxy group” include alkylcarbonyloxy group, alkoxycarbonyloxy group, carbamoyloxy group, alkylcarbamoyloxy group, alkylsulfinyloxy group, alkylsulfonyloxy group and the like.
Examples of the “alkylcarbonyloxy group” include a C _1-6 alkyl-carbonyloxy group (for example, acetyloxy, propionyloxy group and the like).
Examples of the “alkoxycarbonyloxy group” include a C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy group, etc.).
Examples of the “alkylcarbamoyloxy group” include C _1-6 alkyl-carbamoyloxy groups (eg, methylcarbamoyloxy, ethylcarbamoyloxy groups, etc.).
Examples of the “alkylsulfinyloxy group” include a C _1-7 alkylsulfinyloxy group (eg, methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy group, etc.).
Examples of the “alkylsulfonyloxy group” include C _1-7 alkylsulfonyloxy groups (eg, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy groups, etc.).
The “5- to 10-membered heterocyclic group” includes, for example, a 5- to 10-membered (including 1 to 3) heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( (Preferably 5 or 6 membered) heterocyclic group is mentioned, and specific examples include 2- or 3-thienyl group, 2-, 3- or 4-pyridyl group, 2- or 3-furyl group, 1-, 2 -Or 3-pyrrolyl group, 2-, 3-, 4-, 5- or 8-quinolyl group, 1-, 3-, 4- or 5-isoquinolyl group, 1-, 2- or 3-indolyl group and the like. Can be mentioned. Of these, a 5- or 6-membered heterocyclic group such as a 1-, 2- or 3-pyrrolyl group is preferable.
Preferably, ring A has a substituent selected from a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group, and a 5- or 6-membered heterocyclic group. It is a benzene ring which may have one or two.

As the “aralkyl group” of the “aralkyl group optionally having substituent (s)” represented by R ¹ , for example, a C _7-16 aralkyl group (for example, C _6-10 aryl C _{1- 1} such as benzyl, phenethyl and the like) ₆ alkyl group). Examples of the “substituent” of the “aralkyl group which may have a substituent” include the same substituents as the “substituent” of the “alkyl group which may have a substituent”. The number of groups is about 1 to 4. When the number of substituents is 2 or more, each substituent may be the same or different.
Examples of the “acyl group” represented by R ¹ include the “acyl group” described as the substituent for the ring A.
Examples of the “acyloxy group” represented by R ¹ include the “acyloxy group” described as the substituent for the ring A.
Preferred R ¹ is a hydrogen atom.
As the “alkyl group optionally having substituent (s)” represented by R ² , R ³ or R ⁴ , the “alkyl group optionally having substituent (s)” described as the substituent of ring A above Can be mentioned.
As the “optionally substituted alkoxy group” represented by R ² , R ³ or R ⁴ , the “optionally substituted alkoxy group” described as the substituent of the ring A is Can be mentioned.
Examples of the “optionally substituted amino group” represented by R ² , R ³ or R ⁴ include an amino group and a mono-C _1-6 alkylamino group (for example, methylamino, ethylamino, etc.). Mono-C _6-14 arylamino group (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), di-C _{6 -14} arylamino group (for example, diphenylamino etc.) etc. are mentioned.
Preferred R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group, or a di-C _1-6 alkylamino group. More preferred R ² is a C _1-3 alkyl group or a C _1-3 alkoxy group.
Preferable R ³ is a hydrogen atom, a C _1-6 alkoxy-C _1-6 alkoxy group or an optionally halogenated C _1-6 alkoxy group. Further preferred R ³ is a C _1-3 alkoxy group which is halogenated or optionally substituted with a C _1-3 alkoxy group.
Preferred R ⁴ is a hydrogen atom or a C _1-6 alkyl group. More desirable R ⁴ is a hydrogen atom or a C _1-3 alkyl group (particularly a hydrogen atom).
Preferred Y is a nitrogen atom.

Specific examples of compound (I) include the following compounds.
2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole, 2-[[(3,5-dimethyl-4-methoxy 2-pyridinyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole, 2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole -Sodium salt, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and the like.
Of these compounds, 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (lansoprazole) is preferred. Compound (I) may be a racemate or an optically active form such as an R-form and an S-form. For example, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (referred to as R-soprazole R-form) It may be an optically active substance such as

The salt of compound (I) is preferably a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic base, a salt with an organic base, and a salt with a basic amino acid.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like.
Suitable examples of salts with organic bases include, for example, alkylamines (trimethylamine, triethylamine, etc.), heterocyclic amines (pyridine, picoline, etc.), alkanolamines (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine. And salts with N, N′-dibenzylethylenediamine and the like.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Of these salts, alkali metal salts or alkaline earth metal salts are preferable. The sodium salt is particularly preferable.
As PPI that can be used in the present preparation, a prodrug compound of PPI of compound (I) or other benzimidazole compounds or PPI of imidazopyridine compounds can also be used. Examples of such prodrugs include prodrugs described in WO2003-27098, US Pat. No. 4,045,563, US Pat. No. 6,093,734, US Pat. No. 5,039,806, WO2002 / 30920, and the like.
Compound (I) can be produced by a method known per se, such as the methods described in JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10-195068, WO 98/21201, etc. It is manufactured by the method according to. The optically active compound (I) can be obtained by a method such as optical resolution (fractional recrystallization method, chiral column method, diastereomer method, method using microorganisms or enzymes), asymmetric oxidation and the like. For example, in the case of lansoprazole R-form, it can also be produced according to the methods described in WO 00/78745, WO 01/83473, WO 01/87874 and WO 02/44167.
The PPI used in the present invention includes benzimidazole compounds having antiulcer activity such as lansoprazole, omeprazole, rabeprazole, pantoprazole, and imidazopyridine compounds such as tenatoprazole, or optically active substances thereof, and pharmaceutically Acceptable salts are preferred. PPI is more preferably lansoprazole, omeprazole, tenatoprazole, and particularly preferably lansoprazole.

As a salt of the PPI compound, a pharmacologically acceptable salt as described above as a salt of the compound (I), for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid And salts with basic or acidic amino acids.
Specifically, preferable examples of salts with inorganic bases include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with aluminum and ammonium.
Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.

  The granules, fine granules, and tablets containing PPI in the present invention are particulate solid preparations having a relatively small particle size, which are called multiple unit preparations such as granules, fine granules, tablets, pellets, etc., used in ordinary oral solid preparations. In the case of a tablet, a mini tablet is preferable. Granules are usually preferred as PPI-containing preparations. The NSAID-containing granules or fine granules may be solid preparations referred to as similar multiple unit preparations, but granules and fine granules are preferred, and granules are particularly preferred. In the present invention, it is preferable that a PPI-containing granule or the like and an NSAID-containing granule or the like are basically orally administered to a patient in a form in which a plurality of capsules or sachets are filled. As a multiple unit preparation (hereinafter sometimes collectively referred to as a multiple unit preparation) such as granules, fine granules, and tablets (preferably mini-tablets) in the present invention, a particulate preparation having an average particle diameter of 3 mm or less is preferred. Alternatively, a mini tablet having a diameter of 7 mm or less is suitable. More preferred are granules or fine granules having an average particle size of 2 mm or less. In the case of tablets, the gastric emptying rate of the preparation is greatly affected by the presence or absence of a meal, and the pharmacokinetics of the drug tends to vary. However, since the preparation of the present invention is a multiple unit, the absorption of PPI and NSAID, etc. It is characterized in that the dynamics are not easily affected by the presence or absence of a meal.

Since the multiple unit preparation containing PPI used in the present invention is unstable to an acid, a form coated with an enteric base is preferable. Specifically, agents such as enteric coated granules and enteric coated fine granules The shape can be mentioned. Two or more of these may be used in combination at an appropriate ratio. Of these, particularly preferred dosage forms are enteric coated granules.
Examples of the multiple unit preparation containing NSAID used in the present invention include sustained-release preparations such as immediate release, enteric, sustained-release, etc. for granules, fine granules, pellets and the like. May be used in combination at an appropriate ratio. Of these, a particularly preferred dosage form is a once-per-day sustained granule. By using such a once-daily granule or the like, a preparation combined with PPI has an effect of improving the compliance of medication as a once-daily preparation.

  The combination of the multiple unit preparation containing PPI and one or more NSAIDs used in the present invention is preferably in the form of a preparation filled in the unit. Multiple unit preparations containing PPI and multiple unit preparations containing one or more NSAIDs may be filled and mixed in the same unit, without being mixed in the same unit You may divide and fill with another group. Examples of the unit to be combined include capsules and sachets, but capsules are more preferable. Examples of capsules include hard gelatin capsules and hard hydroxypropyl methylcellulose capsules.

A particularly preferred combination of PPI and NSAID in the solid dosage form of the present invention is a combination of lansoprazole and diclofenac sodium or a combination of lansoprazole and piroxicam. PPI and one or more NSAIDs are preferably combined in a weight ratio of about 3 to 1 to 1 to 300 and filled into the unit, depending on the drug used.
For example, in the case of a solid preparation of a combination of lansoprazole and diclofenac sodium, a solid preparation containing a weight ratio of about 1: 1 to 1:20 is preferred.
In the case of a solid preparation of a combination of lansoprazole and piroxicam, it is usually preferable to form a solid preparation containing a weight ratio of about 2: 1 to 1: 2.

The density of the multiple unit preparation containing PPI or NSAID in the present invention is about 0.5 to about 2.0, preferably about 0.7 to about 1.7.
Each multiple unit preparation of the present invention has a physically sufficient hardness and maintains its properties without being damaged when filled into a hard capsule. Moreover, the characteristic is maintained without damaging each multiple unit preparation in the hard capsule during transportation.
The preparation obtained by filling the capsule with the enteric multiple unit preparation containing PPI and the multiple unit preparation containing NSAID in the present invention is excellent in stability and compoundability, and the preparation may be colored even after long-term storage. In addition, it has excellent characteristics such that the content of each drug does not decrease and the dissolution property of each drug from the preparation does not change.
The present invention thus fills a single unit with multiple unit formulations containing a proton pump inhibitor (PPI) and multiple unit formulations containing one or more non-steroidal anti-inflammatory agents (NSAIDs). The present invention also provides a novel method for producing a solid preparation.
The pharmacokinetics of each drug after oral administration of a preparation obtained by filling an enteric granule containing PPI and a granule containing NSAID in the same capsule according to the present invention is as follows: capsule containing PPI enteric granule and NSAID granule Is not different from the combined administration.

The solid preparation of the present invention may contain additives commonly used in the technical field of preparation. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, a sour agent, a fragrance, and a fluidizing agent. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations.
Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars such as lactose, fructose, glucose, mannitol, sorbitol, Sugar alcohols: anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like.
As the disintegrant, for example, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like are used. The amount of the disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight with respect to 100 parts by weight of the solid preparation.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like. The amount of the binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight with respect to 100 parts by weight of the solid preparation. The binder is preferably hydroxypropylcellulose or polyvinylpyrrolidone.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like.
Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and iron sesquioxide.
Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.

Examples of the stabilizer include tocopherol, edetate tetrasodium, nicotinamide, and cyclodextrins.
Examples of the sour agent include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
Examples of the fragrances include menthol, mint oil, lemon oil, and vanillin.
Examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide. Here, the light anhydrous silicic acid only needs to contain hydrous silicon dioxide (SiO ₂ · nH ₂ O) (n represents an integer) as a main component. As a specific example thereof, for example, Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.) and the like.
Two or more of the above-described additives may be mixed and used at an appropriate ratio.

The content of PPI used in the present invention varies depending on the type and dose of the active ingredient, but is, for example, 1 to 40 parts by weight, preferably 3 to 30 parts by weight with respect to 100 parts by weight of the solid preparation of the present invention. is there.
In particular, when the PPI is lansoprazole, the content of lansoprazole in the solid preparation of the present invention is preferably 1 to 40 parts by weight, more preferably 5 to 30 parts by weight with respect to 100 parts by weight of the solid preparation of the present invention. is there.
The content of NSAID in the solid preparation of the present invention is, for example, 1 to 60 parts by weight, preferably 5 to 50 parts by weight with respect to 100 parts by weight of the solid preparation of the present invention.
In particular, when the NSAID is diclofenac sodium, the content of diclofenac sodium in the solid preparation of the present invention is preferably 5 to 60 parts by weight, more preferably 15 to 50 parts by weight, for example, with respect to 100 parts by weight of the solid preparation of the present invention. Part.
When NSAID is piroxicam, the content of piroxicam in the solid preparation of the present invention is preferably 5 to 30 parts by weight, more preferably 10 to 20 parts by weight, for example, with respect to 100 parts by weight of the solid preparation of the present invention. is there.

  The solid preparation of the present invention can be produced according to a conventional method. As a typical production method, a PPI-containing preparation, preferably a multiple unit preparation containing an enteric coating or the like, and a multiple unit preparation containing an NSAID are separately produced, and then one unit (preferably a capsule) It is manufactured by filling the appropriate amount. Specifically, for example, in the case of a preparation containing lansoprazole and diclofenac sodium, an enteric granule of lansoprazole and a sustained-release granule of diclofenac sodium are separately produced and then filled into gelatin hard capsules in appropriate amounts. The enteric granules can be produced, for example, by the production method described in US Pat. No. 6,365,184. Moreover, as a manufacturing method of this sustained release granule, various known manufacturing methods can be adopted. For example, it can also be manufactured by a manufacturing method described in International Publication No. WO02 / 22108.

Examples of the coating base for producing the multiple unit preparation include enteric film coating base and sustained-release film coating base.
Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Rohm Pharma Co.], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]; Examples include natural products such as shellac.
Examples of sustained-release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as turbid liquid [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] can be used.

Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use a coating additive in the case of coating.
Examples of the coating additive include light-shielding agents and / or colorants such as titanium oxide, talc, and iron sesquioxide; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates; citric acid, tartaric acid, malic acid And organic acids such as ascorbic acid.

The enteric-coated multiple unit preparation containing PPI in the present invention contains about 6% to about 40% by weight of PPI based on the total amount of the multiple unit preparation, and about 0.2 parts by weight based on 1 part by weight of PPI. It is preferable to contain about 1.0 part by weight of one or more basic inorganic salts selected from the group consisting of basic salts of sodium, potassium, aluminum, magnesium and calcium salts. It is preferable to provide an enteric coating layer on such a main agent layer. You may have the intermediate | middle coating layer formed on this active ingredient layer as needed.
The sustained-release multiple unit preparation containing NSAID in the present invention comprises a main drug layer containing about 15% by weight to about 60% by weight of NSAID and an appropriate excipient, acrylic polymer, etc. And a sustained-release coating layer.

Since the active ingredients PPI and NSAID used in the present invention are both low-toxic drugs, the solid preparation of the present invention can be used in mammals (eg, mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.). In contrast, it can be safely administered orally.
The solid preparation of the present invention is useful as an antipyretic / analgesic / anti-inflammatory agent or the like having an effect of preventing, treating, or reducing gastrointestinal disorders by NSAID. When aspirin or the like is used as the NSAID, it is useful as a prophylactic or therapeutic drug for platelet aggregation pharmacy, angina pectoris, myocardial infarction and the like.
If desired, the solid preparation of the present invention may be combined with other drugs, or may be used in combination with a pharmaceutical preparation containing other drugs. Examples of such combination or combination drugs include other anti-inflammatory agents, antibiotics (eg, penicillin antibiotics (eg, amoxicillin) and erythromycin antibiotics (eg, clarithromycin)), antibacterial agents, And antacids, selective muscarinic receptor antagonists, antigastrin drugs, gastrointestinal motility regulators (gastrointestinal motility promoters) (such as 5-HT ₄ receptor agonists such as mosapride and cisapride), and the like.

The dosage of the solid preparation of the present invention may be an effective amount as PPI and NSAID contained in the solid preparation.
Here, the effective amount of PPI is usually 0.01 to 500 mg / day, preferably 0.1 to 100 mg / day, for example, per adult (body weight 60 kg).
In particular, when the PPI is lansoprazole, the effective amount of lansoprazole is usually 7.5 to 60 mg / day, preferably 15 to 30 mg / day, per adult (body weight 60 kg).
The effective amount of NSAID is usually 0.01 to 10,000 mg / day, preferably 0.1 to 5000 mg / day, for example, per adult (body weight 60 kg).
In particular, when NSAID is a phenylacetic acid compound (preferably diclofenac sodium, fenbufen), the effective amount of diclofenac sodium is usually 10 to 500 mg / day, preferably 25 to 200 mg / day per adult (60 kg body weight). It is. The effective amount of fenbufen is usually 600 to 1000 mg / day per adult (60 kg body weight). Further, when the NSAID is a propionic acid compound (preferably ibuprofen, ketoprofen, naproxen, loxoprofen sodium, pranoprofen), an effective amount of the propionic acid compound (preferably ibuprofen, ketoprofen, naproxen, loxoprofen sodium) (Weight 60 kg) per person is usually 50 to 1000 mg / day, preferably 150 to 600 mg / day.
When NSAID is a salicylic acid compound (preferably aspirin), the effective amount of the salicylic acid compound (preferably aspirin) is usually 100 to 5000 mg / day, preferably 1000 to 4500 mg per adult (body weight 60 kg). / Day.
When NSAID is an indoleacetic acid compound (preferably indomethacin, sulindac), the effective amount of indomethacin is usually 10 to 100 mg / day, preferably 25 to 75 mg / day per adult (60 kg body weight). . The effective amount of sulindac is usually 100 to 600 mg / day, preferably 250 to 350 mg / day, per adult (body weight 60 kg).
When NSAID is an anthranilic acid compound (eg, mefenamic acid), the effective amount of the anthranilic acid compound (eg, mefenamic acid) is usually 200 to 1000 mg / day, preferably per adult (body weight 60 kg). Is 400-600 mg / day.
When NSAID is an oxicam compound (preferably piroxicam or meloxicam), the effective amount of piroxicam is usually 10 to 50 mg / day, preferably 20 to 30 mg / day per adult (body weight 60 kg). The effective amount of meloxicam is usually 5 to 20 mg / day, preferably 10 to 20 mg / day, per adult (body weight 60 kg).
When NSAID is a COX-2 inhibitor (preferably rofecoxib, celecoxib, valdecoxib), the effective amount of rofecoxib is usually 10 to 50 mg / day for an adult (body weight 60 kg). The effective amount of celecoxib is usually 100 to 400 mg / day, preferably 200 to 400 mg / day, per adult (body weight 60 kg). The effective amount of valdecoxib is usually 10-40 mg / day for an adult (body weight 60 kg).
The frequency of administration of the solid preparation of the present invention to the mammal per day is preferably 1 to 2 times a day, more preferably once a day.

Although representative examples of the dose of the PPI of the present invention and one or more NSAIDs have been described above, these can be appropriately selected based on the clinically used dose. The mixing ratio of the solid preparation of the present invention can be appropriately selected depending on the administration subject, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.5 to 300 parts by weight of NSAID may be used for 1 part by weight of PPI. More preferably, for example, 1 to 20 parts by weight of NSAID may be used with respect to 1 part by weight of lansoprazole.
Thus, by using a combination of multiple units of PPI and multiple units of NSAID, an antipyretic / analgesic / anti-inflammatory agent having excellent effects such as treatment and prevention of gastrointestinal disorders by NSAID can be obtained.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
In the following examples, Japanese Pharmacopoeia 14th revision compatible products were used as various additives such as magnesium stearate.

Example 1
Lansoprazole enteric granules were prepared by the manufacturing method described in US Pat. No. 6,365,184. Further, sustained release granules of diclofenac sodium were produced by the production method described in International Publication No. WO02 / 22108. Gelatin hard capsules (size 0) were filled with enteric granules containing 30 mg equivalent as lansoprazole and sustained-release granules containing 100 mg equivalent as diclofenac sodium to obtain the desired preparation.

The solid preparation of the present invention contains an active ingredient NSAID, is useful as a therapeutic agent for rheumatoid arthritis, a therapeutic agent for osteoarthritis, an anti-inflammatory agent, an antipyretic analgesic and the like, and by the action of the active ingredient PPI, Has the effect of treating and preventing gastrointestinal disorders and can reduce gastrointestinal disorders such as ulcers. Furthermore, the preparation of the present invention is excellent in stability and compounding property, and the pharmacokinetics of each drug is not different from that at the time of concomitant administration, and is hardly affected by meals.
Furthermore, the solid preparation of the present invention has an advantageous feature for industrial implementation that it can be easily produced by a simple method.

Claims (17)

A solid formulation comprising a combination of granules, granules or tablets containing a proton pump inhibitor (PPI) and granules or granules containing one or more non-steroidal anti-inflammatory drugs (NSAIDs). The solid preparation according to claim 1, wherein the PPI is a benzimidazole compound. The benzimidazole compound is represented by the formula (I):

[Wherein, ring A is an optionally substituted benzene ring, R ¹ is a hydrogen atom, an optionally substituted aralkyl group, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ is the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent or an amino group which may have a substituent, and Y Is a nitrogen atom or CH], or an optically active compound thereof or a salt thereof. The solid preparation according to claim 2, wherein the benzimidazole compound is lansoprazole, omeprazole, rabeprazole, pantoprazole, an optically active substance thereof, or a salt thereof. The solid preparation according to claim 1, wherein the PPI is an imidazopyridine compound. 6. The solid preparation according to claim 5, wherein the imidazopyridine compound is tenatoprazole or an optically active form thereof or a salt thereof. The solid preparation according to claim 1, wherein the granules, fine granules or tablets containing PPI are enteric-coated. The solid preparation according to claim 1, wherein the granules or fine granules containing NSAID are persistent granules or fine granules. The solid preparation according to claim 1, wherein a combination of granules, granules or tablets containing PPI and granules or granules containing one or more NSAIDs is filled in one unit. The solid preparation according to claim 9, wherein one unit is a capsule. The solid preparation according to claim 1, wherein the NSAID is a phenylacetic acid compound, a propionic acid compound, a salicylic acid compound, an indole acetic acid compound, an anthranilic acid compound, an oxicam compound or a salt thereof. The solid preparation according to claim 1, wherein the NSAID is a COX-2 inhibitor. Enteric coated granules and diclofenac sodium, ibuprofen, ketoprofen, naproxen, loxoprofen sodium, aspirin, indomethacin, mefenam containing PPI selected from lansoprazole, omeprazole, rabeprazole, pantoprazole and tenatoprazole, optically active forms thereof and salts thereof The solid preparation according to claim 9, wherein granules containing one or more NSAIDs selected from acids, piroxicam, rofecoxib, celecoxib and valdecoxib are filled in a capsule. The solid preparation according to claim 1, comprising PPI and one or more NSAIDs in a weight ratio of 3: 1 to 1: 300. The solid preparation according to claim 14, comprising lansoprazole and diclofenac sodium in a weight ratio of 1: 1 to 1:20. The solid preparation according to claim 14, comprising lansoprazole and piroxicam in a weight ratio of 2: 1 to 1: 2. The solid preparation according to claim 1, which is an antipyretic / analgesic / anti-inflammatory agent having an effect of preventing, treating, or reducing gastrointestinal disorders by NSAID.