JP2004155773A - Stable solid formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an unstable amorphous benzimidazole-based compound having proton pump-inhibiting action and prepare a stable solid pharmaceutical formulation containing the same. <P>SOLUTION: The stable solid pharmaceutical formulation contains granules prepared by blending a nontoxic base such as a basic inorganic salt, or the like, with the amorphous benzimidazole-based compound, applying an intermediate coating layer on an active ingredient-containing layer and coating the same with an enteric coating layer, a controlled release layer, or the like. <P>COPYRIGHT: (C)2004,JPO

Description

  The present invention relates to a stable pharmaceutical solid preparation containing an amorphous benzimidazole-based compound which is not only unstable to acids but also unstable to water, which is useful as a proton pump inhibitor (PPI).

Benzimidazole (also referred to as benzimidazole) -based compounds such as lansoprazole, omeprazole, and rabeprazole (hereinafter, referred to as benzimidazole-based compounds in the present specification) are proton pump inhibitors (hereinafter, referred to as gastric acid secretion inhibitory action and gastric mucosal defense action). It is widely used as a therapeutic agent for peptic ulcer and the like because of its action.
However, the stability of these compounds, particularly amorphous benzimidazole compounds, is poor. In a solid state, the compounds are unstable not only to temperature, humidity, and light but also to water, and are remarkably discolored. In particular, they are very unstable to acids, and become extremely unstable in aqueous solutions or suspensions as the pH decreases.
In addition, the stability of the formulation, i.e., tablets, powders, fine granules, capsules, etc., becomes unstable due to stronger interaction with other components in the formulation than the compound alone, and changes in color during production and storage Alternatively, degradation is observed. In order to stabilize these, for example, in Patent Document 1, after mixing a stabilizer composed of a basic inorganic salt of magnesium and / or calcium, enteric coated granules or enteric fine granules coated with an enteric coating. Agents and the like are disclosed.
A benzimidazole compound having a PPI action generally has a property of being hardly soluble in water and is unstable to an acid, so that it is necessary to apply an enteric coating. The enteric coating is applied with the expectation that the benzimidazole-based compound will be dissolved and absorbed in the small intestine, which has a low pH and a relatively high water content, will not dissolve in the stomach, and has a low water content and a high pH. However, there is known a literature specifically examining the stabilization of a formulation containing an amorphous benzimidazole-based compound which is not only unstable to acids but also has poor stability to moisture in the air. Absent.
Further, Patent Documents 2 and 3 disclose solutions, suspensions, tablets, capsules and the like obtained by combining omeprazole or lansoprazole with an alkali metal salt of bicarbonate which is not subjected to an enteric coating treatment. I have.
However, since these are preparations in which bicarbonate is combined, they react with acid in the stomach and generate carbon dioxide gas, which causes burp, which is not preferable in terms of compliance.
JP-A-62-277322 U.S. Pat. No. 5,840,737 WO 00/26185 pamphlet

  An object of the present invention is to provide a stable pharmaceutical solid preparation containing an unstable amorphous benzimidazole compound having a proton pump inhibitor (PPI) action.

〔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を示し、＊は不斉中心を示す〕で表される化合物またはその塩である上記（２）記載の固形製剤、
（４）ベンズイミダゾール系化合物の光学活性体が、ランソプラゾール、オメプラゾール、ラベプラゾールまたはパントプラゾールの光学活性体である上記（２）記載の固形製剤、
（５）ベンズイミダゾール系化合物の光学活性体が、ランソプラゾールの光学活性体である上記（２）記載の固形製剤、
（６）ランソプラゾールの光学活性体が、Ｒ体である上記（５）記載の固形製剤、
（７）ランソプラゾールの光学活性体が、Ｓ体である上記（５）記載の固形製剤、
（８）無毒性塩基が、その１％水溶液または１％水懸濁液のｐＨが２５℃で８．０以上を示す無機塩である上記（１）記載の固形製剤、
（９）無毒性塩基が、炭酸マグネシウム、炭酸カルシウム、水酸化マグネシウム、酸化マグネシウム、炭酸ナトリウム、炭酸水素ナトリウムおよび水酸化ナトリウムからなる群から選ばれる１種以上の塩基性無機塩である上記（１）記載の固形製剤、
（１０）被覆層を有する上記（１）記載の固形製剤、
（１１）被覆層が、腸溶性被膜層を含む上記（１０）記載の固形製剤、
（１２）被覆層が、放出制御被膜層を含む上記（１０）記載の固形製剤、
（１３）被覆層が、非晶形ベンズイミダゾール系化合物を含有する層上に形成された中間被覆層と該中間被覆層上に形成された放出制御被膜層および／または腸溶性被膜層を含む上記（１０）記載の固形製剤、
（１４）無毒性塩基が、金属酸化物から選ばれる少なくとも１種と金属水酸化物から選ばれる少なくとも１種とを含有する上記（１）記載の固形製剤、
（１５）胃崩壊性である上記（１４）記載の固形製剤、
（１６）酸化マグネシウム、ケイ酸マグネシウム、乾燥水酸化アルミニウムゲルおよびメタケイ酸アルミン酸マグネシウムからなる群から選ばれる少なくとも１種の金属酸化物を含有する上記（１４）記載の固形製剤、
（１７）水酸化マグネシウム、水酸化アルミニウム、合成ヒドロタルサイト、水酸化アルミニウムと水酸化マグネシウムの共沈物、水酸化アルミニウムと炭酸マグネシウムと炭酸カルシウムの共沈物および水酸化アルミニウムと炭酸水素ナトリウムの共沈物からなる群から選ばれる少なくとも１種の金属水酸化物を含有する上記（１４）記載の固形製剤、
（１８）さらにアルカリ土類金属の炭酸塩を含有する塩基性無機塩安定化剤を含有する上記（１４）記載の固形製剤、
（１９）非晶形のランソプラゾール光学活性Ｒ体と炭酸マグネシウム、炭酸カルシウム、水酸化マグネシウム、酸化マグネシウム、炭酸ナトリウム、炭酸水素ナトリウムおよび水酸化ナトリウムからなる群から選ばれる少なくとも１種の塩基性無機塩とを含有する層と、該層上に形成された中間被覆層と、該中間被覆層上に形成された腸溶性被覆層とを含む安定化された固形製剤、
（２０）塩基性無機塩が、炭酸マグネシウムまたは炭酸カルシウムである上記（１９）記載の固形製剤、
（２１）酸素透過を抑制した包装、ガス置換包装、真空包装および脱酸素剤封入包装からなる群から選択される包装形態にすることを特徴とする非晶形のＰＰＩ作用をもつベンズイミダゾール系化合物を含有する安定な固形製剤の製造方法、
（２２）無毒性塩基を配合する上記（２１）記載の製造方法、
（２３）ランソプラゾール光学活性体（Ｒ体）の含水結晶を約２０〜約１００℃に保持することを特徴とする非晶形ランソプラゾール光学活性体の製造法、
（２４）約４０〜約８０℃に加熱することを特徴とする上記（２３）記載の非晶形ランソプラゾール光学活性体の製造法、
（２５）ランソプラゾール光学活性体（Ｒ体）の０．５乃至１．５水和物結晶を約５０〜約７０℃に加熱する上記（２３）記載の製造法、および
（２６）温度の保持を減圧下または通風下に行う上記（２３）記載の製造法を提供する。 That is, the present invention
(1) a stable solid preparation containing a non-toxic base and an amorphous benzimidazole compound having a proton pump inhibitor (PPI) action;
(2) The solid preparation according to the above (1), wherein the benzimidazole compound is an optically active substance.
(3) The optically active form of the benzimidazole compound is represented by the formula (I):

[In the formula, ring A is a benzene ring which may have a substituent, R ¹ is a hydrogen atom, an aralkyl group which may have a substituent, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ is the same or different and is 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, * represents an asymmetric center]] or a salt thereof, the solid preparation according to the above (2),
(4) The solid preparation according to the above (2), wherein the optically active form of the benzimidazole compound is an optically active form of lansoprazole, omeprazole, rabeprazole or pantoprazole.
(5) The solid preparation according to the above (2), wherein the optically active form of the benzimidazole compound is an optically active form of lansoprazole,
(6) The solid preparation according to the above (5), wherein the optically active form of lansoprazole is an R-form.
(7) The solid preparation according to the above (5), wherein the optically active form of lansoprazole is the S-form.
(8) The solid preparation according to the above (1), wherein the non-toxic base is an inorganic salt showing a pH of 1% aqueous solution or 1% aqueous suspension at 25 ° C. of 8.0 or more,
(9) The non-toxic base is one or more basic inorganic salts selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. ) Described solid preparation,
(10) The solid preparation according to the above (1), having a coating layer.
(11) The solid preparation according to the above (10), wherein the coating layer comprises an enteric coating layer.
(12) The solid preparation according to the above (10), wherein the coating layer comprises a controlled release coating layer,
(13) The coating layer comprising an intermediate coating layer formed on a layer containing an amorphous benzimidazole compound and a controlled release coating layer and / or an enteric coating layer formed on the intermediate coating layer. 10) The solid preparation according to the above,
(14) The solid preparation according to the above (1), wherein the nontoxic base contains at least one selected from metal oxides and at least one selected from metal hydroxides.
(15) The solid preparation according to (14), which is gastric disintegrating,
(16) The solid preparation according to the above (14), comprising at least one metal oxide selected from the group consisting of magnesium oxide, magnesium silicate, dried aluminum hydroxide gel, and magnesium metasilicate aluminate.
(17) Magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, co-precipitates of aluminum hydroxide and magnesium hydroxide, co-precipitates of aluminum hydroxide, magnesium carbonate and calcium carbonate, and of aluminum hydroxide and sodium hydrogen carbonate The solid preparation according to the above (14), comprising at least one metal hydroxide selected from the group consisting of coprecipitates;
(18) The solid preparation according to the above (14), further comprising a basic inorganic salt stabilizer containing a carbonate of an alkaline earth metal,
(19) Amorphous lansoprazole optically active R form and at least one basic inorganic salt selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide And a stabilized solid preparation comprising: an intermediate coating layer formed on the intermediate coating layer; and an enteric coating layer formed on the intermediate coating layer.
(20) The solid preparation according to the above (19), wherein the basic inorganic salt is magnesium carbonate or calcium carbonate,
(21) A benzimidazole-based compound having an amorphous PPI action, wherein the benzimidazole-based compound is formed into a packaging form selected from the group consisting of packaging in which oxygen permeation is suppressed, gas displacement packaging, vacuum packaging, and oxygen-containing packaging. A method for producing a stable solid preparation containing,
(22) The production method according to (21), wherein a non-toxic base is blended.
(23) A method for producing an optically active amorphous lansoprazole, which comprises maintaining the hydrous crystal of the optically active lansoprazole (R-form) at about 20 to about 100 ° C.
(24) The method for producing an optically active amorphous lansoprazole according to the above (23), wherein the method is heated to about 40 to about 80 ° C.
(25) The method according to the above (23), wherein the 0.5 to 1.5 hydrate crystal of the lansoprazole optically active substance (R form) is heated to about 50 to about 70 ° C, and (26) the temperature is maintained. The production method according to the above (23), which is performed under reduced pressure or under ventilation.

According to the present invention, a non-toxic base represented by a basic inorganic salt such as magnesium, calcium, and sodium is mixed with a very unstable amorphous benzimidazole-based compound having a proton pump inhibitor action. Still more preferably, a stable solid preparation can be obtained by further providing an intermediate coating layer on the active ingredient-containing layer and coating this with an enteric coating layer or a controlled release coating layer.
Further, the present invention provides a novel production method for obtaining an amorphous form of a benzimidazole-based compound which is useful as a once crystallized PPI, especially an amorphous form of an optically active substance, for example, an amorphous lansoprazole R form. .

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。
とりわけ、上記式（Ｉ）で表される光学活性体またはその塩が、医薬として好ましい。これら化合物は非晶形では上述のように不安定で、単独では、分解や変色が顕著であるが、意外にも製剤化することにより安定化され、医薬として有用であることが見出された。 The solid preparation according to the present invention is a non-toxic base, preferably an amorphous benzimidazole-based compound having a PPI action and represented by the above formula (I) which is unstable, particularly very unstable to an acid. Direct contact between these coatings and the core particles, if necessary, by incorporating a basic inorganic salt, or by providing an enteric coating or a controlled release coating on the core particles containing these active ingredients. This is a solid preparation in which an unstable active ingredient is stabilized by providing an intermediate film for cutting off the active ingredient. As used herein, the term “enteric coating” refers to a coating that dissolves at a normal pH of about 5.5, and the “controlled release coating” does not include a normal enteric coating, but a normal enteric coating. A pH-dependent coating or a diffusion-controlling film that dissolves in a pH range different from the above does not dissolve, but releases an active ingredient through pores formed in the film.
As the benzimidazole compound having a PPI action used in the present invention, a compound represented by the following formula (I ′), an optically active form thereof, or a salt thereof is preferable.

In the formula, ring A is a benzene ring which may have a substituent, R ¹ is a hydrogen atom, an aralkyl group which may have a substituent, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ Are the same or different and are each 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 Indicates a nitrogen atom or CH.
In particular, the optically active substance represented by the above formula (I) or a salt thereof is preferable as a medicine. These compounds are unstable in the amorphous form as described above, and when used alone, they are markedly decomposed and discolored. However, they have been unexpectedly stabilized by being formulated and found to be useful as pharmaceuticals.

Preferred compounds are those represented by the above formulas (I ′) and (I), wherein ring A is a halogen atom, an optionally halogenated C _1-4 alkyl group, or an optionally halogenated C _1-4 alkoxy group. And a benzene ring which may have a substituent selected from a 5- or 6-membered heterocyclic group, wherein 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 a di-C _1-6 alkylamino group, wherein R ³ is a hydrogen atom, a C _1-6 alkoxy-C _1-6 alkoxy group or a halogenated is also a C _1-6 alkoxy group, R ⁴ is a hydrogen atom or a C _1-6 alkyl group, Y is a nitrogen atom, or a salt thereof.

〔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〕で表される化合物もしくはその光学活性体またはその塩である。
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もしくはその光学活性体またはその塩が特に好ましい。 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, and R ³ is a halogenated or C _1-3 optionally substituted with 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)], an optically active form thereof, or a salt thereof.
In the formula (Ia), R ¹ is a hydrogen atom, R ² is a C _1-3 alkyl group, R ³ is a C _1-3 alkoxy group which may be halogenated, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom Alternatively, a compound which is an optionally halogenated C _1-3 alkoxy group, an optically active form thereof, or a salt thereof is particularly preferable.

  The compound represented by the above formula (I ′) [hereinafter, referred to as compound (I ′); The compound (I ′) is a compound represented by the formula (I) or the formula (Ia) and an optically active compound thereof, , A compound (I), a compound (Ia) and an optically active form thereof, hereinafter collectively referred to as a compound (I ')]. As the “substituent”, for example, a halogen atom, a cyano group, a nitro group, an alkyl group optionally having a substituent, a hydroxy group, an alkoxy group optionally having a substituent, an aryl group, an aryloxy Groups, a carboxy group, an acyl group, an acyloxy group, and a 5- to 10-membered heterocyclic group. These substituents may substitute about 1 to 3 benzene rings. When the number of substituents is two or more, each substituent may be the same or different. Among 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, and bromine atoms. Of these, fluorine is preferred.
As the “alkyl group” of the “alkyl group optionally having substituent (s)”, for example, a C _1-7 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, hexyl, heptyl and the like). 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.) and a carbamoyl group, and the number of these substituents may be about 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
Examples of the “alkoxy group” of the “optionally substituted alkoxy group” include, for example, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, etc.). No. As the “substituent” of the “optionally substituted alkoxy group”, those similar to the “substituent” of the above “optionally substituted alkyl group” can be exemplified. Is the same.
As the “aryl group”, for example, a C _6-14 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl group and the like) and the like can be mentioned.
As the “aryloxy group”, for example, a C _6-14 aryloxy group (eg, phenyloxy, 1-naphthyloxy, 2-naphthyloxy group, etc.) and the like can be mentioned.
Examples of the “acyl group” include formyl, alkylcarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylsulfinyl, and alkylsulfonyl groups.
As the “alkylcarbonyl group”, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl group, etc.) and the like can be mentioned.
As the "alkoxycarbonyl group", for example, a _C1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and the like can be mentioned.
As the “alkylcarbamoyl group”, an N—C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.), an N, N-diC _1-6 alkyl-carbamoyl group (eg, N, N- Dimethylcarbamoyl, N, N-diethylcarbamoyl group and the like).
Examples of the “alkylsulfinyl group” include a C _1-7 alkylsulfinyl group (for example, a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl group and the like).
As the “alkylsulfonyl group”, for example, a C _1-7 alkylsulfonyl group (for example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl group and the like) can be mentioned.
Examples of the “acyloxy group” include an alkylcarbonyloxy group, an alkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxy group, an alkylsulfinyloxy group, an alkylsulfonyloxy group, and the like.
Examples of the “alkylcarbonyloxy group” include a C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy group, etc.).
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 a C _1-6 alkyl-carbamoyloxy group (for example, a methylcarbamoyloxy group, an ethylcarbamoyloxy group, and the like).
Examples of the “alkylsulfinyloxy group” include, for example, a C _1-7 alkylsulfinyloxy group (for example, methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy group, etc.).
As the “alkylsulfonyloxy group”, for example, a C _1-7 alkylsulfonyloxy group (for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy group and the like) can be mentioned.
As the "5- to 10-membered heterocyclic group", for example, a 5- to 10-membered heterocyclic group containing one or more (for example, 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( Preferred is a 5- or 6-membered) heterocyclic group, and specific examples thereof include a 2- or 3-thienyl group, a 2-, 3- or 4-pyridyl group, a 2- or 3-furyl group, and a 1-2 or 2-furyl group. -Or 3-pyrrolyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl and the like. No. Of these, a 5- or 6-membered heterocyclic group such as a 1-, 2- or 3-pyrrolyl group is preferred.
Preferably, ring A is 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)” for R ¹ , for example, a C _7-16 aralkyl group (for example, C _6-10 aryl C _1- such as benzyl and phenethyl) ₆ alkyl groups). Examples of the “substituent” of the “optionally substituted aralkyl group” include the same substituents as the “substituent” of the above “optionally substituted alkyl group”. The number of groups is about 1 to 4. When the number of substituents is two or more, each substituent may be the same or different.
As the “acyl group” for R ¹ , for example, the “acyl group” described as a substituent for ring A above can be mentioned.
As the “acyloxy group” for R ¹ , for example, the “acyloxy group” described as a substituent for ring A above can be mentioned.
Preferred R ¹ is a hydrogen atom.

As the “alkyl group optionally having substituent (s)” for R ² , R ³ or R ⁴ , the “alkyl group optionally having substituent (s)” described above as the substituent for the ring A can be mentioned. No.
Examples of the “optionally substituted alkoxy group” represented by R ² , R ³ or R ⁴ include the “optionally substituted alkoxy group” described as the substituent of the ring A. No.
Examples of the “optionally substituted amino group” represented by R ² , R ³ or R ⁴ include, for example, an amino group, a mono-C _1-6 alkylamino group (eg, methylamino, ethylamino, etc.) A mono-C _6-14 arylamino group (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), di-C _{6 -14} arylamino group (for example, diphenylamino and the like).
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.
Desirable 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. More preferred R ³ is a C _1-3 alkoxy group which may be halogenated or substituted with a C _1-3 alkoxy group.
Desirable R ⁴ is a hydrogen atom or a C _1-6 alkyl group. More preferred 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 the 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 optically active forms thereof.
Among these compounds, in particular, lansoprazole, ie, 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole and its optically active substance Is preferred.
The compound (I ′) may be a racemic form or an optically active form such as an R-form or an S-form represented by the formula (I). For example, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (hereinafter referred to as lansoprazole R-form) ) And (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (hereinafter lansoprazole S Optically active compounds such as R isomers are preferred, and those having an optically active R form are particularly suitable for the present invention. In addition, lansoprazole, lansoprazole R-form, lansoprazole S-form, and the like are stabilized by being formulated themselves, and are further compounded with a nontoxic salt, preferably a basic inorganic salt, and further provided with an intermediate coating layer. Since it is more stabilized, an amorphous type can be used, but a crystalline type may be mixed. In the present invention, the amorphous benzimidazole-based compound refers to a benzimidazole-based compound in which the amorphous form is larger than the crystalline form and usually contains about 60% or more of the whole.

As the salt of compound (I ′), a pharmaceutically acceptable salt is preferable, 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 an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an ammonium salt.
Preferred examples of the salt with an organic base include, for example, alkylamine (trimethylamine, triethylamine, etc.), heterocyclic amine (pyridine, picoline, etc.), alkanolamine (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine , N, N'-dibenzylethylenediamine and the like.
Suitable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like.
Of these salts, an alkali metal salt or an alkaline earth metal salt is preferred. Particularly, a sodium salt is preferable.

  Compound (I ′) and a salt thereof can be produced by a method known per se, for example, JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10-195068, WO 98/22101, It is produced by the method described in JP-A-52-62275, JP-A-54-141783 or the like or a method analogous thereto. The optically active compound (I) or a salt thereof can be obtained by a method such as an optical resolution method (a fractional recrystallization method, a chiral column method, a diastereomer method, a method using a microorganism or an enzyme), asymmetric oxidation, or the like. it can. The lansoprazole R-form can be produced, for example, according to the production methods described in WO 00-78745, WO 01/83473, WO 02/44167, and the like. Lansoprazole S form can also be produced according to the method described in WO 01/02389. The amorphous lansoprazole or an optically active substance thereof is a hydrated crystal of lansoprazole or an optically active substance thereof (preferably hydrated lansoprazole, more preferably lansoprazole 0.5 hydrate or lansoprazole 1.5 hydrate). ) At about 20 to about 100 ° C (preferably about 40 to about 80 ° C, more preferably about 50 to about 70 ° C). In addition, drying may be performed at the time of heating, and the pressure may be reduced, ventilation may be performed, or heating may be performed simply.

  The compounding amount of the benzimidazole compound having a PPI effect (hereinafter may be abbreviated as PPI) used in the present invention varies depending on the kind and dosage of the active ingredient. About 1% to 100% by weight, preferably about 5% to 50% by weight, based on the total amount of the solid preparation. According to the present invention, a formulation containing a high content of the active ingredient is also possible, and in the case of a formulation containing such a high content, about 12% to about 40% by weight, preferably about 12% by weight to About 20%, more preferably about 14% to about 20% by weight of PPI may be included. When the benzimidazole compound having a PPI action is lansoprazole or its optically active substance, a high content of about 14% to about 20% by weight is possible. In the case of a gastric disintegrating preparation, the amount is 0.001 to 0.3 part by weight, preferably 0.002 to 0.2 part by weight, based on 1 part by weight of the solid preparation of the present invention.

Examples of the non-toxic base used in the present invention include basic inorganic salts and organic bases. The non-toxic base may be any one as long as the pH of the 1% aqueous solution or suspension shows basicity (pH 7 or more), and preferably one showing a pH of 8.0 or more at 25 ° C. In particular, inorganic salts exhibiting such basicity are preferred. Preferred examples of such basic inorganic salts include sodium, potassium, magnesium and calcium basic inorganic salts. Preferably, a basic inorganic salt of magnesium or calcium is used.
Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, and sodium hydroxide.
Examples of the basic inorganic salt of potassium include potassium carbonate, potassium hydrogen carbonate, potassium hydroxide and the like.
Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg ₆ Al ₂ (OH ₁₆ ) CO ₃ .4H ₂ O] and magnesium hydroxide alumina [2.5MgO.Al ₂ O ₃ .xH ₂ O], preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc. Can be
Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
More preferably, the basic inorganic salt includes magnesium carbonate, calcium carbonate and the like.
The basic inorganic salt may be used alone or in combination of two or more.
Examples of the organic base include an alkylamine (such as trimethylamine and triethylamine), a heterocyclic amine (such as pyridine and picoline), an alkanolamine (such as ethanolamine, diethanolamine and triethanolamine), dicyclohexylamine, and N, N′-diamine. Examples include benzylethylenediamine and basic amino acids (arginine, lysine, ornithine, and the like).

  The amount of the basic inorganic salt to be added is about 0.1 to about 20 parts by weight, preferably about 0.2 to about 10 parts by weight, and preferably about 0.2 to about 7 parts by weight may be blended. In the above-mentioned preparation containing a high content of PPI, about 0.2 to 7% by weight, preferably about 0.2 to 3% by weight, and more preferably about 0.2 to 1% by weight is possible. is there. In particular, when the PPI is a high-content preparation of lansoprazole or an optically active substance thereof, about 0.2 to about 1 part by weight, preferably about 0.2 to about 0.4 part by weight of the basic inorganic compound per 1 part by weight of the PPI. It is preferable to add a salt (preferably, a basic inorganic salt of magnesium or calcium, and more preferably, magnesium carbonate or magnesium oxide). As shown in the following formulation test, the amorphous benzimidazole-based compound which is extremely unstable by itself is also allowed to coexist with a base, especially a basic inorganic salt, more preferably magnesium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide and the like. It has also been found that if a solid preparation such as granules is used together with excipients and the like used in other pharmaceutical preparations if necessary, decomposition and discoloration are unexpectedly suppressed and the preparation is used as a medicine. Particularly in the case of a high-content preparation of lansoprazole or its optically active substance, it is preferable to add a basic inorganic salt of magnesium or calcium, more preferably magnesium carbonate or magnesium oxide.

  In the case of a gastric disintegrating preparation, in order to prevent a substantial portion of the active ingredient from being exposed to stomach acid and becoming unstable, preferably together with the disintegration of the solid preparation in the stomach, immediately prior to elution of the active ingredient, It is blended in an amount to elute and neutralize stomach acid. Although depending on the ability of each basic inorganic salt to neutralize the stomach acid, one part by weight of the acid-labile active ingredient is usually added to the basic inorganic salt (preferably magnesium oxide, magnesium hydroxide or magnesium oxide). About 0.05 to 2000 parts by weight, preferably about 0.1 to 1000 parts by weight, and more preferably about 0.1 to 800 parts by weight. For example, 0.1 to 1500 parts by weight, preferably 0.5 to 800 parts by weight, and more preferably 0.1 to 400 parts by weight, per 1 part by weight of the benzimidazole compound. When the active ingredient is a benzimidazole compound, the pH in the stomach usually rises with the start of dosing, but is preferably within about 60 minutes after administration, more preferably within about 40, in the stomach in a normal pH range. Is added in an amount to raise the pH to 4 or more.

A benzimidazole compound having a PPI action has a property of being hardly soluble in water and is unstable to an acid. Therefore, it is preferable to form an enteric coating by applying an enteric coating to the benzimidazole compound. The enteric coating has a low pH and does not dissolve in the stomach with relatively high water content, and the enteric coating dissolves in the small intestine with a low water content and high pH, whereby the benzimidazole compound is dissolved and absorbed. That is, since the composition containing the benzimidazole compound needs to be rapidly disintegrated in the small intestine, granules or fine particles having a large surface area and easily disintegrating or dissolving quickly are desirable. If desired, such granules or fine granules may be tableted or filled into capsules to make capsules.
As a more preferred embodiment, the amount of the benzimidazole-based compound having a PPI action represented by lansoprazole, lansoprazole R-form and lansoprazole S-form is appropriately changed depending on the compound and the dosage form. To prepare a high-content preparation suitable for a once-daily preparation of 90 mg, preferably 40 mg to 60 mg, a benzimidazole having a PPI action of about 12% to about 40% by weight based on the total amount of granules It is preferable to form granules having an average particle size of about 600 μm or more containing a basic compound and containing a basic inorganic salt as a stabilizer. When the particle diameter is small, the surface area becomes large, and it is necessary to coat the enteric coating in a large amount, so that it is difficult to increase the concentration of the benzimidazole compound. That is, by making the particle diameter at least about 600 μm or more and reducing the amount of the enteric coating, it is possible to obtain a highly concentrated preparation. In order to obtain such a high-content preparation, it is preferable to use granules having an average particle size of about 600 to about 2500 μm. A more preferred average particle size is from about 1000 to about 2000 μm. The granules may include particles having a particle diameter of about 400 to about 3000 μm, preferably particles having a particle diameter of about 500 to about 2500 μm, but any granules having an average particle diameter in the above range may be used.
The particle diameter is measured using a sieving method (powder-theory and application-475 pages, 1979, Maruzen), and the average particle diameter is calculated based on the average value of the openings of the corresponding sieve and the weight distribution. . That is, arithmetic averaging is performed based on the product of the average value and each weight.

In the present invention, in order to obtain a solid preparation as the above granules, it can be produced by a known granulation method. For example, a tumbling granulation method (eg, centrifugal tumbling granulation method), a fluidized granulation method, a stirring granulation method (eg, a tumbling fluidized granulation method) and the like can be mentioned. Among them, the tumbling granulation method and the stirring granulation method (the tumbling fluidized granulation method are preferable).
A specific example of the tumbling granulation method includes, for example, a CF device manufactured by Freund Corporation. Specific examples of the tumbling fluidized-granulation method include, for example, a method using a spiral flow manufactured by Freund, a multiplex manufactured by Powrex, and a new malmé manufactured by Fuji Paudal. The method of spraying the binding liquid can be appropriately selected according to the type of the granulating device, and may be any of a top spray method, a bottom spray method, a tangential spray method, and the like.

In the case of an enteric disintegrating preparation, the granules of the present invention comprise a main drug layer containing the main drug, an intermediate coating layer formed on the main drug layer, and an enteric coating layer or a release controlling coating layer on the intermediate coating layer. It is preferable to make granules having the same.
The granules in the present invention have a higher sphericity and a granule having a narrow particle size distribution, so that the benzimidazole compound is coated on core particles composed of at least one selected from sucrose, starch, lactose and crystalline cellulose. It is preferable to form a main drug layer by performing the following steps. For example, nucleated granules may be produced by the method described in JP-A-63-301816. While spraying a binding solution such as hydroxypropylcellulose on the sugar nucleus, a method of coating a powdery spray containing a benzimidazole compound having an anti-ulcer effect, a basic metal salt, an excipient, a disintegrant and the like is obtained. Can be Examples of the core granules include non-pareil (Nonpareil) obtained by coating sucrose (75 parts by weight) with corn starch (25 parts by weight) by a method known per se, and spherical core granules using crystalline cellulose. Alternatively, the core component itself may be the above-mentioned main component, in which the core granules themselves are the main component. The average particle size of the core granules is generally 14 to 80 mesh.
Examples of the core include spherical granules of sucrose and starch, spherical granules of crystalline cellulose, and spherical granules of crystalline cellulose and lactose.
It is desirable that the nucleus has a spherical shape as uniform as possible in order to reduce the dispersion of the coating.
The ratio of the coating layer to the core can be selected within a range that can control the dissolution property of the benzimidazole compound and the particle size of the granules.For example, based on 1 part by weight of the core, usually about 0.2 parts by weight to about 5 parts by weight, preferably Is from about 0.1 to about 5 parts by weight.

The coating layer covering the main drug layer may be formed of a plurality of layers. The plurality of coating layers may include various coating layers such as a controlled release coating layer and an undercoat coating layer, in addition to the drug-free intermediate coating layer and the enteric coating layer. Can be selected.
Since benzimidazole compounds having an amorphous PPI action are particularly unstable, when enteric coated granules are used, since the enteric coating layer component is an acidic substance, it contains an amorphous benzimidazole compound or the like. It is more preferable to provide an intermediate coating layer between the main drug layer and the enteric coating layer to block direct contact between the two layers in order to improve the stability of the drug. Also in the case of providing a controlled release coating layer, it is preferable to provide an intermediate coating layer in advance in consideration of the instability of the amorphous compound.
Such an intermediate coating layer may be any coating layer that prevents contact between the benzimidazole compound as the main drug and the enteric coating layer, and the amount and material of the coating layer are limited as long as such an object is achieved. Not done. For example, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (for example, TC-5, etc.), polyvinylpyrrolidone, polyvinylalcohol, methylcellulose, hydroxyethylmethylcellulose, and other polymer bases are added to sucrose [purified sucrose ( Pulverized (pulverized sugar) or non-pulverized)], starch saccharides such as corn starch, lactose, honey, and layers appropriately mixed with sugars such as sugar alcohols (D-mannitol, erythritol and the like). In addition to the intermediate coating layer, excipients (eg, concealing agents (titanium oxide, etc.), antistatic agents (titanium oxide, talc, etc.)) which are added as necessary for the following formulation are appropriately added to the intermediate coating layer. May be.
The coating amount of the intermediate coating layer is, for example, usually about 0.02 parts by weight to about 1.5 parts by weight, preferably about 0.05 to about 1 part by weight, based on 1 part by weight of the granule containing the benzimidazole compound. Coating can be performed by a conventional method. For example, it is preferable that these intermediate layer coating layer components are diluted with purified water or the like, sprayed as a liquid, and coated. In that case, it is preferable to carry out while spraying a binder such as hydroxypropylcellulose.

The “enteric coating layer” that coats the granules according to the present invention dissolves at about pH 5.5 and starts to release the drug. Examples of such a substance that forms the enteric coating layer include cellulose acetate. Aqueous enteric polymer bases such as tophthalate (CAP), hydroxypropylmethylcellulose-sphthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer, carboxymethylethylcellulose, shellac, ethyl acrylate / methacrylic acid copolymer, etc. And a plasticizer such as a water-soluble polymer, triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, and castor oil. These may be used alone or in combination of two or more.
The enteric coating layer is an enteric polymer base, preferably an aqueous enteric methacrylic acid copolymer.
The coating amount of the enteric coating layer is about 10% by weight to about 70% by weight, preferably about 10% by weight to about 50% by weight, more preferably about 15% by weight, based on the total amount of the granules before applying the enteric coating. % To about 30% by weight.

In the solid preparation of the present invention, in particular, granules, a "controlled release coating layer" may be formed to give a preparation with a long-lasting effect. Examples of such a “controlled release coating layer” include a coating which dissolves in a pH range different from a normal enteric coating (for example, pH 6 or more, preferably 6.5 or more), that is, releases a drug in a pH-dependent manner. Although the film itself does not dissolve, a diffusion control film that controls the release of a drug through pores formed in the film may be used. Here, “pH-dependent” means that an active ingredient is released in an environment having a certain pH or higher.
Examples of such a substance for a controlled release coating for controlling the release of the pharmaceutically active ingredient in a pH-dependent manner include hydroxypropyl methylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate, Carboxymethyl ethyl cellulose (CMEC, manufactured by Freund Corporation), methyl methacrylate methacrylate copolymer (Eudragit L100, manufactured by Rohm), ethyl methacrylate acrylate copolymer (Eudragit L100-55, Eudragit L30D-55, manufactured by Rohm) ), Hydroxypropylcellulose acetate succinate (HPMCAS Shin-Etsu Chemical Co., Ltd.), polyvinyl acetate phthalate, shellac and the like. These may be used alone, in combination of at least two or more polymers, or sequentially coated with at least two or more polymers. It is desirable to use the coating substance alone or in combination as necessary so that it is dissolved preferably at pH> 6.0 or more, more preferably at pH> 6.5, further preferably at pH 6.75 or more. Further, a plasticizer such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin, and triethyl citrate, a stabilizer, and the like may be used as needed for the coating. The amount of the coating substance is preferably 5% to 100% based on the core particles.
Diffusion control films that control the release of active components by diffusion include aminoalkyl methacrylate copolymers (Eudragit RS, RL, manufactured by Rohm), ethyl acrylate / methyl methacrylate copolymer (Eudragit NE 30D Rohm), ethyl cellulose Can be formed by coating the granules with a mixture mixed in a certain ratio with hydrophilic pore-forming substances such as HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, and organic acids. it can.

Excipients for further formulation (e.g., glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, crystalline cellulose, anhydrous cellulose) Silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, etc.), binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinylalcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, Sodium alginate, pullulan, gum arabic, gelatin, etc.), disintegrant (eg, low-substituted hydroxypropylcellulose, carmellose, carmellose skull) Sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, etc.), flavoring agents (for example, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, dipotassium glycyrrhizinate, Sodium glutamate, 5'-sodium inosinate, 5'-sodium guanylate, etc., surfactants (for example, polysorbate (such as polysorbate 80), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, etc.), fragrance (Eg, lemon oil, orange oil, menthol, pepper oil, etc.), lubricants (eg, magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, Thearic acid, talc, polyethylene glycol, etc.), coloring agents (eg, titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, etc.), antioxidants (eg, sodium ascorbate, L Additives such as cysteine, sodium sulfite, etc., concealing agents (eg, titanium oxide), antistatic agents (eg, talc, titanium oxide, etc.) can be used.
There is no particular limitation on the particle size of the raw materials used in these, but particles of about 500 μm or less are preferred from the viewpoint of manufacturability and ingestibility.

As the solid preparation of the present invention, granules, capsules, tablets, foaming agents, suspensions and the like can also be used. As described above, in the case of a capsule or a tablet, granules or fine granules may be prepared in advance to improve stability or the like, and then used as a tablet or capsule.
Capsules and tablets are preferred in terms of ease of handling and the like. As capsules, gelatin capsules, HPMC capsules, pullulan capsules and the like may be used. When used as a capsule, the size is preferably 3 to 5 capsules so that it can be easily taken. For example, in the case of a capsule filled with granules containing amorphous lansoprazole or its optically active substance, about 14% by weight to about 20% by weight of lansoprazole or its optically active substance with respect to the total amount of granules, magnesium and / or calcium A basic salt of lansoprazole or about 0.2 parts by weight to 1 part by weight of an optically active substance thereof is contained in the main drug layer containing about 0.2 parts by weight to about 0.4 parts by weight, an intermediate coating layer is provided, and an enteric coating layer is coated thereon. Capsules filled with granules of 1000 μm to about 2000 μm are preferred. As capsules containing 30 mg of lansoprazole per capsule, the conventional products are Nos. 1 and 2, whereas in the present invention, stable capsules Nos. 3 to 5 can be produced. Furthermore, in the case of a capsule containing 15 mg per lansoprazole filled with the granules, it is possible to reduce the size of the capsule to No. 4 to No. 5 capsules. No. 3 to No. 1 capsules are also possible as capsules containing 60 mg of an optically active substance of lansoprazole such as R-lansoprazole R-form, and capsules No. 4 to No. 2 are available as capsules containing 40 mg, and 30 mg-containing capsules No. 5 to No. 3 capsules are possible.

  In the solid preparation of the present invention, the benzimidazole compound having the PPI action of the main drug has excellent anti-ulcer action, gastric acid secretion inhibitory action, mucosal protective action, anti-Helicobacter pylori action, etc., and has low toxicity. Useful as a medicine. In this case, the granules of the present invention can be used in mammals (eg, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice, etc.) in peptic ulcers (eg, gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.). ), Zollinger-Ellison syndrome, gastritis, reflux esophagitis, gastroesophageal reflux disease without esophagitis (Symptomatic GERD), NUD (Non Ulcer Dyspepsia), gastric cancer (interleukin) -1 (including gastric cancer associated with promotion of production of interleukin-1β), treatment and prevention of gastric MALT lymphoma, eradication of Helicobacter pylori, peptic ulcer, acute stress ulcer, and upper digestion due to hemorrhagic gastritis Suppression of ductal bleeding, invasive stress (major surgery requiring intensive management after surgery, cerebrovascular disorder requiring intensive care, head trauma, Oral administration for the purpose of suppressing upper gastrointestinal bleeding due to organ failure and stress caused by extensive burns, treating and preventing ulcers caused by nonsteroidal anti-inflammatory drugs; treating and preventing hyperacidity and ulcers due to postoperative stress it can. For eradication of Helicobacter pylori or the like, the granules and capsules of the present invention may be used in combination with other active ingredients (for example, 1 to 3 kinds of active ingredients).

"Other active ingredients" include, for example, antimicrobial agents such as anti-Helicobacter pylori active substances, imidazole compounds, quinolone compounds, and bismuth salts. In particular, a medicament obtained by combining the granules or capsules of the present invention with an antibacterial agent is preferred. Of these, combination use with antibacterial agents such as anti-Helicobacter pylori active substances and imidazole compounds is preferred. Examples of the “anti-Helicobacter pylori active substance” include, for example, penicillin antibiotics (eg, amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), cephem antibiotics (eg, cefixime, cefaclor, etc.), macrolide antibiotics ( Examples include erythromycin antibiotics such as erythromycin and clarithromycin), tetracycline antibiotics (eg, tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (eg, gentamicin, amikacin, etc.), imipenem and the like. Among them, penicillins and macrolides are preferred.
Examples of the “imidazole compound” include metronidazole, miconazole and the like. Examples of the “bismuth salt” include bismuth acetate, bismuth citrate and the like. Also preferred are "quinolone-based compounds" antibacterial agents, for example, ofloxacin, ciploxacin and the like. In particular, for the eradication of Helicobacter pylori, the granules and capsules of the present invention are used in combination with a penicillin antibiotic (eg, amoxicillin) and / or an erythromycin antibiotic (eg, clarithromycin). It is preferable to use them. Further, combination with metronidazole is also preferable, and two agents selected from amoxicillin, clarithromycin and metronidazole, and imidazole-based compounds, particularly, a three-drug combination with lansoprazole or lansoprazole R-form show an excellent Helicobacter pylori eradication effect. .
For example, in the case of lansoprazole, the capsule containing 15 mg of lansoprazole in the conventional crystalline form was often filled in the No. 3 capsule, and the capsule containing 30 mg in the conventional form was often filled in the No. 1 capsule. And the amount of components other than the active ingredient can be reduced without compromising the stability of the preparation, so that capsules containing 15 mg can be reduced to capsules 4 to 5 and capsules containing 30 mg can be reduced to capsules 3 to 5 respectively. .
Further, in capsules containing 60 mg, No. 1 to No. 3 capsules can be used.
Also, in the case of the optically active substance of lansoprazole, No. 3 to No. 5 capsules, No. 2 to No. 4 capsules and No. 1 to No. 3 capsules can be used for capsules containing 30 mg, 40 mg and 60 mg, respectively. . No. 1 to No. 3 capsules can be used for the capsule containing 90 mg.
For example, a capsule containing 60 mg of amorphous lansoprazole or lansoprazole R-form contains an active ingredient at a high concentration and is easy to swallow, and thus is particularly suitable for treatment of acid hypersecretion symptoms including Zollinger-Ellison syndrome.
The daily dose varies depending on the degree of symptoms, age, gender, body weight, administration timing, interval, type of active ingredient, etc. of the subject, and is not particularly limited. For example, as an anti-ulcer agent, an adult (60 kg) On the other hand, when administered orally, the dose is about 0.5 to 1500 mg / day, preferably about 5 to 150 mg / day as an active ingredient. These benzimidazole-based compound-containing preparations may be administered once or twice or three times a day.

  In order to improve the stability of the solid preparation of the present invention during storage and transportation, the solid preparation may be stabilized in a package form. For example, the amorphous benzimidazole-based compound of the present invention can be obtained by using a package form such as a package in which oxygen permeation is suppressed, a gas replacement package (that is, a package in which a gas other than oxygen is replaced), a vacuum package, and a package containing an oxygen absorber. The stabilization of a solid preparation containing the compound can be improved. By adopting such a packaging form, stabilization is improved by reducing the amount of oxygen directly contacted by the solid preparation. When encapsulating the oxygen scavenger, the pharmaceutical solid preparation may be packaged with a material through which oxygen can pass, and then a new package may be provided together with the packaged product.

As the benzimidazole-based compound having a PPI action, which is the main drug of the present invention, conventionally, both racemic and optically active compounds are usually crystals. In general, a benzimidazole compound having a PPI action is easily crystallized. Therefore, even when a compound is synthesized in an amorphous state (amorphous form, synonymous with amorphous) at the beginning of discovery, once the compound is crystallized, the compound becomes non-crystalline. It is difficult to synthesize as crystalline. In particular, the lansoprazole R-form was initially synthesized as an amorphous form, but it has been difficult to synthesize an amorphous form since the subsequent successful crystallization (WO00 / 78745, etc.). This is a common phenomenon, and once crystals are obtained, it is usually not easy to synthesize an amorphous form in the same manner as before. In other words, the anhydrous lansoprazole R form does not become amorphous even when heated as it is, and also when the solution containing lansoprazole is concentrated, once it is crystallized, the anhydrous crystals or hydrate crystals are now crystallized. Amorphous materials cannot be synthesized by conventional methods.
However, amorphous has a higher solubility than crystals, or has advantages such as good absorbability.Therefore, the present inventors intensively studied a method for producing amorphous lansoprazole. A method for producing amorphous lansoprazole has been found. That is, hydrated crystals of lansoprazole R form (preferably hydrate of lansoprazole R form, more preferably lansoprazole 0.5 hydrate or lansoprazole R form 1.5 hydrate) are kept at about 20 to about 100 ° C. It has been found that they can be prepared by heating or, if necessary, by heating. Preferably, holding or heating is performed while drying. The lansoprazole® amorphous can be produced by heating to preferably about 40 to about 80 ° C., more preferably about 50 to about 70 ° C. When heating, the pressure may be reduced for drying. Moreover, you may heat under ventilation. Alternatively, it may be simply heated.
Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
(Production Example 1)

Synthesis of Amorphous Lansoprazole R Form A solution obtained by dissolving 40 g of anhydrous lansoprazole R form crystals (attached to a powder X-ray diffraction diagram) in 180 mL of acetone was dropped into a mixture of 55 mL of acetone and 270 mL of water over about 10 minutes. Next, 340 mL of water was added dropwise over about 20 minutes, and the mixture was stirred at 0 to 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with 90 mL of a mixed solution of acetone / water (1/5) and subsequently with 90 mL of water. The obtained wet crystals were dried under reduced pressure at about 65 ° C. for about 7 hours to obtain an amorphous lansoprazole R form (yield: 38.4 g, yield: 96%). The crystals before drying under reduced pressure are lansoprazole R-form 1.5 hydrate.
Elemental analysis theoretical values: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43, O: 8.66
Obtained values: C: 51.77, H: 3.84, N: 11.39, S: 8.59, F: 15.48
¹ H-NMR (CDCl ₃ ): 2.25 (3 H, s), 4.39 (2 H, q, J = 7.8 Hz), 4.72 (1 H, d, J = 13.8 Hz), 4.85 (1 H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
X-ray powder diffraction: Chemical purity (area percentage value) with no particular peak: 98.3%
Optical purity: 100% ee
Moisture (KF method): 0.5%
(Production Example 2)

Synthesis of amorphous lansoprazole R-form Lansoprazole R-form · 1.5 hydrate (10 g) was dried under reduced pressure at about 60 ° C. for about 8 hours to obtain amorphous lansoprazole R-form (yield: 9.3 g, yield) : 100%).
Elemental analysis theoretical value: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43, O: 8.66
Measured value: C: 52.17, H: 3.92, N: 11.23, S: 8.58, F: 15.40
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
X-ray powder: no particular peak Chemical purity: 97.9% (area percentage value)
Optical purity: 99.8% ee
Moisture (KF method): 0.7%
(Production Example 3)

Synthesis of amorphous lansoprazole R-form Lansoprazole R-form 1.5 hydrate (10 g) was air-dried at about 65 ° C. for about 7 hours to obtain amorphous lansoprazole R-form (yield: 9.3 g, yield) : 100%).
Elemental analysis theoretical value: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43, O: 8.66
Measured value: C: 52.08, H: 3.90, N: 11.25, S: 8.56, F: 15.37
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
Powder X-ray: no particular peak Chemical purity: 98.4% (area percentage value)
Optical purity: 100% ee
Moisture (KF method): 0.4%
(Production Example 4)

Synthesis of Amorphous Lansoprazole R Form Lansoprazole R form hemihydrate (10 g) was heated at about 65 ° C. for about 8 hours to obtain an amorphous lansoprazole R form (yield: 9.3 g, yield: 100%).
Elemental analysis theoretical value: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43, O: 8.66
Measured value: C: 52.12, H: 3.74, N: 11.30, S: 8.74, F: 15.40
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
Powder X-ray: no particular peak Chemical purity: 97.6% (area percentage value)
Optical purity: 99.7% ee
Moisture (KF method): 0.5%
(Production Example 5)

Synthesis of amorphous lansoprazole R-form Lansoprazole R-form pentahydrate (10 g) was dried under reduced pressure at about 70 ° C. for about 6 hours to obtain amorphous lansoprazole R-form (yield: 9.8 g, yield: 100%).
Elemental analysis theoretical value: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43, O: 8.66
Obtained: C: 51.98, H: 3.95, N: 11.30, S: 8.78, F: 15.35
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
Powder X-ray: Chemical purity without any particular peak: 98.0% (area percentage value)
Optical purity: 99.6% ee
Moisture (KF method): 0.7%

Reference Example 1

Synthesis of lansoprazole R-form 0.5 hydrate An aqueous solution of 40 g of lansoprazole R-form anhydrous crystals (see FIG. 1: powder X-ray diffraction diagram) in 180 mL of acetone was dissolved in a mixture of 55 mL of acetone and 270 mL of water in about 10 mL. Dropped over minutes. Next, 340 mL of water was added dropwise to the solution over about 20 minutes, and the mixture was stirred at 0 to 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with 90 mL of a mixed solution of acetone / water (1/5) and subsequently with 90 mL of water. The obtained wet crystals were dried under reduced pressure at about 30 ° C. for about 7 hours to obtain lansoprazole R-form / 0.5 hydrate (yield: 39.3 g, 96%). The crystals before drying under reduced pressure are lansoprazole R-form 1.5 hydrate.
Elemental analysis theoretical value: C: 50.79, H: 4.00, N: 11.11, S: 8.47, F: 15.06, O: 10.57
Measured value: C: 51.00, H: 3.92, N: 11.23, S: 8.65, F: 15.10
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
Powder X-ray diffraction: lattice spacing (d) 9.50, 8.73, 8.31, 5.57, 5.18, 4.80, 4.20
Chemical purity: 99.6% (area percentage value)
Optical purity: 100%
Moisture (KF method): 2.4%

Reference Example 2

Synthesis of lansoprazole R-form 1.5 hydrate An aqueous solution of 40 g of lansoprazole R-form anhydrous crystals (see FIG. 1: powder X-ray diffractogram) in 180 mL of acetone was dissolved in a mixture of 55 mL of acetone and 270 mL of water in about 10%. Dropped over minutes. Next, 340 mL of water was added dropwise to the solution over about 20 minutes, and the mixture was stirred at 0 to 10 ° C for about 1 hour. The precipitated crystals were collected by filtration, and washed with 90 mL of a mixed solution of acetone / water (1/5) and subsequently with 90 mL of water. The obtained wet crystals were dried under reduced pressure at about 15 ° C. for about 5 hours to obtain lansoprazole R-form · 1.5 hydrate (yield: 41.6 g, 97%). The crystals before drying under reduced pressure are lansoprazole R-form 1.5 hydrate.
Elemental analysis theoretical value: C: 50.39, H: 4.05, N: 11.02, S: 8.41, F: 14.94, O: 11.19
Measured value: C: 50.50, H: 3.94, N: 11.32, S: 8.25, F: 14.73
¹ H-NMR (CDCl ₃ ): 2.25 (3H, S), 4.39 (2H, q, J = 7.8 Hz), 4.72 (1H, d, J = 13.8 Hz), 4.85 (1H, d, J = 13.8 Hz) ), 6.69 (1H, d), 7.31-7.80 (4H, m), 8.35 (1H, d), 11.5 (1H, br S)
Powder X-ray diffraction: lattice spacing (d) 8.91, 8.07, 6.62, 6.00, 5.92, 5.66, 5.04, 4.51
Chemical purity: 99.6% (area percentage value)
Optical purity: 100%
Moisture (KF method): 6.8%
(Formulation Example 1)

The composition is shown in Table 1. Amorphous lansoprazole R, magnesium carbonate, sucrose (crushed product), corn starch and low-substituted hydroxypropylcellulose are thoroughly mixed to give a main agent spraying agent. In addition, sucrose (crushed product), corn starch and low-substituted hydroxypropylcellulose are well mixed to prepare an intermediate layer spray. Put the sucrose and starch spherical granules in a centrifugal tumbling granulator (manufactured by Freund Corporation, CF), spray the hydroxypropylcellulose solution (2%: W / W) and spray the above active agent and intermediate layer. The spraying agent is sequentially coated to obtain spherical granules. The coating operation conditions are as follows: rotor rotation speed: 300 rpm, injection speed: 1.8 g / min, spray air pressure: 0.2 kg / cm ² , slit air pressure: 0.2 kg / cm ² . The obtained spherical granules are dried under vacuum at 40 ° C. for 20 hours and sieved with a round sieve to obtain granules of 710 μm to 1420 μm.
The above granules are coated with an enteric coating solution using a fluid granulation coating machine (LAB-1 manufactured by Powrex), dried as it is, and sieved with a round sieve to obtain enteric granules of 850 to 1420 μm. Coating operation conditions are as follows: supply air volume: 0.6 m ³ / min, supply air temperature: 85 ° C., injection rate: 8 g / min, spray air pressure: 1 kg / cm ² .
The talc and aerosil are mixed with the obtained granules. 150 mg (equivalent to 30 mg lansoprazole R), 200 mg (equivalent to 40 mg lansoprazole R) and 300 mg (equivalent to 60 mg lansoprazole R) of the obtained mixed particles are filled in No. 4, No. 3 and No. 2 capsules, respectively.
(Formulation Example 2)

The composition is shown in Table 1. Amorphous lansoprazole R, magnesium carbonate, sucrose (pulverized product) and low-substituted hydroxypropylcellulose are thoroughly mixed to give a main agent spraying agent. Also, sucrose (crushed product), low-substituted hydroxypropylcellulose and titanium oxide are well mixed to prepare a middle layer spray. Put the sucrose and starch spherical granules in a centrifugal tumbling granulator (manufactured by Freund Corporation, CF), spray the hydroxypropylcellulose solution (2%: W / W) and spray the above active agent and intermediate layer. The spraying agent is sequentially coated to obtain spherical granules. The coating operation conditions are as follows: rotor rotation speed: 300 rpm, injection speed: 1.8 g / min, spray air pressure: 0.2 kg / cm ² , slit air pressure: 0.2 kg / cm ² . The obtained spherical granules are dried under vacuum at 40 ° C. for 20 hours and sieved with a round sieve to obtain granules of 710 μm to 1420 μm.
The above-mentioned granules are coated with an enteric coating solution using a fluid granulation coating machine (LAB-1 manufactured by Powrex), dried as it is, and sieved with a round sieve to obtain enteric granules of 850 to 1420 μm. Coating operation conditions are as follows: supply air volume: 0.6 m ³ / min, supply air temperature: 85 ° C., injection rate: 8 g / min, spray air pressure: 1 kg / cm ² .
The talc and aerosil are mixed with the obtained granules. 150 mg (equivalent to 30 mg lansoprazole R), 200 mg (equivalent to 40 mg lansoprazole R) and 300 mg (equivalent to 60 mg lansoprazole R) of the obtained mixed particles are filled in No. 4, No. 3 and No. 2 capsules, respectively.
(Formulation Example 3)

The composition is shown in Table 1. Amorphous lansoprazole R, magnesium carbonate, sucrose (crushed product), low-substituted hydroxypropylcellulose and titanium oxide are mixed well to give a main agent spraying agent. Put sucrose and starch spherical granules into a centrifugal tumbling granulator (Freund, CF) and coat the above active agent spraying agent while spraying hydroxypropylcellulose solution (2%: W / W). Obtain spherical granules. The coating operation conditions are as follows: rotor rotation speed: 300 rpm, injection speed: 1.8 g / min, spray air pressure: 0.2 kg / cm ² , slit air pressure: 0.2 kg / cm ² . The obtained spherical granules are dried under vacuum at 40 ° C. for 20 hours and sieved with a round sieve to obtain granules of 710 μm to 1420 μm.
The above-mentioned granules are coated with an enteric coating solution using a fluid granulation coating machine (LAB-1 manufactured by Powrex), dried as it is, and sieved with a round sieve to obtain enteric granules of 850 to 1420 μm. Coating operation conditions are as follows: supply air volume: 0.6 m ³ / min, supply air temperature: 85 ° C., injection rate: 8 g / min, spray air pressure: 1 kg / cm ² .
The talc and aerosil are mixed with the obtained granules. 150 mg (equivalent to 30 mg lansoprazole R), 200 mg (equivalent to 40 mg lansoprazole R) and 300 mg (equivalent to 60 mg lansoprazole R) of the obtained mixed particles are filled in No. 4, No. 3 and No. 2 capsules, respectively.

Table 1
Composition table
Composition in granules 160mg
Example 1 Example 2 Example 3
Sucrose and starch spherical granules 50mg 50mg 50mg
Active agent spraying agent amorphous lansoprazole R form 40mg 40mg 40mg
Magnesium carbonate 14mg 14mg 14mg
Sucrose (ground product) 26mg 26mg 36mg
Corn starch 9mg 0mg 0mg
Low substituted hydroxypropylcellulose 10mg 10mg 12.5mg
Titanium oxide 0mg 0mg 6.5mg
Middle layer spray sucrose (crushed product) 5mg 10mg
Cornstarch 2.5mg 0mg
Low-substituted hydroxypropylcellulose 2.5mg 2.5mg
Titanium oxide 0mg 6.5mg
Binding liquid hydroxypropylcellulose 1mg 1mg 1mg
Purified water 49μl 49μl 49μl
160mg in total

Enteric coating liquid composition Methacrylic acid copolymer 86.7 mg (solid component 26 mg)
Talc 7.8mg
2.5 mg polyethylene glycol
2.5mg titanium oxide
Polysorbate 80 1.0mg
Purified water 119.5μl
39.8mg in total (as solid)
Composition of enteric granules 160mg
Enteric coating 39.8mg
199.8mg in total
Composition of mixed granules Enteric coated granules 199.8mg
Talc 0.1mg
Aerosil 0.1mg
200mg in total
Composition of capsule
Lansoprazole R form 30 mg equivalent 40 mg equivalent 60 mg equivalent Mixed grain 150 mg 200 mg 300 mg
1 capsule (4) 1 (3) 1 (2)

Test example

Stability test of amorphous lansoprazole R form (1) Under low humidity casten, 100 mg of amorphous lansoprazole R form was precisely weighed and placed in a transparent glass bottle. Subsequently, 100 mg of a basic substance as a stabilizer for a basic inorganic salt shown below was accurately weighed under a low-moisture casten and placed in a bottle containing an amorphous lansoprazole R form. Thereafter, the mixture was capped and shaken by hand to mix.
<Basic substance>
(I) Magnesium carbonate MgCO ₃
(Ii) Calcium carbonate CaCO ₃
(Iii) Magnesium oxide MgO
(Iv) magnesium hydroxide Mg (OH) ₂
(V) No basic substance (2) The prepared sample was stored under storage conditions of 40 ° C./75% RH (opened) for 5 days. Every day, to evaluate the appearance change of the sample, the color tone was named and a color code was assigned based on the International Color Manual. At the time of completion, the stability was judged by comparing the color tone with the product stored at 5 ° C. as an initial.
(3) Table 2 shows changes in the appearance of the test results. In addition, in Table 2, A shows the amorphous lansoprazole R form.
Table 2

  From Table 2, it was confirmed that magnesium carbonate, calcium carbonate, magnesium oxide and magnesium hydroxide had a stabilizing effect when stored at 40 ° C./75% RH for 5 days. That is, the effect of preventing a change in appearance was obtained by adding these basic inorganic salts.

  By blending non-toxic salts such as basic inorganic salts with amorphous benzimidazole compounds having a PPI action that is extremely unstable to acids and water, the compounds containing these amorphous drugs are useful. A stable solid preparation can be provided.

It is a powder X-ray chart of a lansoprazole R form anhydrous crystal. 3 is an X-ray powder diffraction chart showing an amorphous form of Production Example 1. 3 is a powder X-ray chart showing a lansoprazole R-form / 0.5 hydrate of Reference Example 1. 4 is a powder X-ray chart showing a lansoprazole R-form 1.5 hydrate of Reference Example 2.

Claims (26)

  A stable solid preparation containing a non-toxic base and an amorphous benzimidazole compound having a proton pump inhibitor (PPI) action.   The solid preparation according to claim 1, wherein the benzimidazole compound is an optically active substance. The optically active form of the benzimidazole compound is represented by the formula (I):

[In the formula, ring A is a benzene ring which may have a substituent, R ¹ is a hydrogen atom, an aralkyl group which may have a substituent, an acyl group or an acyloxy group, R ² , R ³ and R ⁴ is the same or different and is 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, and * represents an asymmetric center.] Or a salt thereof.   The solid preparation according to claim 2, wherein the optically active form of the benzimidazole compound is an optically active form of lansoprazole, omeprazole, rabeprazole or pantoprazole.   The solid preparation according to claim 2, wherein the optically active form of the benzimidazole compound is an optically active form of lansoprazole.   The solid preparation according to claim 5, wherein the optically active form of lansoprazole is the R form.   The solid preparation according to claim 5, wherein the optically active form of lansoprazole is an S-form.   The solid preparation according to claim 1, wherein the non-toxic base is an inorganic salt having a pH of 1% or more at 25 ° C of a 1% aqueous solution or a 1% aqueous suspension thereof.   The solid according to claim 1, wherein the non-toxic base is at least one basic inorganic salt selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. Formulation.   The solid preparation according to claim 1, which has a coating layer.   The solid preparation according to claim 10, wherein the coating layer includes an enteric coating layer.   The solid preparation according to claim 10, wherein the coating layer comprises a controlled release coating layer.   The coating layer according to claim 10, wherein the coating layer includes an intermediate coating layer formed on the layer containing the amorphous benzimidazole compound, and a controlled release coating layer and / or an enteric coating layer formed on the intermediate coating layer. Solid preparation.   The solid preparation according to claim 1, wherein the nontoxic base contains at least one selected from metal oxides and at least one selected from metal hydroxides.   15. The solid preparation according to claim 14, which is gastric disintegrating.   The solid preparation according to claim 14, comprising at least one metal oxide selected from the group consisting of magnesium oxide, magnesium silicate, dried aluminum hydroxide gel, and magnesium aluminate metasilicate.   Magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, co-precipitates of aluminum hydroxide and magnesium hydroxide, co-precipitates of aluminum hydroxide, magnesium carbonate and calcium carbonate, and co-precipitates of aluminum hydroxide and sodium hydrogen carbonate The solid preparation according to claim 14, comprising at least one metal hydroxide selected from the group consisting of:   The solid preparation according to claim 14, further comprising a basic inorganic salt stabilizer containing a carbonate of an alkaline earth metal.   It contains an amorphous R-form of lansoprazole and at least one basic inorganic salt selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. A stabilized solid dosage form comprising a layer, an intermediate coating layer formed on the layer, and an enteric coating layer formed on the intermediate coating layer.   The solid preparation according to claim 19, wherein the basic inorganic salt is magnesium carbonate or calcium carbonate.   A stable form containing a benzimidazole compound having an amorphous PPI action, characterized in that the form is a package form selected from the group consisting of a package in which oxygen permeation is suppressed, a gas displacement package, a vacuum package, and a package containing an oxygen absorber. Method for producing a solid preparation.   The production method according to claim 21, wherein a nontoxic base is blended.   A method for producing an optically active amorphous lansoprazole, characterized by maintaining the hydrous crystal of the optically active lansoprazole (R-form) at about 20 to about 100 ° C.   24. The method for producing an optically active amorphous lansoprazole according to claim 23, wherein the lansoprazole is heated to about 40 to about 80C.   24. The method according to claim 23, wherein 0.5 to 1.5 hydrate crystals of the optically active lansoprazole (R form) are heated to about 50 to about 70C. The method according to claim 23, wherein the temperature is maintained under reduced pressure or under ventilation.

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