JP2005154431A - Solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation as a chewable tablet comprising an acid-labile active ingredient like a PPI (proton pump inhibitor) such as benzimidazole compounds and imidazopyridine compounds, capable of rapidly neutralizing gastric acid and which is not enteric-coated, has quick exhibition of the pharmacological effect of the active ingredient and is easily administrable to children and aged. <P>SOLUTION: This invention relates to the chewable tablet comprising a group which contains the acid-labile active ingredient and at least one basic substance selected from carbonate salt, oxide and hydroxide of an alkaline earth metal, and a group which does not contain the acid-labile active ingredient but contains at least one ingredient selected from carbonate salt, oxide and hydroxide of the alkaline earth metal. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to solid preparations, and more particularly to pharmaceutical solid preparations containing an acid labile active ingredient, in particular an acid labile active ingredient such as a benzimidazole compound useful as an anti-ulcer agent.

Proton pump inhibitors (hereinafter sometimes referred to as PPI) of benzimidazole compounds such as lansoprazole, omeprazole, and rabeprazole, and PPI of imidazopyridine compounds such as tenatoprazole have gastric acid secretion inhibitory action and gastric mucosal protective action, etc. Therefore, it is widely used as a therapeutic agent for peptic ulcer.
However, these compounds have poor stability and are unstable to humidity, temperature and light. In particular, it is unstable to acids, and an aqueous solution or suspension becomes extremely unstable as the pH decreases.
In addition, the stability in preparations, ie tablets, powders, fine granules, capsules, etc., becomes unstable due to strong interaction with other ingredients in the formulation rather than the compound alone, and changes in color during production and storage Alternatively, degradation is observed. In order to stabilize these, Japanese Patent Application Laid-Open No. 62-277322 contains a stabilizer composed of a basic inorganic salt such as magnesium and / or calcium for a pharmaceutical solid composition, and then an enteric coating is applied. Enteric enteric granules or enteric fine granules are disclosed.
However, in order to manufacture such an enteric preparation, it is necessary to prepare a fine granule or granule containing PPI such as a benzimidazole compound in advance and then apply an enteric coating. In addition, since it takes time for the enteric film to dissolve and the drug to be absorbed in the gastrointestinal tract after taking, it is difficult to expect a rapid pharmacological effect at the initial stage of taking.
On the other hand, US Pat. No. 5,840,737 and WO 00/26185 disclose solutions, suspensions, tablets, and capsules comprising omeprazole without enteric coating treatment, or a combination of lansoprazole and an alkali metal bicarbonate. Etc. are disclosed.
JP-A-62-277322 US Pat. No. 5,840,737 International Publication No. WO00 / 26185 Pamphlet

The present invention relates to a stable pharmaceutical solid containing an active ingredient unstable to acid, including PPI such as benzimidazole (also referred to as benzimidazole) -based compound and imidasopyridine-based compound having proton pump inhibitor (PPI) action. The object is to provide a formulation, in particular a stable chewable tablet.
More specifically, the present invention is a solid preparation that does not have an enteric coating that can quickly neutralize the acid in the stomach, eliminating the above-mentioned problems in PPI such as benzimidazole compounds. An object of the present invention is to provide a chewable tablet that can be easily taken even by children and the elderly, as well as the rapid pharmacological effect of the active ingredient.

  In order to provide a solid preparation that contains an acid-labile active ingredient such as PPI, such as a benzimidazole compound or an imidazopyridine compound, and that can quickly neutralize acid in the stomach. As a result of intensive studies, it was found that if a chewable agent containing alkaline earth metal carbonates, metal oxides and metal hydroxides in PPI is used, the storage stability is excellent and the pharmacological effect is rapidly developed. It was. As a result of further research based on this finding, the present inventors have completed the present invention.

〔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光学活性体あるいはその塩である前記（７）記載のチュアブル錠、
（９）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、イラプラゾールまたはそれらの光学活性体あるいはそれらの塩である前記（７）記載のチュアブル錠、
（１０）ＰＰＩがイミダゾピリジン系化合物である前記（６）記載のチュアブル錠、
（１１）イミダゾピリジン系化合物がテナトプラゾールまたはその光学活性体あるいはそれらの塩である前記（１０）記載のチュアブル錠、
（１２）アルカリ土類金属の炭酸塩が、炭酸カルシウムまたは炭酸マグネシウムである前記（１）記載のチュアブル錠、
（１３）金属酸化物および金属水酸化物が、それら金属酸化物および金属水酸化物の１％（Ｗ／Ｗ）水溶液または１％（Ｗ／Ｗ）水懸濁液のｐＨが８．０以上を示す金属酸化物および金属水酸化物である前記（１）記載のチュアブル錠、
（１４）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前記（１）記載のチュアブル錠、
（１５）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前記（１）記載のチュアブル錠、
（１６）水溶性の高い塩基性添加物がトロメタモール、コハク酸二ナトリウム、リン酸水素ナトリウム、リン酸三ナトリウム、リン酸二カリウムまたはＬ−アルギニンである前記（２）および（４）記載のチュアブル錠、
（１７）炭酸カルシウムを含有する前記（１）記載のチュアブル錠、
（１８）酸化マグネシウムを含有する前記（１）記載のチュアブル錠、
（１９）水酸化マグネシウムを含有する前記（１）記載のチュアブル錠、
（２０）炭酸カルシウムと酸化マグネシウムおよび／または水酸化マグネシウムを含有する前記（１）記載のチュアブル錠および
（２１）ベンツイミダゾール系化合物１重量部に対し、アルカリ土類金属の炭酸塩、金属酸化物および金属水酸化物から選ばれる少なくとも１種の成分を０．１〜１５００重量部含有する前記（７）記載のチュアブル錠に関する。 That is, the present invention
(1) A chewable tablet comprising an active ingredient unstable to acid and at least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides,
(2) The chewable tablet according to (1), further containing a basic additive having high water solubility,
(3) a group containing an acid labile active ingredient, at least one basic substance selected from alkaline earth metal carbonates, metal oxides and metal hydroxides, and acid labile activity The chewable tablet according to (1), wherein the chewable tablet is divided into a group containing at least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides, which does not contain an ingredient,
(4) The chewable tablet according to the above (3), further comprising a basic additive having high water solubility in a group not containing an acid labile active ingredient,
(5) The chewable tablet according to the above (1), which is a preparation not having an enteric coating,
(6) The chewable tablet according to the above (1), wherein the acid labile active ingredient is a proton pump inhibitor (PPI),
(7) The chewable tablet according to the above (6), wherein PPI is a benzimidazole compound,
(8) 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 chewable tablet according to the above (7), which is a compound represented by the formula:
(9) The chewable tablet according to the above (7), wherein the benzimidazole compound is lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole, an optically active substance thereof, or a salt thereof.
(10) The chewable tablet according to the above (6), wherein PPI is an imidazopyridine compound,
(11) The chewable tablet according to the above (10), wherein the imidazopyridine compound is tenatoprazole, an optically active substance thereof, or a salt thereof.
(12) The chewable tablet according to the above (1), wherein the alkaline earth metal carbonate is calcium carbonate or magnesium carbonate,
(13) The metal oxide and metal hydroxide have a pH of 8.0% or higher in a 1% (W / W) aqueous solution or 1% (W / W) aqueous suspension of the metal oxide and metal hydroxide. The chewable tablet according to the above (1), which is a metal oxide and a metal hydroxide showing
(14) The chewable tablet according to the above (1), which contains at least one metal oxide selected from the group consisting of magnesium oxide, magnesium silicate, dry aluminum hydroxide gel and magnesium aluminate metasilicate.
(15) Magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, aluminum hydroxide / magnesium hydroxide coprecipitate, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate and aluminum hydroxide / sodium bicarbonate The chewable tablet according to the above (1), which contains at least one metal hydroxide selected from the group consisting of coprecipitates,
(16) The chewable according to (2) and (4) above, wherein the basic additive having high water solubility is trometamol, disodium succinate, sodium hydrogen phosphate, trisodium phosphate, dipotassium phosphate or L-arginine Tablets,
(17) The chewable tablet according to the above (1), which contains calcium carbonate,
(18) The chewable tablet according to (1), containing magnesium oxide,
(19) The chewable tablet according to (1), containing magnesium hydroxide,
(20) The chewable tablet according to the above (1) containing calcium carbonate and magnesium oxide and / or magnesium hydroxide, and (21) alkaline earth metal carbonate, metal oxide with respect to 1 part by weight of the benzimidazole compound. And the chewable tablet according to (7) above, containing 0.1 to 1500 parts by weight of at least one component selected from metal hydroxides.

〔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光学活性体あるいはその塩である前記（２５）記載のチュアブル錠、
（２７）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、イラプラゾールまたはそれらの光学活性体あるいはそれらの塩である前記（２５）記載のチュアブル錠、
（２８）ＰＰＩがイミダゾピリジン系化合物である前記（２４）記載のチュアブル錠、
（２９）イミダゾピリジン系化合物がテナトプラゾールまたはその光学活性体あるいはそれらの塩である前記（２８）記載のチュアブル錠、
（３０）アルカリ土類金属の炭酸塩が、炭酸カルシウムおよび／または炭酸マグネシウムである前記（２２）記載のチュアブル錠、
（３１）金属酸化物および金属水酸化物が、それら金属酸化物および金属水酸化物の１％（Ｗ／Ｗ）水溶液または１％（Ｗ／Ｗ）水懸濁液のｐＨが８．０以上を示す金属酸化物および金属水酸化物である前記（２２）記載のチュアブル錠、
（３２）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前記（２２）記載のチュアブル錠、
（３３）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前記（２２）記載のチュアブル錠、
（３４）アルカリ土類金属の炭酸塩が、炭酸カルシウムである前記（２２）記載のチュアブル錠、
（３５）金属酸化物が、酸化マグネシウムである前記（２２）記載のチュアブル錠、
（３６）金属水酸化物が、水酸化マグネシウムである前記（２２）記載のチュアブル錠、
（３７）ベンツイミダゾール系化合物１重量部に対し、アルカリ土類金属の炭酸塩、金属酸化物および金属水酸化物から選ばれる少なくとも１種の成分を０．１〜１５００重量部含有する前記（２５）記載のチュアブル錠、
（３８）酸に不安定な活性成分とアルカリ土類金属の炭酸塩とを含有する群と、酸に不安定な活性成分を含有せず、金属酸化物および金属水酸化物から選ばれる少なくとも１種の成分を含有する群とを含むチュアブル錠、
（３９）アルカリ土類金属の炭酸塩が炭酸カルシウムであり、金属酸化物が酸化マグネシウムであり、金属水酸化物が水酸化マグネシウムである前記（３８）記載のチュアブル錠、
（４０）ランソプラゾールまたはその光学活性体あるいはその塩を、製剤１重量部に対して０．００１〜０．３重量部と炭酸カルシウムを、ランソプラゾールまたはその光学活性体あるいはその塩１重量部に対して０．２〜２００重量部含有する群と、ランソプラゾールまたはその光学活性体あるいはその塩を含有せず、酸化マグネシウムおよび水酸化マグネシウムを、ランソプラゾールまたはその光学活性体あるいはその塩１重量部に対して合計０．２〜２００重量部含有する群とを含むチュアブル錠。
（４１）酸化マグネシウムと水酸化マグネシウムとの重量比が１：０．２〜１：５０である前記（４０）記載のチュアブル錠に関する。 The present invention also relates to (22) a group containing an acid labile active ingredient, at least one basic substance selected from alkaline earth metal carbonates, metal oxides and metal hydroxides; A chewable tablet that contains at least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides,
(23) The chewable tablet according to the above (22), which is a preparation not having an enteric coating,
(24) The chewable tablet according to the above (22), wherein the acid labile active ingredient is a proton pump inhibitor (PPI),
(25) The chewable tablet according to the above (24), wherein PPI is a benzimidazole compound,
(26) 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 chewable tablet according to the above (25), which is a compound represented by the formula:
(27) The chewable tablet according to the above (25), wherein the benzimidazole compound is lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole, an optically active substance thereof, or a salt thereof,
(28) The chewable tablet according to the above (24), wherein PPI is an imidazopyridine compound,
(29) The chewable tablet according to the above (28), wherein the imidazopyridine compound is tenatoprazole, an optically active substance thereof, or a salt thereof,
(30) The chewable tablet according to the above (22), wherein the alkaline earth metal carbonate is calcium carbonate and / or magnesium carbonate,
(31) The metal oxide and metal hydroxide have a pH of 8.0 or higher in a 1% (W / W) aqueous solution or 1% (W / W) aqueous suspension of the metal oxide and metal hydroxide. The chewable tablet according to the above (22), which is a metal oxide and a metal hydroxide,
(32) The chewable tablet according to the above (22), which contains at least one metal oxide selected from the group consisting of magnesium oxide, magnesium silicate, dry aluminum hydroxide gel and magnesium aluminate metasilicate.
(33) Magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, aluminum hydroxide / magnesium hydroxide coprecipitate, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate and aluminum hydroxide / sodium bicarbonate The chewable tablet according to the above (22), which contains at least one metal hydroxide selected from the group consisting of coprecipitates,
(34) The chewable tablet according to the above (22), wherein the alkaline earth metal carbonate is calcium carbonate,
(35) The chewable tablet according to the above (22), wherein the metal oxide is magnesium oxide,
(36) The chewable tablet according to the above (22), wherein the metal hydroxide is magnesium hydroxide,
(37) The above (25) containing 0.1 to 1500 parts by weight of at least one component selected from an alkaline earth metal carbonate, metal oxide and metal hydroxide with respect to 1 part by weight of a benzimidazole compound. ) Chewable tablets as described,
(38) at least one selected from the group comprising an acid labile active ingredient and an alkaline earth metal carbonate, and containing no acid labile active ingredient and a metal oxide and metal hydroxide; Chewable tablets, including a group containing seed ingredients,
(39) The chewable tablet according to (38), wherein the alkaline earth metal carbonate is calcium carbonate, the metal oxide is magnesium oxide, and the metal hydroxide is magnesium hydroxide,
(40) Lansoprazole or an optically active form thereof or a salt thereof, 0.001 to 0.3 parts by weight with respect to 1 part by weight of the preparation and calcium carbonate, and 1 part by weight of lansoprazole or an optically active form thereof or a salt thereof. 0.2 to 200 parts by weight of the group, and lansoprazole or its optically active substance or its salt are not contained, and magnesium oxide and magnesium hydroxide are added to 1 part by weight of lansoprazole or its optically active substance or its salt A chewable tablet comprising 0.2 to 200 parts by weight.
(41) The chewable tablet according to (40), wherein the weight ratio of magnesium oxide to magnesium hydroxide is 1: 0.2 to 1:50.

  Since the pharmaceutical solid preparation of the present invention contains an acid-labile active ingredient, for example, a benzimidazole compound or an imidasopyridine compound which is PPI, an enteric coating is not applied, and thus a simple production method Can be obtained. In addition, since the initial dissolution of the active ingredient from the preparation is faster than that of the preparation with an enteric coating, the time for developing the pharmacological action can be shortened. Further, by blending alkaline earth metal carbonate, metal oxide or metal hydroxide, or a basic additive having high water solubility, it is neutralized in the stomach and the active ingredient is stabilized. In addition, the chewable tablet of the present invention is easy to take even for children and the elderly, and has the effect that it can be taken without water by chewing.

  The acid labile active ingredient in the present invention is not particularly limited, and can be applied to any active ingredient that becomes unstable when exposed to gastric acid. Examples of such acid labile active ingredients include anti-inflammatory enzyme agents such as PPI, erythromycin-based antibacterial compounds, serrapeptase, semi-alkaline proteinase, and the like. In particular, the present invention is suitable for PPI. Examples of such PPI include benzimidazole compounds such as lansoprazole and similar compounds such as imidazopyridine compounds such as tenatoprazole. Specific examples of the benzimidazolazole-based compound will be described later, but the present invention is not limited to these, and can be similarly applied to other acid-labile active ingredients.

〔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。 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 represented by 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.

〔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。 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.
The “alkyl group” of the “alkyl group optionally having substituent (s)” is, for example, a C _1-7 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl). 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 and the like). 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, 2-[(RS)-[(4-methoxy-3-methyl Pyridin-2-yl) methyl] sulfinyl] -5- (1H-pyrrol-1-yl) -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 lansoprazole R-form) 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 an acid-labile active ingredient that can be used in the preparation of the present application, PPI prodrug compounds of compound (I) or other benzimidazole compounds and imidazopyridine compounds are also relatively unstable to acids. It can be used to improve the storage stability and to make the preparation in a form that is quickly neutralized in the stomach. 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, ilaprazole, and imidazopyridine compounds such as tenatoprazole, or optically active substances thereof and Pharmaceutically acceptable salts are preferred.
The compounding amount of the benzimidazole compound used in the present invention varies depending on the type and dosage of the active ingredient, but is, for example, 0.0001 to 0.3 parts by weight, preferably 1 part by weight of the solid preparation of the present invention. Is 0.001 to 0.3 parts by weight, more preferably 0.002 to 0.2 parts by weight.

Examples of the alkaline earth metal carbonate used in the present invention include pharmaceutical magnesium carbonate and calcium carbonate. In particular, calcium carbonate is preferred.
The metal oxide and metal hydroxide used in the present invention preferably have a 1% (W / W) aqueous solution or 1% (W / W) aqueous suspension having a pH of 8.0 or more. Examples of the oxide include pharmaceutical magnesium oxide, magnesium silicate (2MgO.3SiO ₂ .xH ₂ O), dry aluminum hydroxide gel (Al ₂ O ₃ .xH ₂ O), magnesium metasilicate aluminate (Al _{2 O 3 · MgO · 2SiO 2} · xH 2 O) , and the like. In particular, magnesium oxide can be preferably used.
As the magnesium oxide, those that can be used for medical purposes, excellent in acid reactivity, and having neutralizing power are preferable. As such magnesium oxide, those obtained by a normal production method or commercially available products can be used, but so-called light-burned magnesia fired at a low temperature is preferable. What was baked at the temperature of about 500 to about 1000 degreeC is generally preferable, and what was baked at about 600 to about 900 degreeC from the point of especially neutralization power, and most preferably baked at about 800 degreeC is good. Among these magnesium oxides, preferred is magnesium oxide that functions to neutralize the environment and increase the residual rate of the active ingredient before the preparation is disintegrated in the stomach and the active ingredient unstable to acid is released. although, as such magnesium oxide, generally a BET specific surface area of 10 to 50 m ² / g, preferably preferably those having 20 to 50 m ² / g.
Here, the BET specific surface area is a specific surface area measured by a nitrogen gas adsorption method and depends on the amount of nitrogen gas adsorbed, including the surface of a certain amount of magnesium oxide and pores within the range where nitrogen gas enters. The specific surface area is measured.

Examples of magnesium oxide include commercially available heavy magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.), heavy magnesium oxide (Tonda Pharmaceutical Co., Ltd.), and heavy N magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.). ) And light magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.). In particular, heavy magnesium oxide (Kyowa Chemical Industry Co., Ltd., Tomita Pharmaceutical Co., Ltd.), heavy N magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.) and the like are preferable.
Examples of the metal hydroxide include pharmaceutical magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite (Mg ₆ Al ₂ (OH) ₁₆ CO ₃ .4H ₂ O), a combination of aluminum hydroxide and magnesium hydroxide. Examples thereof include a precipitate, a coprecipitate of aluminum hydroxide, magnesium carbonate and calcium carbonate, and a coprecipitate of aluminum hydroxide and sodium hydrogen carbonate. Among these, magnesium hydroxide is particularly preferable in view of acid reactivity, disintegration of the preparation, dissolution property and manufacturability. Alkaline earth metal carbonates, metal oxides and metal hydroxides may be used alone or in combination of two or more selected from these. If desired, a basic additive having high water solubility may be used in combination.

Some metal oxides and metal hydroxides may grind the surface of the formulation equipment during manufacturing, resulting in a black or black dot, line, or surface that makes the tablet surface entirely or partially black . In addition, it has been confirmed that it adheres to the bag at the time of tableting. Since these physical properties significantly impair manufacturability, when selecting a metal oxide or metal hydroxide having abrasiveness and wrinkle adhesion, carbonates of alkaline earth metals that do not have such properties In combination with metal oxides or metal hydroxides, or wet or dry granulation with the following additives (excipients, binders, disintegrants, etc.) that can be used as pharmaceuticals Thus, the polishing action and wrinkle adhesion can be suppressed.
Especially in the case of PPI preparations, in terms of compounding and dissolution properties with these main ingredients, disintegration, manufacturability, etc., magnesium carbonate, calcium carbonate alone or calcium carbonate and magnesium hydroxide or magnesium oxide, Alternatively, a combination of calcium carbonate, magnesium hydroxide and magnesium oxide is preferred.

  These alkyl earth metal carbonates and / or metal oxides and / or metal hydroxides are rapidly removed in the stomach to prevent a substantial portion of the active ingredient from being destabilized by exposure to gastric acid. In an amount that neutralizes gastric acid. Depending on the acid-acid neutralizing ability of the individual alkaline earth metal carbonates, metal oxides and metal hydroxides, the alkaline earth metal carbonate is usually added to 1 part by weight of the acid-labile active ingredient. About 0.05 to 2000 parts by weight, preferably about 0.1 to 1000 parts by weight of a salt, a metal oxide, a metal hydroxide and a combination thereof (hereinafter sometimes collectively referred to as a basic additive) Parts, 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 with respect to 1 part by weight of the benzimidazole compound. When the active ingredient is a benzimidazole compound, the pH in the stomach usually increases with the start of dosing, but preferably within about 60 minutes after administration in the stomach in the normal pH range, more preferably about 40 minutes. Within an amount that raises the pH to 3 or more.

In the present invention, if necessary, at least one component selected from basic additives having high water solubility in addition to these alkaline earth metal carbonates and / or metal oxides and / or metal hydroxides. You may mix | blend. Examples of basic additives with high water solubility include trometamol, disodium succinate, sodium hydrogen phosphate, trisodium phosphate, dipotassium phosphate, L-arginine, meglumine and other pharmaceutical additives having an antacid action. Can be mentioned. These may be used alone or in combination of two or more.
These are also formulated in an amount that quickly neutralizes gastric acid in the stomach to prevent a substantial portion of the active ingredient from being exposed to gastric acid and destabilizing, thereby enhancing the gastric acid neutralizing ability of the individual additives. However, the total amount of the metal oxide and the metal hydroxide is about 0.05 to 2000 parts by weight, preferably about 0.1 to 1200 parts by weight, with respect to 1 part by weight of the acid-labile active ingredient. More preferably, about 0.1 to 800 parts by weight is blended. Usually, the total amount of metal oxide and metal hydroxide is 0.1 to 1800 parts by weight, preferably 0.5 to 1000 parts by weight, and more preferably 1 to 800 parts per 1 part by weight of the benzimidazole compound. Part by weight is blended. Preferably, in the stomach in the normal pH range, it is formulated in an amount that raises the pH to 3 or more within about 60 minutes after administration, more preferably within about 40 minutes.

The chewable tablet formulation of the present invention further comprises excipients for formulation (eg, glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch , Rice starch, microcrystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, etc.), binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxy Sodium methylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, etc.), disintegrant (eg low substituted hydroxy) Lopylcellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, etc.), taste-masking agents (eg, citric acid, ascorbic acid, tartaric acid, malic acid, dipotassium glycyrrhizin, glutamic acid Sodium, 5'-sodium inosinate, 5'-sodium guanylate, etc.), sweeteners (eg, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizin, etc.), surfactants (eg, polysorbate, polyoxyethylene Polyoxypropylene copolymer, sodium lauryl sulfate, etc., perfume (eg lemon oil, orange oil, menthol, brackish oil etc.), lubricant (eg steer) Magnesium phosphate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, etc.), colorant (for example, edible yellow No. 5, edible blue No. 2, ferric sesquioxide, yellow ferric oxide, etc.), anti Additives such as an oxidizing agent (for example, sodium ascorbate, L-cysteine, sodium sulfite, etc.) can be used.
The particle diameter of the raw material used for these is not particularly limited, but particles of 500 μm or less (preferably 300 μm or less) are preferable from the viewpoint of manufacturability.

  The chewable tablet of the present invention is selected from an acid labile active ingredient and an alkaline earth metal carbonate, metal oxide and metal hydroxide in order to further stabilize the acid labile active ingredient. A group containing at least one basic substance and at least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides without containing an acid labile active ingredient You may make it a chewable tablet containing the group to contain. More specifically, an acid-labile active ingredient and at least one basic substance selected from alkaline earth metal carbonates, metal oxides and metal hydroxides, if necessary, other excipients, etc. At least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides, and other excipients, which are granulated with the components of The composition may be granulated with ingredients such as these and mixed in a conventional manner, and basic ingredients such as active ingredients and alkaline earth metal carbonates, metal oxides and metal hydroxides, and as necessary. Layers containing other excipients and other active ingredients and no basic additives such as alkaline earth metal carbonates, metal oxides and metal hydroxides, and other excipients if necessary Formulated in separate layers (eg, two-layer formulation) Layered pharmaceutical formulation of or a group containing an active ingredient in the core layer may be a group containing no active ingredient in the formulation, etc.) that the covering layer.

A more preferred embodiment of the present invention comprises a group comprising an acid labile active ingredient and an alkaline earth metal carbonate (preferably calcium carbonate), no acid labile active ingredient, And a group containing at least one component selected from metal oxides and metal hydroxides.
Since alkaline earth metal carbonates such as calcium carbonate are excellent in the effect of improving the stability of an active ingredient unstable to an acid, it is desirable to be present in the vicinity of the active ingredient.
A preferred combination of metal oxide and metal hydroxide is magnesium oxide and magnesium hydroxide. As described above, metal oxides such as magnesium oxide are excellent in the effect of quickly neutralizing gastric acid, but it is desirable to combine with metal hydroxides such as magnesium hydroxide in order to improve manufacturability. A preferred weight ratio between a metal oxide such as magnesium oxide and a metal hydroxide such as magnesium hydroxide is 1: 0.2 to 1:50.

In a more preferred embodiment of the present invention, lansoprazole or an optically active substance thereof or a salt thereof, about 0.001 to about 0.3 parts by weight of calcium carbonate and lansoprazole or an optically active substance thereof or A group containing about 0.2 to about 200 parts by weight with respect to 1 part by weight of the salt, and containing no lansoprazole or its optically active substance or salt thereof, magnesium oxide and magnesium hydroxide, lansoprazole or its optically active substance or A chewable tablet comprising a total of about 0.2 to about 200 parts by weight per 1 part by weight of the salt.
The method for producing the solid preparation which is the chewable tablet of the present invention may be a method known per se, such as benzimidazole compound, alkaline earth metal carbonate and / or metal oxide and / or metal hydroxide, necessary A method of directly compressing by combining an appropriate amount of a basic additive, an excipient, further a binder, a disintegrant, a lubricant, a corrigent, a sweetener, a colorant, a fragrance, etc., which is highly water-soluble and has an antacid action To make chewable tablets. Alternatively, it is preferable to obtain granules for chewable tablets by a wet granulation method.
Here, the wet granulation method means, for example, a mixture of a benzimidazole compound, an alkaline earth metal carbonate and / or a metal oxide and / or a metal hydroxide and an excipient, or a binder dispersed or It is a method of granulating using a dissolved liquid and then obtaining a granulated powder by drying or the like, and the granulation mechanism may be any method such as extrusion, flow, rolling, centrifugation, stirring, spraying, etc. Good. A chewable tablet is obtained by combining this granulated powder with an appropriate amount of a disintegrant, a lubricant, a corrigent, a sweetener, a fragrance, a colorant and the like, and compression.

  Also, for example, a mixture of a benzimidazole compound, an alkaline earth metal carbonate and / or metal oxide and / or metal hydroxide and an excipient, etc., is prepared using a solution in which a binder is dispersed or dissolved. A mixture of a group containing the granulated active ingredient and an alkaline earth metal carbonate and / or metal oxide and / or metal hydroxide and / or a highly water-soluble basic additive, further an excipient, etc. , A group containing no active ingredients granulated using a solution in which a binder is dispersed or dissolved, and a suitable amount of a disintegrant, a lubricant, a corrigent, a sweetener, a fragrance, a colorant, and the like, A chewable tablet is obtained by compression. Further, for example, a group containing a suitable amount of a disintegrant, a lubricant, a corrigent, a sweetener, a fragrance, a colorant and the like in a group containing a benzimidazole compound and a disintegrant or lubricant in a group not containing an active ingredient A layered chewable tablet is obtained by compressing a layer in which an appropriate amount of a corrigent, sweetener, fragrance, colorant and the like are combined.

In addition, when the preparation is divided into groups, an additive having a binding power to the group containing the active ingredient (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, Partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, polyethylene oxide, carboxymethylethylcellulose, carboxyvinyl polymer, ethylcellulose, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate copolymer, etc. ) To delay elution. In addition, the group containing the active ingredient is hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, ethylcellulose, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate copolymer, methacrylic acid polymer, hydroxypropyl methylcellulose It is also possible to delay elution by coating with a component comprising phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, or the like.
The chewable tablet of the present invention may have any tablet hardness that can be chewed, but is preferably 30N to 500N, more preferably 50N to 300N.
The hardness can be evaluated by using, for example, a Toyama tablet hardness tester (Toyama Sangyo Co., Ltd.) or Pharma Test WHT-1 type (PHARMA TEST APPARATEBAU GMBH).
Moreover, the chewable tablet of the present invention may be large because it can be chewed and taken, but the maximum diameter is preferably 25 mm or less from the viewpoint of dosing. Also, the shape may be any of an oval shape, an oblong shape, a triangular shape, etc. in addition to a circular shape.

The solid preparation of the present invention can be chewed and administered orally. In addition, it can be swallowed with saliva in the oral cavity without being chewed and swallowed.
In the solid preparation of the present invention, when the active ingredient is a benzimidazole compound represented by the formula (I) such as lansoprazole or an optically active substance thereof, these compounds have an excellent antiulcer action, gastric acid It has a secretory inhibitory action, mucosal protective action, anti-Helicobacter pylori action, etc. and has low toxicity, so it is useful as a medicine. In this case, the solid preparation of the present invention is used in mammals (eg, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice, etc.) peptic ulcers (eg, gastric ulcer, duodenal ulcer, anastomotic ulcer) , Zollinger-Ellison syndrome, etc.), gastritis, GERD (Gastroesophageal Reflux Diseases, etc.), NUD (Non Ulcer Dyspepsia), gastric cancer, etc. (Including gastric cancer associated with interleukin-1β production promotion by interleukin-1 gene polymorphism), gastric MALT lymphoma treatment and prevention, Helicobacter pylori eradication, peptic ulcer, acute stress ulcer and hemorrhagic gastritis Suppresses upper gastrointestinal bleeding and causes invasive stress (major surgery requiring intensive management after surgery and cerebrovascular disease requiring intensive treatment , Head trauma, multiple organ failure, suppression of upper gastrointestinal bleeding due to extensive burns, treatment and prevention of ulcers caused by non-steroidal anti-inflammatory agents; treatment and prevention of gastric hyperacidity and ulcers due to post-operative stress It can be administered orally for the purpose. For Helicobacter pylori sterilization, it is preferable to use the solid preparation of the present invention in combination with a penicillin antibiotic (eg, amoxicillin) and an erythromycin antibiotic (eg, clarithromycin).

In particular, the preparation of the present invention is suitably applied to a therapeutic or prophylactic agent for GERD (Symptomatic GERD, reflux esophagitis, etc.). The chewable tablet of the present invention is suitably used for children and elderly people as long as they can be chewed.
The daily dose varies depending on the degree of symptoms, age of the subject, sex, body weight, timing of administration, interval, type of active ingredient, etc., and is not particularly limited. For example, as an anti-ulcer agent, adult (60 kg) On the other hand, when administered orally, the active ingredient is about 0.5-1500 mg / day, preferably about 5-150 mg / day. These benzimidazolazole-based compound-containing preparations may be administered once a day or divided into 2 to 3 times a day.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example and a test example, this invention is not limited to these.

Example 1
Manufacture of the group containing the active ingredient: 150 g of lansoprazole, 1875 g of calcium carbonate, 635 g of D-mannitol are charged into a fluidized bed granulator, and an aqueous solution in which 120 g of hydroxypropylcellulose is dissolved in 1880 g of purified water is sprayed, granulated, and dried. 2695 g of granulated powder was obtained.
Manufacture of a group containing no active ingredient Magnesium hydroxide 1450 g, D-mannitol 853.2 g, aspartame 96 g, crospovidone 64.8 g were charged into a fluidized bed granulator, and an aqueous solution in which 96 g of hydroxypropyl cellulose was dissolved in 1504 g of purified water. Sprayed to granulate and dried to obtain 2503 g of granulated powder.
A group of 1668 g containing the active ingredient, 1920 g of the group containing no active ingredient, 360 g of crystalline cellulose (Theolas KG-801), 180 g of crospovidone, and 72 g of magnesium stearate were mixed in a bag to obtain a mixed powder. Using a rotary tableting machine, 1400 mg of 1 tablet was tableted with a scissors on a 17 mm corner plane. No darkening was observed in the obtained tablets.

Manufacture of the group containing the active ingredient 30 g of lansoprazole, 750 g of calcium carbonate and 284 g of D-mannitol were charged into a fluidized bed granulator, and sprayed with an aqueous solution in which 48 g of hydroxypropylcellulose was dissolved in 752 g of purified water, granulated and dried. 1066 g of granulated powder was obtained.
Manufacture of a group not containing an active ingredient An aqueous solution in which 725 g of magnesium hydroxide, 426.6 g of D-mannitol, 48 g of aspartame, and 32.4 g of crospovidone were charged into a fluidized bed granulator, and 48 g of hydroxypropylcellulose was dissolved in 752 g of purified water. It sprayed and granulated, and it dried and obtained 1161g of granulated powder.
834 g of the group containing the active ingredient, 960 g of the group containing no active ingredient, 180 g of crystalline cellulose (Theolas KG-801), 90 g of crospovidone, and 36 g of magnesium stearate were mixed in a bag to obtain a mixed powder. Using a rotary tableting machine, 1400 mg of 1 tablet was tableted with a scissors on a 17 mm corner plane. No darkening was observed in the obtained tablets.

Manufacture of a group containing the active ingredient 60 g of lansoprazole, 750 g of calcium carbonate, and 254 g of D-mannitol were charged into a fluidized bed granulator, sprayed with an aqueous solution in which 48 g of hydroxypropylcellulose was dissolved in 752 g of purified water, granulated and dried. 1070.5 g of granulated powder was obtained.
Manufacture of a group not containing an active ingredient An aqueous solution in which 435 g of magnesium hydroxide, 716.6 g of D-mannitol, 48 g of aspartame, 32.4 g of crospovidone were charged into a fluidized bed granulator, and 48 g of hydroxypropylcellulose was dissolved in 752 g of purified water. It sprayed and granulated, and it dried and obtained 1245.4g granulated powder.
834 g of the group containing the active ingredient, 960 g of the group containing no active ingredient, 180 g of crystalline cellulose (Theolas KG-801), 90 g of crospovidone, and 36 g of magnesium stearate were mixed in a bag to obtain a mixed powder. Using a rotary tableting machine, 1400 mg of 1 tablet was tableted with a scissors on a 17 mm corner plane. No darkening was observed in the obtained tablets.

Manufacture of the group containing the active ingredient 75 g of lansoprazole, 937.5 g of calcium carbonate, 317.5 g of D-mannitol were charged into a fluidized bed granulator, and granulated by spraying an aqueous solution in which 60 g of hydroxypropylcellulose was dissolved in 940 g of purified water. And dried to obtain 1306 g of a granulated powder.
Production of a group containing no active ingredient 300 g of magnesium oxide, 651.6 g of D-mannitol, 48 g of aspartame, 32.4 g of crospovidone were charged into a fluidized bed granulator, and an aqueous solution in which 48 g of hydroxypropylcellulose was dissolved in 752 g of purified water was sprayed. And granulated and dried to obtain 1053 g of granulated powder.
333.6 g of the group containing the active ingredient, 324 g of the group containing no active ingredient, 72 g of crystalline cellulose (Theolas KG-801), 36 g of crospovidone, and 14.4 g of magnesium stearate were mixed in a bag to obtain a mixed powder. Using a rotary tableting machine, 1300 mg of 1 tablet was tableted with a 16-m square-faced punch. No darkening was observed in the obtained tablets.

Manufacture of the group containing the active ingredient 75 g of lansoprazole, 937.5 g of calcium carbonate, 317.5 g of D-mannitol were charged into a fluidized bed granulator, and granulated by spraying an aqueous solution in which 60 g of hydroxypropylcellulose was dissolved in 940 g of purified water. And dried to obtain 1306 g of a granulated powder.
Production of a group containing no active ingredient 400 g of magnesium oxide, 145 g of magnesium hydroxide, 406.6 g of D-mannitol, 48 g of aspartame, 32.4 g of crospovidone were charged into a fluidized bed granulator, and 48 g of hydroxypropylcellulose was added to 752 g of purified water. The dissolved aqueous solution was sprayed and granulated, and dried to obtain 1027 g of granulated powder.
333.6 g of the group containing the active ingredient, 324 g of the group containing no active ingredient, 72 g of crystalline cellulose (Theolas KG-801), 36 g of crospovidone, and 14.4 g of magnesium stearate were mixed in a bag to obtain a mixed powder. Using a rotary tableting machine, 1300 mg of 1 tablet was tableted with a 16 mm corner plane scissors. No darkening was observed in the obtained tablets.

Test example

The tablets obtained in Examples 1, 2, 3, 4 and 5 were placed in a glass bottle and stored at 60 ° C. for 2 weeks. About the tablet after a preservation | save, the residual rate of the lansoprazole was measured by the liquid chromatography.

Manufacture of a group containing the active ingredient 420 g of lansoprazole, 7000 g of calcium carbonate and 6543.6 g of D-mannitol were charged into a fluidized bed granulator, 582.4 g of hydroxypropylcellulose was dissolved in 814.3 g of purified water, and 14 g of iron sesquioxide was separately added. An aqueous solution to which 1000 g of dispersed water was added was sprayed and granulated, and dried to obtain 13989.0 g of a granulated powder.
Production of a group containing no active ingredient 2100 g of magnesium oxide, 6090 g of magnesium hydroxide, 406.6 g of D-mannitol, 945 g of aspartame, 588 g of crospovidone were charged into a fluid bed granulator, and 588 g of hydroxypropylcellulose was dissolved in 8212 g of purified water. Separately, an aqueous solution containing 1000 g of water in which 14.7 g of iron sesquioxide was dispersed was sprayed and granulated, followed by drying to obtain 13945.0 g of a granulated powder.
3640 g of the group containing the active ingredient, 4760 g of the group not containing the active ingredient, 805 g of crystalline cellulose (Theolas KG-802), 350 g of crospovidone, 98 g of strawberry flavor, and 147 g of magnesium stearate were mixed to obtain a mixed powder. Using a rotary tableting machine, 1400 mg of 1 tablet was tableted with a 16 mm corner plane scissors. No darkening was observed in the obtained tablets.

Production of group containing active ingredients 840 g of lansoprazole, 7000 g of calcium carbonate and 613.6 g of D-mannitol were charged into a fluid bed granulator, 582.4 g of hydroxypropylcellulose was dissolved in 814.3 g of purified water, and 14 g of iron sesquioxide was separately added. The aqueous solution added with 1000 g of dispersed water was sprayed and granulated, and dried to obtain 13865.8 g of granulated powder.
Production of a group containing no active ingredient 2100 g of magnesium oxide, 6090 g of magnesium hydroxide, 406.6 g of D-mannitol, 945 g of aspartame, 588 g of crospovidone were charged into a fluid bed granulator, and 588 g of hydroxypropylcellulose was dissolved in 8212 g of purified water. Separately, an aqueous solution containing 1000 g of water in which 14.7 g of iron sesquioxide was dispersed was sprayed and granulated, followed by drying to obtain 13945.0 g of a granulated powder.
3640 g of the group containing the active ingredient, 4760 g of the group not containing the active ingredient, 805 g of crystalline cellulose (Theolas KG-802), 350 g of crospovidone, 98 g of strawberry flavor, and 147 g of magnesium stearate were mixed to obtain a mixed powder. Using a rotary tableting machine, 1400 mg of 1 tablet was tableted with a 16 mm corner plane scissors. No darkening was observed in the obtained tablets.

Production of group containing active ingredients Lansoprazole 405 g, calcium carbonate 6750 g, D-mannitol 7192.8 g were charged into a fluid bed granulator, 648 g of hydroxypropylcellulose was dissolved in 9152 g of purified water, and 16.2 g of iron sesquioxide was dispersed. An aqueous solution added with 1000 g of water was sprayed and granulated, and dried to obtain 14662.2 g of a granulated powder.
Manufacture of a group not containing an active ingredient 1500 g of magnesium oxide, 6525 g of magnesium hydroxide, 4354.5 g of D-mannitol, 900 g of aspartame, and 315 g of crospovidone were charged into a fluidized bed granulator, and 493.5 g of hydroxypropyl cellulose was purified by 6731. An aqueous solution in which 1000 g of water in which 12 g of iron sesquioxide was dispersed was added and dissolved in 5 g was sprayed and granulated, and dried to obtain 13780.1 g of granulated powder.
A group containing 3892 g containing the active ingredient, 6580 g group containing no active ingredient, 721 g crystalline cellulose (Theolas KG-802), 721 g crospovidone, 119 g strawberry flavor, and 168 g magnesium stearate were mixed to obtain a mixed powder. Using a rotary tableting machine, 1700 mg of 1 tablet was tableted with a scissors with an 18 mm corner plane. No darkening was observed in the obtained tablets.

Production of group containing active ingredient 810 g of lansoprazole, 6750 g of calcium carbonate and 6787.8 g of D-mannitol were charged into a fluidized bed granulator, 648 g of hydroxypropylcellulose was dissolved in 9152 g of purified water, and 16.2 g of iron sesquioxide was dispersed. An aqueous solution added with 1000 g of water was sprayed and granulated, and dried to obtain 13967.9 g of a granulated powder.
Manufacture of a group not containing an active ingredient 1500 g of magnesium oxide, 6525 g of magnesium hydroxide, 4354.5 g of D-mannitol, 900 g of aspartame, and 315 g of crospovidone were charged into a fluidized bed granulator, and 493.5 g of hydroxypropyl cellulose was purified by 6731. An aqueous solution in which 1000 g of water in which 12 g of iron sesquioxide was dispersed was added and dissolved in 5 g was sprayed and granulated, and dried to obtain 13780.1 g of granulated powder.
A group containing 3892 g containing the active ingredient, 6580 g group containing no active ingredient, 721 g crystalline cellulose (Theolas KG-802), 721 g crospovidone, 119 g strawberry flavor, and 168 g magnesium stearate were mixed to obtain a mixed powder. Using a rotary tableting machine, 1700 mg of 1 tablet was tableted with a scissors with an 18 mm corner plane. No darkening was observed in the obtained tablets.

Manufacture of a group containing the active ingredient 75 g of lansoprazole, 1250 g of calcium carbonate and 1168.5 g of D-mannitol were charged into a fluidized bed granulator, and 1735.8 g of a 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide was sprayed. Granulate.
Manufacture of a group containing no active ingredient: 6% hydroxy containing 800 g magnesium oxide, 580 g magnesium hydroxide, 731.2 g D-mannitol, 208 g aspartame, 70 g crospovidone, and 2.8 g iron sesquioxide. Spray and granulate 1469.5 g of aqueous propylcellulose solution.
1560 g of the group containing the active ingredient, 1860 g of the group containing no active ingredient, 378 g of crystalline cellulose (Theolas KG-802), 150 g of crospovidone, 40.5 g of strawberry flavor, and 61.5 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1350 mg of 1 tablet is tableted with a 16 mm corner plane scissors.

Production of group containing active ingredient Lansoprazole 150 g, calcium carbonate 1250 g, D-mannitol 1093.5 g were charged into a fluidized bed granulator and sprayed with 1735.8 g of 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide. Granulate.
Manufacture of a group containing no active ingredient: 6% hydroxy containing 800 g magnesium oxide, 580 g magnesium hydroxide, 731.2 g D-mannitol, 208 g aspartame, 70 g crospovidone, and 2.8 g iron sesquioxide. Spray and granulate 1469.5 g of aqueous propylcellulose solution.
1560 g of the group containing the active ingredient, 1860 g of the group containing no active ingredient, 378 g of crystalline cellulose (Theolas KG-802), 150 g of crospovidone, 40.5 g of strawberry flavor, and 61.5 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1350 mg of 1 tablet is tableted with a 16 mm corner plane scissors.

Manufacture of a group containing the active ingredient 75 g of lansoprazole, 1250 g of calcium carbonate and 1168.5 g of D-mannitol were charged into a fluidized bed granulator, and 1735.8 g of a 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide was sprayed. Granulate.
Production of a group containing no active ingredient 700 g of magnesium oxide, 1015 g of magnesium hydroxide, 732.2 g of D-mannitol, 217 g of aspartame, 52.5 g of crospovidone were charged into a fluidized bed granulator and 6 containing 2.8 g of iron sesquioxide 6 Spray and granulate 1636.1 g of an aqueous hydroxypropylcellulose solution.
1560 g of the group containing the active ingredient, 2415 g of the group containing no active ingredient, 409.2 g of crystalline cellulose (Theolas KG-802), 180 g of crospovidone, 46.8 g of strawberry flavor, and 69 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1560 mg of 1 tablet is tableted with a scissors on an 18 mm corner plane.

Production of group containing active ingredient Lansoprazole 150 g, calcium carbonate 1250 g, D-mannitol 1093.5 g were charged into a fluidized bed granulator and sprayed with 1735.8 g of 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide. Granulate.
Production of a group containing no active ingredient 700 g of magnesium oxide, 1015 g of magnesium hydroxide, 732.2 g of D-mannitol, 217 g of aspartame, 52.5 g of crospovidone were charged into a fluidized bed granulator and 6 containing 2.8 g of iron sesquioxide 6 Spray and granulate 1636.1 g of an aqueous hydroxypropylcellulose solution.
1560 g of the group containing the active ingredient, 2415 g of the group containing no active ingredient, 409.2 g of crystalline cellulose (Theolas KG-802), 180 g of crospovidone, 46.8 g of strawberry flavor, and 69 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1560 mg of 1 tablet is tableted with a scissors on an 18 mm corner plane.

Manufacture of a group containing the active ingredient 75 g of lansoprazole, 1250 g of calcium carbonate and 1168.5 g of D-mannitol were charged into a fluidized bed granulator, and 1735.8 g of a 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide was sprayed. Granulate.
Production of a group containing no active ingredient 1050 g of magnesium oxide, 507.5 g of magnesium hydroxide, 697.2 g of D-mannitol, 210 g of aspartame, 52.5 g of crospovidone were charged into a fluidized bed granulator, and 2.8 g of iron sesquioxide was added. It sprays and granulates 1519.5g of 6% hydroxypropylcellulose aqueous solution containing.
1560 g of the group containing the active ingredient, 2238 g of the group containing no active ingredient, 409.5 g of crystalline cellulose (Theolas KG-802), 180 g of crospovidone, 45 g of strawberry flavor, and 67.5 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1500 mg of one tablet is tableted with a punch having an 18 mm corner plane.

Production of group containing active ingredient Lansoprazole 150 g, calcium carbonate 1250 g, D-mannitol 1093.5 g were charged into a fluidized bed granulator and sprayed with 1735.8 g of 6% hydroxypropylcellulose aqueous solution containing 2.5 g of iron sesquioxide. Granulate.
Production of a group containing no active ingredient 1050 g of magnesium oxide, 507.5 g of magnesium hydroxide, 697.2 g of D-mannitol, 210 g of aspartame, 52.5 g of crospovidone were charged into a fluidized bed granulator, and 2.8 g of iron sesquioxide was added. It sprays and granulates 1519.5g of 6% hydroxypropylcellulose aqueous solution containing.
1560 g of the group containing the active ingredient, 2238 g of the group containing no active ingredient, 409.5 g of crystalline cellulose (Theolas KG-802), 180 g of crospovidone, 45 g of strawberry flavor, and 67.5 g of magnesium stearate are mixed to obtain a mixed powder. Using a rotary tableting machine, 1500 mg of one tablet is tableted with a punch having an 18 mm corner plane.

Claims (20)

  Contains an acid-labile active ingredient, a group containing at least one basic substance selected from alkaline earth metal carbonates, metal oxides and metal hydroxides, and an acid-labile active ingredient And a group containing at least one component selected from alkaline earth metal carbonates, metal oxides and metal hydroxides.   The chewable tablet according to claim 1, which is a preparation not having an enteric coating.   The chewable tablet according to claim 1, wherein the acid labile active ingredient is a proton pump inhibitor (PPI).   The chewable tablet according to claim 3, wherein 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 chewable tablet according to claim 4, wherein the benzimidazole compound is lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole, an optically active compound thereof, or a salt thereof.   The chewable tablet according to claim 3, wherein PPI is an imidazopyridine compound.   The chewable tablet according to claim 7, wherein the imidazopyridine compound is tenatoprazole, an optically active form thereof, or a salt thereof.   The chewable tablet according to claim 1, wherein the alkaline earth metal carbonate is calcium carbonate and / or magnesium carbonate.   Metals having a pH of 8.0 or higher in a 1% (W / W) aqueous solution or 1% (W / W) aqueous suspension of the metal oxide and metal hydroxide. The chewable tablet according to claim 1, which is an oxide or a metal hydroxide.   The chewable tablet according to claim 1, comprising at least one metal oxide selected from the group consisting of magnesium oxide, magnesium silicate, dry aluminum hydroxide gel and magnesium aluminate metasilicate.   Magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, coprecipitate of aluminum hydroxide and magnesium hydroxide, coprecipitate of aluminum hydroxide, magnesium carbonate and calcium carbonate, and coprecipitate of aluminum hydroxide and sodium bicarbonate The chewable tablet according to claim 1, comprising at least one metal hydroxide selected from the group consisting of:   The chewable tablet according to claim 1, wherein the alkaline earth metal carbonate is calcium carbonate.   The chewable tablet according to claim 1, wherein the metal oxide is magnesium oxide.   The chewable tablet according to claim 1, wherein the metal hydroxide is magnesium hydroxide.   The chewable according to claim 4, comprising 0.1 to 1500 parts by weight of at least one component selected from an alkaline earth metal carbonate, a metal oxide and a metal hydroxide with respect to 1 part by weight of the benzimidazole compound. Tablets.   A group containing an acid-labile active ingredient and an alkaline earth metal carbonate; and at least one ingredient selected from a metal oxide and a metal hydroxide without containing an acid-labile active ingredient A chewable tablet comprising a group containing   18. The chewable tablet according to claim 17, wherein the alkaline earth metal carbonate is calcium carbonate, the metal oxide is magnesium oxide, and the metal hydroxide is magnesium hydroxide.   Lansoprazole or its optically active substance or salt thereof, 0.001 to 0.3 part by weight with respect to 1 part by weight of the preparation and calcium carbonate, and 0.2 part by weight of lansoprazole or its optically active substance or salt thereof. A group containing ˜200 parts by weight, lansoprazole or its optically active substance or salt thereof, and containing magnesium oxide and magnesium hydroxide in a total amount of 0.2 relative to 1 part by weight of lansoprazole or its optically active substance or its salt A chewable tablet comprising -200 parts by weight. The chewable tablet according to claim 19, wherein the weight ratio of magnesium oxide to magnesium hydroxide is 1: 0.2 to 1:50.