JP2001270827A - Benzimidazole compound-containing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To plan the more physicochemical stabilization of a tablet containing a benzimidazole compound or its physiologically permissible salt. SOLUTION: The stabilized tablet is obtained by formulating the benzimidazole compound or its physiologically permissible salt and a tablet lubricant other than (1) clospovidone and (2) magnesium stearate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound comprising a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, and a lubricant other than 1) crospovidone and 2) magnesium stearate. To a stable tablet comprising:

[0002]

2. Description of the Related Art Benzimidazole compounds or physiologically acceptable salts thereof have a strong inhibitory effect on the so-called proton pump, and are widely used as therapeutic agents for gastric ulcer, duodenal ulcer, etc. by suppressing gastric acid secretion. Have been. On the other hand, benzimidazole-based compounds are very unstable chemically, and therefore various approaches have been taken to formulate them. For example, Japanese Patent Application Laid-Open No. 62-277322 discloses a method for producing a stabilized pharmaceutical composition characterized by blending a basic inorganic salt of magnesium and / or calcium with a benzimidazole compound, Showa 6
JP-A-2-258320 discloses a tablet containing a benzimidazole compound containing an alkali compound and a water-soluble or water-soluble tablet excipient, or a polymer-soluble film-forming compound. Also disclosed are oral pharmaceutical formulations coated with an enteric coating. further,
International Publication WO99 / 53918 discloses a benzimidazole compound or a physiologically acceptable salt thereof.
A preparation (A) comprising one or more substances selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone; Or a preparation obtained by coating this preparation (A) with an enteric coating, or a preparation (A)
Which is coated with an intermediate film and further coated with an enteric film. As a specific example, rabeprazole or a physiologically acceptable salt thereof is mixed with 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate, or rabeprazole or a physiologically acceptable salt thereof. 1) Crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate, and a core coated with an enteric coating, or rabeprazole or a physiologically acceptable salt thereof. The salt obtained is composed of 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate. The core is coated with an intermediate coating, and the preparation is coated with an enteric coating. Is disclosed.

[0003]

However, the stability of a benzimidazole compound or a physiologically acceptable salt thereof in a preparation containing the benzimidazole-based compound is still low.
Not enough. Crospovidone or a benzimidazole compound or a physiologically acceptable salt thereof, or
Tablets containing crospovidone and sodium hydroxide may contain a lubricant such as magnesium stearate at the time of tablet compression. Depending on the storage conditions and the like, the disintegration time of the tablet may be prolonged or the dissolution may be delayed, and improvement is required. That is, an object of the present invention is to further stabilize a tablet containing a benzimidazole-based compound or a physiologically acceptable salt thereof in a more physicochemical manner.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a benzimidazole compound represented by the following structural formula (formula 1) or a physiologically acceptable salt thereof, and 1) crospovidone and 2) a compound other than magnesium stearate. It is a stable tablet containing a lubricant.

Embedded image The present invention also relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, and a lubricant other than 1) crospovidone, 2) sodium hydroxide and 3) magnesium stearate. It is a stable tablet formulated. The lubricant to be mixed with the benzimidazole compound represented by (Formula 1) or the physiologically acceptable salt thereof in the present invention is not particularly limited as long as it is a lubricant other than magnesium stearate. Various oils and fats including sodium stearyl acid, calcium stearate, stearic acid, and hydrogenated oil are mentioned, preferably, sodium stearyl fumarate, calcium stearate or stearic acid, and particularly preferably, sodium stearyl fumarate or stearic acid. It is calcium phosphate. That is, the present invention relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate, and stearin. It is a stable tablet containing one or more lubricants selected from acids.

Further, the present invention relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, It is a stable tablet obtained by coating an enteric coating on a tablet containing at least one lubricant selected from calcium phosphate and stearic acid. The benzimidazole compound is extremely unstable in an acidic state. When the benzimidazole compound is taken, the benzimidazole compound decomposes immediately upon contact with gastric acid in the stomach and loses its physiological activity. Therefore, in order to prevent decomposition in the stomach, it is necessary to prepare a preparation that does not dissolve in the stomach, that is, a preparation in which a tablet containing a benzimidazole compound is coated with an enteric substance.

The present invention further relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide, 3) sodium stearyl fumarate, and calcium stearate. A stable tablet obtained by coating a tablet containing one or more lubricants selected from stearic acid with an intermediate film and further coated with an enteric film. Since the enteric film is generally an acidic substance, direct contact with the benzimidazole compound is not preferable. Therefore, an inert intermediate film can be applied between the core containing the benzimidazole compound and the enteric film. Here, inactive is a substance that does not adversely affect the stability of the benzimidazole compound. The inert intermediate film may be any of a water-soluble polymer, a water-soluble or water-dispersible substance, and a water-insoluble substance.Specifically, hydroxypropylcellulose, hydroxypropylmethylcellulose, aminoalkyl methacrylate copolymer E, lactose, mannitol , Starch, crystalline cellulose, ethyl cellulose, vinyl acetate and the like. In addition, Japanese Patent Application Laid-Open No. 1-229028
In the case where an intermediate film is formed using a water-insoluble substance as disclosed in Japanese Unexamined Patent Publication, the water-insoluble fine particles may be mixed into the film.

Preferred examples of the benzimidazole compound or a physiologically acceptable salt thereof in the present invention include rabeprazole, omeprazole, pantoprazole, lansoprazole or their sodium and potassium salts. Formula 3 shows the structural formula of each compound.

Embedded image

In the present invention, when the benzimidazole compound represented by the formula 1 or the physiologically acceptable salt thereof is rabeprazole or its sodium salt, a particularly excellent effect is exhibited. That is, the present invention relates to rabeprazole or a sodium salt thereof, and 1) crospovidone,
It is a stable tablet comprising one or more lubricants selected from 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. In the present invention, particularly excellent effects are exhibited when the lubricant is sodium stearyl fumarate.
That is, the present invention is a stable tablet comprising rabeprazole or its sodium salt, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate.

The benzimidazole compound of the present invention can be produced by a known method. For example,
JP-A-52-62275, JP-A-54-1417
No. 83, JP-A No. 1-6270 and the like.

[0010] The sodium stearyl fumarate in the present invention is a product listed in NF and / or pharmaceutical additive standards, and a commercially available product (Nippon Oil & Fats, Sankei Pharmaceutical) can be easily obtained. Calcium stearate and stearic acid are listed in the Japanese Pharmacopoeia. Crospovidone is an additive listed in the pharmaceutical excipient standard. The mixing ratio of sodium stearyl fumarate in the present invention is not particularly limited, but is 0.1 to 10% by weight based on the uncoated tablet containing the benzimidazole compound or a physiologically acceptable salt thereof. Is preferred. The mixing ratio of crospovidone and sodium hydroxide is also not particularly limited, but is 5 to 70% by weight based on the uncoated tablet containing a benzimidazole compound or a physiologically acceptable salt thereof, 0.2-25%
It is preferably in parts by weight.

The benzimidazole compounds generally have high hygroscopicity, and when decomposed under heating and humidified storage conditions, a large change in the coloration of the tablet is particularly observed. Tablets obtained by blending crospovidone and sodium hydroxide with a benzimidazole compound or a physiologically acceptable salt thereof are usually blended with a lubricant such as magnesium stearate at the time of tablet compression. During the disintegration test, a part of the disintegrated tablet floats on the interface of the disintegration test solution, or the disintegration time of the tablet may be prolonged due to fluctuations in the manufacturing conditions of the granular powder, overgranulation, and fluctuations in the mixing time of the lubricant. The dissolution of the benzimidazole compound or a physiologically acceptable salt thereof from the tablet may be delayed. Further, when the tablet is stored under warm or humidified conditions, the disintegration time of the tablet is prolonged and the dissolution delay of the benzimidazole compound or a physiologically acceptable salt thereof from the tablet is further accelerated. The present invention has surprisingly solved these problems and aims at further physicochemical stabilization of a tablet containing a benzimidazole compound or a physiologically acceptable salt thereof. Tablets in the present invention, not only improved content stability under warming and / or humidified storage conditions,
It is possible to prevent the phenomenon that a part of the disintegrated tablet floats on the interface of the disintegration test solution, and to prevent the dissolution delay of the benzimidazole compound or the physiologically acceptable salt thereof from the tablet and the prolongation of disintegration of the tablet over time. Has a remarkable effect. In particular, sodium stearyl fumarate is water-soluble and is dissolved in a buffer aqueous solution used for disintegration tests and dissolution tests. is there.

A stable tablet or benzimidazole comprising the benzimidazole compound according to the present invention or a physiologically acceptable salt thereof and 1) crospovidone and 2) a lubricant other than magnesium stearate. Or a stable tablet comprising a physiologically acceptable salt thereof and 1) crospovidone, 2) sodium hydroxide and 3) a lubricant other than magnesium stearate, or a benzimidazole compound or A stable mixture comprising a physiologically acceptable salt thereof and 1 or more lubricants selected from 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. For producing tablets, commonly used excipients such as lactose and mannitol can be used. The binder is not particularly limited, but it is desirable to use hydroxypropyl cellulose.
In the tablet according to the present invention, crospovidone and a lubricant such as sodium stearyl fumarate, calcium stearate and stearic acid have an average particle size of several μm.
It is preferred to use a product with a particle size of ５０50 μm, preferably 4 μm-50 μm.

The present invention also relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof: 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, stearate. A method for producing a stable tablet containing a benzimidazole compound or a physiologically acceptable salt thereof, characterized in that one or more lubricants selected from calcium phosphate and stearic acid are blended and tableted. . Also, the present invention
A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, and 1) crospovidone;
2) a benzimidazole-based compound characterized in that it contains at least one lubricant selected from sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid, and after tableting, coats an enteric film. Or a method for producing a stable tablet containing a physiologically acceptable salt thereof. Furthermore, the present invention relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearin. A tablet containing at least one lubricant selected from acids, and after tableting, a benzimidazole compound or a physiologically acceptable salt thereof, which is characterized by coating an intermediate film and further coating an enteric film. This is a method for producing a stable tablet.

The present invention also relates to a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, and stearic acid. A method for preventing the dissolution delay of a benzimidazole compound or a physiologically acceptable salt thereof from a tablet containing one or more lubricants selected from calcium phosphate and stearic acid, and / or prolonging the disintegration of the tablet It is a method to prevent. In the tablet according to the present invention, it is needless to say that the benzimidazole compound or a physiologically acceptable salt thereof is physicochemically stabilized. It has the property that the dissolution delay of the imidazole compound or a physiologically acceptable salt thereof and / or the disintegration prolongation of the tablet are prevented.

[0015] The present invention further provides a method for preventing the dissolution of a drug from a tablet, comprising mixing the drug with one or more lubricants selected from crospovidone, sodium stearyl fumarate, calcium stearate and stearic acid. And / or a method of preventing the tablet from prolonging disintegration. The drug is not particularly limited.

Hereinafter, the benzimidazole compound or a physiologically acceptable salt thereof is referred to as a benzimidazole compound.

The composition or preparation according to the present invention can be produced by a commonly used method. That is, for example, 1) crospovidone or 1) crospovidone and 2) sodium hydroxide are added to a benzimidazole-based compound, and various excipients are added and uniformly mixed to perform dry or wet granulation. . 3) One or more lubricants selected from sodium stearyl fumarate, calcium stearate, and stearic acid are added to the granulated product after sizing, and tableting is performed by adding a disintegrant such as crospovidone as necessary. Can be manufactured. Of course, it is not limited to this method. As a specific example, for example, rabeprazole sodium 10 g, which is a benzimidazole-based compound, crospovidone 20 g, mannitol 42.7 g, and hydroxypropyl cellulose 1.5 g are mixed, and sodium hydroxide dissolved or dispersed in ethanol while further mixing, and Granulation is performed by gradually adding potassium hydroxide, and after drying, granulation is performed using a speed mill (16 mesh).
To this, 0.8 g of sodium stearyl fumarate is added, mixed and tableted to obtain a tablet of 75 mg per tablet containing 10 mg of rabeprazole sodium. The tablet is sprayed with an ethanol solution of hydroxypropylcellulose in which crospovidone is dispersed by using a fluidized bed apparatus or a pan coating apparatus to form an intermediate film, and further, hydroxypropylmethylcellulose phthalate or ethanol of an enteric methacrylic acid copolymer is applied. An enteric-coated tablet provided with an intermediate film can be produced by spraying a solution or a hydrated ethanol solution.

[0018]

According to the present invention, it is possible to stabilize a tablet containing a very unstable benzimidazole compound or a physiologically acceptable salt thereof in a physicochemical manner. The effect example is shown below. Experimental example

(1) Effect of Preventing Prolongation of Disintegration in Tablets Immediately after Production and Excellent Tablet Properties Tablets having the following formulation of Example 1 (comprising 1.33% of sodium stearyl fumarate as a lubricant) were pressed. Tablets were prepared by changing the tablet pressure at 1000 to 1800 kg, and a tablet was subjected to a disintegration test immediately after production by the disintegration test method (Japanese Pharmacopoeia second liquid) listed in the Japanese Pharmacopoeia. As a control experiment, magnesium stearate was used instead of sodium stearyl fumarate as a lubricant (compounding amount is 1.33).
% (Control example 1), 2.66% (control example 2), two levels),
Formulations each containing a mixture of sodium stearyl fumarate and magnesium stearate (compounding amounts of 1.33% each (Comparative Example 3)) were prepared in the same manner as in Example 1 and evaluated in the same manner. . Table 1 shows each prescription and Table 2
Shows the disintegration time of the tablet. Example 2 shown below
Tablets (comprising 1.47% of sodium stearyl fumarate) in five levels (700, 800, 900, 10
Each of the tablets was prepared at a tableting pressure of 0,1100 kg), and the tablet disintegration test (n = 6), tablet weight evaluation (n = 20), tablet thickness evaluation (n = 20) were performed according to the methods described in the Japanese Pharmacopoeia. ), Tablet hardness was evaluated (n = 20). As a control experiment, a preparation (Control Example 4) containing the same amount of magnesium stearate as a lubricant instead of sodium stearyl fumarate was prepared in the same manner as in Example 2, and the same evaluation was performed.
Table 3 shows the respective formulations, Table 4 shows the physical property values of the tablet of Example 2, and Table 5 shows the physical property values of the tablet of Comparative Example 4.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

As a result of a comparison experiment between the tablet of the formulation of Example 1 and the tablet of the formulation of Control Examples 1 to 3, the disintegration of the tablet depends on the increase in the tableting pressure regardless of the type and the amount of the lubricant. Extension of time was allowed. Tablets containing sodium stearyl fumarate have a disintegration time of less than 4 minutes even at a high tableting pressure of 1800 kg, and magnesium stearate (compounding amount is 1.33% (Control Example 1), 2.66% ( In comparison with the two levels of Comparative Example 2) and the tablet to which a mixture of sodium stearyl fumarate and magnesium stearate was added (Control Example 3), the tablet disintegrated in a shorter time at any tableting pressure. In particular, magnesium stearate is added at 2.66.
In the tablet with% added (Control Example 2), a part of the disintegrated tablet floated on the interface of the disintegration test solution, and the disintegration time was at least 15 minutes or more. In addition, as a result of a comparison experiment of the tablets of the formulations of Example 2 and Control Example 4, a tablet containing 1.47% of sodium stearyl fumarate (Example 2) was a tablet containing 1.47% of magnesium stearate (Example 2). As compared with Control Example 4), tablet disintegration was remarkably fast and tablet hardness was high at all tableting pressures. In addition, the phenomenon that a part of the disintegrated tablet floated on the interface of the disintegration test solution was not recognized, and there was no difference between the tablet weight and the tablet thickness in the comparative experiment, and the tablet was good. From the viewpoint of the disintegration properties of the tablets immediately after production, it is clear that the tablets containing sodium stearyl fumarate of the present invention have more rapid disintegration properties than the tablets containing magnesium stearate. It is also clear that it has a higher tablet strength.

(2) Effect of Preventing Prolongation of Disintegration and Delay of Dissolution in Tablets Stored under Heating Conditions (Uncoated Tablet (Uncoated Tablet)) Example 2 (1.41 sodium stearyl fumarate as a lubricant) shown below %), Example 3 (1.47% of stearic acid as a lubricant)
And uncoated tablets (uncoated tablets) obtained in Example 4 (comprising 1.47% of calcium stearate as a lubricant) with the disintegration test (Japanese Pharmacopoeia liquid 2) described in the Japanese Pharmacopoeia. Evaluation was performed by a dissolution test (900 ml of the second liquid of the Japanese Pharmacopoeia, paddle method, 50 rpm). Both tests were performed on the tablets immediately after production in each example and on the tablets stored at 60 ° C. for 2 days. As a control experiment, a preparation (Control Example 4) containing the same amount of magnesium stearate as a lubricant was prepared in the same manner as in Example 2, and the same evaluation was performed. Table 3 shows the results of each formulation and the disintegration test. FIG. 1 shows the result of the dissolution test of the tablet immediately after production in Example 2, and FIG. 2 shows the result of the dissolution test of the tablet obtained by storing Example 2 at 60 ° C. for 2 days. FIG. 3 shows the results of the dissolution test of the tablet immediately after production in Example 3, and FIG.
The results of the dissolution test of tablets stored at 2 ° C. for 2 days are shown. Further, FIG. 5 shows the results of the dissolution test of the tablet immediately after production in Example 4, and FIG. 6 shows the results of the dissolution test of the tablet obtained by storing Example 4 at 60 ° C. for 2 days. In addition, the results of the dissolution test of the tablet immediately after production of Control Example 4 and the tablet stored at 60 ° C. for 2 days were as follows:
These are shown in FIGS. 7 and 8, respectively.

(Tablets coated with uncoated tablets) Tablets obtained by coating an intermediate film on uncoated tablets containing 1.47% of sodium stearyl fumarate obtained in Example 5 shown below,
Sodium stearyl fumarate obtained in Example 6 1.
Disintegration test (Japanese Pharmacopoeia liquid 2), dissolution test (Japanese Pharmacopoeia liquid 2) for tablets obtained by coating an intermediate film on an uncoated tablet containing 47% and further coated with an enteric film.
(00 ml, paddle method, 50 rpm) and high performance liquid chromatography to evaluate the amount of impurities in the tablets. The disintegration test and dissolution test were performed on the tablet immediately after production in each example and on the tablet stored at 60 ° C. for 2 days.
The stability evaluation based on the amount of LC impurities was performed on the tablets immediately after production in each example and on the tablets stored at 70 ° C. for one week.
As a control experiment, a tablet of Control Example 5 (a tablet in which an intermediate film was coated on an uncoated tablet containing the same amount of magnesium stearate as a lubricant and further coated with an enteric film) was prepared in the same manner as in Example 6. It was prepared in the same manner and evaluated in the same manner. Table 6
The results of each formulation and disintegration test are shown in FIG. FIG. 9 shows the results of the dissolution test of the tablet immediately after the production of Example 4, FIG. 10 shows the results of the dissolution test of the tablet obtained by storing Example 4 at 60 ° C. for 2 days, and FIG. FIG. 12 shows the result of the dissolution test of the tablet immediately after Example 5 was stored at 60 ° C. for 2 days. The results of the dissolution test of the tablet of Control Example 4 immediately after production and the tablet stored at 60 ° C. for 2 days are shown in FIGS. 13 and 14, respectively.

[0028]

[Table 6]

As a result of a comparative experiment between the uncoated tablet (uncoated tablet) of Examples 2 to 4 and the uncoated tablet (uncoated tablet) of Control Example 4, sodium stearyl fumarate (Example 2) and stearic acid (Example 3) ) And tablets containing calcium stearate (Example 4) showed no change in the disintegration test and dissolution test even after storage at 60 ° C for 2 days as compared to tablets immediately after production. On the other hand, in the tablet containing magnesium stearate (Control Example 4), remarkable prolongation of disintegration and dissolution delay were observed after storage at 60 ° C. for 2 days. Also,
Examples 5 to 6 were also applied to tablets obtained by coating uncoated tablets with a film.
(Contains sodium stearyl fumarate as a lubricant)
As a result of a comparative experiment of Comparative Example 5 (containing magnesium stearate as a lubricant), an enteric tablet containing sodium stearyl fumarate was compared with a tablet immediately after production even after storage at 60 ° C. for 2 days. No change was observed in the disintegration test and the dissolution test. On the other hand, the enteric coated tablet containing magnesium stearate (Comparative Example 5) had 60
Upon storage at 2 ° C. for 2 days, significant disintegration prolongation and elution delay were observed. The amount of impurities of the benzimidazole-based compound in the tablets by high performance liquid chromatography was stable without any change even after storage at 70 ° C. for one week in both Example 6 and Control Example 5. It is clear that the tablet containing sodium stearyl fumarate, stearic acid and calcium stearate according to the present invention has an effect of preventing disintegration prolongation and an effect of preventing dissolution delay during storage under heating conditions.

[0030]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 Crospovidone 1 was added to 10 g of rabeprazole sodium.
While 9 g, 43.5 g of mannitol and 1.5 g of hydroxypropyl cellulose were added and mixed, 0.5 g of sodium hydroxide dissolved in ethanol was gradually added, followed by stirring and wet granulation. After drying and sizing the granules, 0.5 g of sodium stearyl fumarate was added to the powder, and the mixture was compressed to give 75 mg tablets each containing 10 mg of rabeprazole sodium. The formulation is shown in Table 1.

Examples 2 to 4 The types of lubricants to be blended were changed to sodium stearyl fumarate (Example 2), stearic acid (Example 3) and calcium stearate (Example 4), respectively. Prepared. That is, 40 g of crospovidone, 83.8 g of mannitol, and 3 g of hydroxypropylcellulose were added to 20 g of rabeprazole sodium, and 1.0 g of sodium hydroxide dissolved in ethanol was gradually added and mixed, followed by stirring and wet granulation. After drying and sizing the granules, sodium stearyl fumarate (Example 2), stearic acid (Example 3), and calcium stearate 2.2 were respectively obtained.
g, and tableted with a tableting pressure of 1200 kg to give a tablet of 150 mg containing 20 mg of rabeprazole sodium. Each formulation is shown in Table 5.

Example 5 The tablets obtained in Example 2 were coated with an ethanol solution containing ethyl cellulose, hydroxypropyl cellulose and magnesium stearate by using a fluidized bed granulator, and rabeprazole having a layer thickness of 8 mg was coated. A tablet of 158 mg containing 20 mg of sodium was obtained. The formulation is shown in Table 5.

Example 6 A fluidized bed granulator was added to the tablet coated with the intermediate film obtained in Example 5 and containing a hydroethanol solution containing hydroxypropylmethylcellulose phthalate, monoglyceride, talc, titanium oxide, iron sesquioxide and magnesium stearate. 1 tablet containing 20 mg of rabeprazole sodium coated with 16 mg of enteric coating
g of enteric coated tablet was obtained. The formulation is shown in Table 5.

[0035]

[Brief description of the drawings]

[0036]

FIG. 1 shows the results of a dissolution test of a tablet immediately after production in Example 2.

[0037]

FIG. 2 shows the results of a dissolution test when Example 2 was stored at 60 ° C. for 2 days.

[0038]

FIG. 3 shows the results of a dissolution test of a tablet immediately after production in Example 3.

[0039]

FIG. 4 shows the results of a dissolution test when Example 3 was stored at 60 ° C. for 2 days.

[0040]

FIG. 5 shows the results of a dissolution test of a tablet immediately after production in Example 4.

[0041]

FIG. 6 shows the results of a dissolution test of tablets obtained by storing Example 4 at 60 ° C. for 2 days.

[0042]

FIG. 7 shows the results of a dissolution test of tablets of Comparative Example 4 immediately after production.

[0043]

FIG. 8 shows the results of a dissolution test of tablets obtained by storing Control Example 4 at 60 ° C. for 2 days.

[0044]

FIG. 9 shows a result of a dissolution test of a tablet immediately after production in Example 4.

[0045]

FIG. 10 shows the results of a dissolution test of tablets obtained by storing Example 4 at 60 ° C. for 2 days.

[0046]

FIG. 11 shows the results of a dissolution test of tablets immediately after production in Example 5.

[0047]

FIG. 12 shows the results of a dissolution test of tablets obtained by storing Example 5 at 60 ° C. for 2 days.

[0048]

FIG. 13 shows the results of a dissolution test of tablets of Control Example 4 immediately after production.

[0049]

FIG. 14 shows the results of a dissolution test of tablets stored at 60 ° C. for 2 days in Control Example 4.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61K 47/14 A61K 47/14 47/32 47/32 A61P 1/04 A61P 1/04 (72) Inventor Hiroshi Funabashi Saitama 3-1-16 Eisai Aounryo 504, Kojimaminami, Honjo City, Prefecture (72) Inventor Ken S. Fujioka 39-1, Izumi, Ichinomiya City, Aichi Prefecture (71) Inventor: Shigeru Aoki 2--15, Midoricho, Kawashima-machi, Hashima-gun, Gifu Prefecture (72) Inventor: Kiyoshi Iwamoto 8-121 Tsutsujigaoka, Kakamigahara-shi, Gifu F-term (reference) 4C076 AA45 BB01 CC16 DD27 DD29 DD30 DD38 DD41 DD46 DD47 EE16 EE32 EE33 FF06 FF25 FF33 GG14 GG16 4C086 AA01 AA02 BC39 GA07 GA08 MA02 MA05 NA03 NA13 ZA68

Claims (15)

[Claims] A stable tablet comprising a benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, and a lubricant other than 1) crospovidone and 2) magnesium stearate. Embedded image 2. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, and a lubricant other than 1) crospovidone, 2) sodium hydroxide and 3) magnesium stearate. Stable tablets 3. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. Stable tablet containing one or more lubricants selected from 4. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. Stable tablets coated with an enteric coating on tablets containing one or more lubricants selected from 5. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. A stable tablet in which an intermediate film is coated on a tablet containing at least one lubricant selected from the group consisting of a lubricant and an enteric film. 6. The benzimidazole compound or a physiologically acceptable salt thereof is rabeprazole, omeprazole, pantoprazole, lansoprazole or a physiologically acceptable salt thereof. Tablets described in 7. Rabeprazole or a sodium salt thereof,
1) Crospovidone, 2) Sodium hydroxide and 3) Stable tablet containing one or more lubricants selected from sodium stearyl fumarate, calcium stearate and stearic acid. 8. An uncoated tablet containing a benzimidazole compound or a physiologically acceptable salt thereof, wherein the blending ratio of one or more lubricants selected from sodium stearyl fumarate, calcium stearate and stearic acid is adjusted. On the other hand, it is 0.1 to 10% by weight.
The tablet according to any one of the above 9. The compounding ratio of crospovidone and sodium hydroxide is 5 to 70% by weight, respectively, based on uncoated tablets containing a benzimidazole compound or a physiologically acceptable salt thereof. The tablet according to any one of claims 2 to 8, which is 2 to 25% by weight. 10. A stable tablet comprising rabeprazole or its sodium salt, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate. 11. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof: 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. A method for producing a stable tablet containing a benzimidazole-based compound or a physiologically acceptable salt thereof, characterized in that at least one lubricant selected from the group consisting of: 12. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. A method for producing a stable tablet containing a benzimidazole compound or a physiologically acceptable salt thereof, which comprises coating at least one lubricant selected from the group consisting of a lubricant, tableting, and coating with an enteric film. 13. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. Containing one or more lubricants selected from the group consisting of a benzimidazole compound or a physiologically acceptable salt thereof, which is coated with an intermediate film after tableting and further coated with an enteric film. For producing stable tablets 14. A benzimidazole compound represented by the formula (1) or a physiologically acceptable salt thereof, 1) crospovidone, 2) sodium hydroxide and 3) sodium stearyl fumarate, calcium stearate and stearic acid. A method for preventing the dissolution delay of a benzimidazole compound or a physiologically acceptable salt thereof from a tablet containing one or more lubricants selected from the group consisting of: 15. A method for preventing a delay in dissolution of a drug from a tablet, comprising mixing the drug with one or more lubricants selected from crospovidone, sodium stearyl fumarate, calcium stearate and stearic acid, and / or
Or, a method for preventing the disintegration of a tablet from being prolonged