JP2000355540A - Stabilized composition comprising benzimidazole-based compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of further stabilizing a solid drug preparation for internal use comprising a benzimidazole-based compound by formulating the benzimidazole-based compound and a specific substance. SOLUTION: This composition is obtained by formulating (A) a benzimidazole- based compound of formula I (Het1 is of formula II; Het2 is of formula III; R1 and R2 are each H, methoxy or difluoromethoxy; R3 is H or sodium, R4 to R6 are each H, methyl, methoxy, methoxypropoxy or trifluoroethoxy) (e.g. rabeprazole of formula IV) with (B) a substance selected from e.g. a sodium carbonate, sodium hydroxide, potassium hydroxide, crospovidone, at preferably 0.01-20 pts.wt per pt.wt. of the ingredient A. It is also possible to make a drug preparation by coating a core composed of the above composition with an intermediate film, enteric film or moistureproof film.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a solid preparation for internal use containing a benzimidazole compound or an alkali metal salt thereof.

[0002]

2. Description of the Related Art Benzimidazole compounds and alkali metal salts thereof have been widely used as therapeutic agents for gastric ulcer, duodenal ulcer, etc. by having a strong inhibitory effect on so-called proton pumps and suppressing gastric acid secretion. 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, 1987
No. 58320 discloses a core portion containing a benzimidazole compound, which is compounded with an alkali compound, and is coated with a water-soluble or water-soluble tablet excipient, or a polymer with a water-soluble film-forming compound. Oral pharmaceutical formulations coated with an enteric coating have been disclosed.

[0003]

However, the stability of the preparation is not sufficient even by the above technique, and a further improvement is required. That is, an object of the present invention is to further stabilize a solid preparation for internal use containing a benzimidazole compound.

[0004]

According to the present invention, a benzimidazole compound represented by the following structural formula (formula 1) or an alkali metal salt thereof is added to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, amino hydroxide. It is a composition comprising one or more substances selected from alkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone.

Embedded image

Further, the present invention relates to a benzimidazole compound represented by the formula (1) or an alkali metal salt thereof, wherein sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E,
It is a preparation comprising an enteric film coated on a nucleus containing at least one substance selected from arginine aspartate, hydroxypropylcellulose and crospovidone.
Further, the present invention relates to a benzimidazole compound represented by the formula 1 or an alkali metal salt thereof, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and It is a preparation in which a core comprising one or more substances selected from crospovidone is coated with an intermediate film, and further coated with an enteric film. The present invention also relates to a benzimidazole compound represented by the formula 1 or an alkali metal salt thereof, wherein sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropyl This is a preparation in which a core formed by mixing one or more substances selected from cellulose and crospovidone is coated with an intermediate coating, further coated with an enteric coating, and then coated with a moisture-proof coating.

[0006] The moisture-proof coating is useful not only for benzimidazole compounds, but also for drugs whose decomposition is promoted in the presence of water and whose decomposition is recognized even upon contact with gastric acid. That is, the present invention is a preparation in which a nucleus containing a drug which is accelerated in the presence of moisture and is chemically unstable in stomach acid is coated with an enteric coating, and further coated with a moisture-proof coating. In addition, the present invention provides an intermediate film coated on a nucleus containing a drug that is accelerated in the presence of moisture and is chemically unstable in stomach acid, further coated with an enteric film, It is a formulation coated with a film.

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

Embedded image Hereinafter, the benzimidazole-based compound or an alkali metal salt thereof is referred to as a benzimidazole-based compound.

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.

The sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and hydroxypropylcellulose in the present invention are listed in the Japanese Pharmacopoeia and can be easily obtained commercially. Aminoalkyl methacrylate copolymer E is listed in the Pharmaceutical Standards outside the Japanese Pharmacopoeia and is easily available. Crospovidone is a substance listed in the excipient standard, and commercially available products of various grades having different particle sizes can be easily obtained.If necessary, use a crusher such as a hammer mill. The particle size can be adjusted. The benzimidazole compound and one or more substances selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone in the present invention The compounding ratio is 0.01 to 20 parts by weight, preferably 0.01 to 10 parts by weight, based on 1 part by weight of the benzimidazole compound. In the present invention, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone can be used alone, or they can be used alone. A combination of two or more species may be used. Among them, it is effective to mix sodium hydroxide, potassium hydroxide and / or sodium carbonate with the benzimidazole compound, and 1) crospovidone and 2) sodium hydroxide, potassium hydroxide with the benzimidazole compound. as well as/
Or, it is more effective to add sodium carbonate. In this combination of substances, the compounding ratio is 0.01 to 20 parts by weight with respect to 1 part by weight of the benzimidazole compound, and desirably 0.5 to 5 parts by weight of crospovidone.
Parts by weight of sodium hydroxide, potassium hydroxide and / or sodium carbonate are 0.01 to 2 parts by weight.

When the benzimidazole compound is decomposed under the conditions of warming and humidification, a large change in the coloration is particularly observed. The composition and / or preparation containing the various additives described above in the present invention has a very remarkable effect of not only improving the content stability but also suppressing the color change.

The benzimidazole compound according to the present invention and sodium carbonate, potassium carbonate, sodium hydroxide,
It is commonly used to produce a formulation using a composition comprising one or more substances selected from potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone. Excipients such as lactose and mannitol can be used. It is desirable to use hydroxypropylcellulose as the binder and crospovidone as the disintegrant. Also, it is known that crospovidone, which is generally used as a disintegrant, can reduce the disintegration power and swelling power as the original disintegrant by pulverization. Crospovidone having a small particle size, which has been finely pulverized, is used as a stabilizer for the benzimidazole-based compound in the present invention, and an addition exceeding a usual addition amount (usually 10% or less) as a disintegrant is required. It is possible. The average particle size of the micronized crospovidone is more preferably several μm to 50 μm and 4 μm to 50 μm.
Therefore, in the composition or the preparation according to the present invention, it is preferable to use crospovidone having a small average particle diameter of several μm to 50 μm, preferably 4 μm to 50 μm as the crospovidone. Of course, fine crospovidone and ordinary crospovidone may be used in combination. In addition, crospovidone often contains a trace amount of peroxide as an impurity, though it varies depending on the manufacturer and lot. Since the benzimidazole-based compound has a property of being easily oxidized, an antioxidant may be contained when blended with crospovidone. Antioxidants include, but are not limited to, for example, sodium sulfite, sodium pyrosulfite, vitamins E, Rongalit, thioglycerol, sodium thiosulfate, ascorbate, acetylcysteine, and the like.

Further, the present invention relates to a benzimidazole compound represented by the formula (1), wherein sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone. A formulation comprising an enteric film coated on a nucleus containing at least one substance selected from the group consisting of: In the present invention, the nucleus is
Tablets, granules, etc. In addition, the present invention provides a benzimidazole compound and sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer, wherein spherical granules composed of purified sucrose, sucrose / starch mixture or crystalline cellulose are used as seed granules. It also includes a preparation in which a core formed by laminating or coating at least one substance selected from E, arginine aspartate, hydroxypropylcellulose and crospovidone is coated with an enteric film. 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 degradation in the stomach, it is necessary to prepare a preparation that does not dissolve in the stomach, that is, a preparation in which a core containing a benzimidazole compound is coated with an enteric substance.

The present invention further relates to a benzimidazole compound represented by the formula (1), wherein sodium carbonate, potassium carbonate,
Coating the core with at least one substance selected from sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone with an intermediate film, and further enteric coating It is a formulation coated with a 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. When an intermediate film is formed from a water-insoluble substance as disclosed in JP-A-1-290628, water-insoluble fine particles may be mixed in the film.

In the present invention, the preparation coated with the above enteric coating may be coated with a moisture-proof coating. A moisture-proof coating is a coating that suppresses the passage of water vapor.Functionally, the coating itself suppresses the permeability of water vapor and captures water vapor in the coating to prevent the flow of water vapor into the interior. Coatings and the like to suppress. The moisture-proof coating has the function of preventing moisture from penetrating into the benzimidazole-based compound, improving stability, and preventing cracking and deformation of the tablet caused by swelling of the finely ground crospovidone when it absorbs moisture. are doing. The moisture-proof coating may be a water-soluble coating or a water-insoluble coating, for example, a coating composed of polyvinyl acetal diethylaminoacetate, HA Sankyo (polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose, a mixture of stearic acid, fumaric acid), polyvinyl alcohol, and the like. , Hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and other cellulose derivatives, and / or a sugar-coating film containing sucrose as a main component, but are not limited thereto.

The moisture-proof coating is useful not only for benzimidazole compounds but also for preparations containing drugs having similar chemical properties. That is, the effect is remarkably recognized in a preparation containing a drug whose decomposition is promoted in the presence of water and whose decomposition is also recognized upon contact with gastric acid. That is, the present invention is a preparation in which a nucleus containing a drug which is accelerated in the presence of moisture and is chemically unstable in stomach acid is coated with an enteric coating, and further coated with a moisture-proof coating. Further, an intermediate film may be coated between the enteric film and the moisture-proof film.

In the present invention, when the benzimidazole compound represented by the formula 1 is rabeprazole, a particularly excellent effect is exhibited. That is, the present invention is preferably a composition obtained by blending sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole represented by Formula 3 or an alkali metal salt thereof. Further, the present invention is preferably a composition obtained by mixing 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole represented by Formula 3 or an alkali metal salt thereof. . Crospovidone is
As described above, it is preferable to use those finely pulverized to an average particle size of several μm to 50 μm. Also, antioxidants
As described above, it may be added to prevent the effect of a trace amount of peroxide contained in crospovidone. Therefore, an antioxidant may be added to a composition comprising 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate in rabeprazole or its alkali metal salt.

The present invention also relates to a nucleus obtained by mixing 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole of the formula 3 or an alkali metal salt thereof. It is a preparation coated with an enteric coating. Further, the present invention preferably provides an intermediate film on a nucleus obtained by mixing 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole represented by Formula 3 or an alkali metal salt thereof. It is a preparation coated with an enteric coating. The present invention also preferably relates to rabeprazole of the formula 3 or an alkali metal salt thereof, wherein 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or
Alternatively, it is a preparation in which an intermediate film is coated on a nucleus containing sodium carbonate, an enteric film is further coated, and then a moisture-proof film is coated.

The composition or preparation according to the present invention can be produced by a commonly used method. That is, for example, a benzimidazole compound or an alkali metal salt thereof is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone. It can be made by mixing more than one kind of substance, adding an excipient, performing dry or wet granulation, and adding a disintegrant such as crospovidone, if necessary, and tableting. Further, for example, benzimidazole compounds or alkali metal salts thereof are selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropylcellulose and crospovidone. After preparing benzimidazole-containing granules containing one or more substances at a high density and placebo granules not containing a benzimidazole compound, both granules are mixed and, if necessary, a disintegrant such as crospovidone is added for tableting. May be. of course,
It is not limited to these methods. As a specific example,
For example, rabeprazole sodium (100 g), sodium carbonate (30 g), and mannitol (130 g), which are benzimidazole compounds, are mixed, hydroxypropylcellulose dissolved in ethanol is gradually added to the mixture, and granulation is performed. I do. 30g of crospovidone and 2g of calcium stearate
And tableting is performed after mixing to obtain a tablet of 135 mg per tablet. This tablet is sprayed with an ethanol solution of hydroxypropylcellulose using a fluidized bed apparatus, and further sprayed with a water / ethanol solution of hydroxypropylmethylcellulose phthalate or an enteric methacrylic acid copolymer to form an enteric coated tablet. Can be manufactured.

[0019]

According to the present invention, a very unstable benzimidazole compound can be stabilized. The effect example is shown below. Experimental Example 50 mg of rabeprazole sodium and 450 mg of the additives shown in the following table were mixed in a mortar. Place this in a clear glass bottle and place in a cool place at 60 ° C and 40 ° C with 75% relative humidity.
After storing for a week, the content was measured by high performance liquid chromatography. Tables 1 to 3 show the residual ratio under each condition when the content of the cold storage product was 100%. Further, the color change of the color was visually evaluated. In Table 1, amorphous rabeprazole was used, and in Tables 2 and 3, crystalline rabeprazole was used. In Table 1, low-substituted hydroxypropylcellulose (L-HP in the table) used as a disintegrant in addition to amorphous rabeprazole sodium alone as a control
C), and Table 2 shows a mixture of aluminum hydroxide (indicated as Al (OH) 3 in the table) which is an alkaline inorganic salt used as an antacid. In No. 3, a sample mixed with polyvinylpyrrolidone (indicated as PVP in the table) used as a binder was used.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3] The color change of each of the compounded samples according to the present invention was smaller than that of the control. Furthermore, from the results of the content stability in Tables 1 to 3, the sodium carbonate (Na2C
O3), potassium carbonate (K2CO3 in the table), sodium hydroxide (NaOH in the table), potassium hydroxide (KOH in the table), aminoalkyl methacrylate copolymer E (Eudragit E in the table (registered) Trademark)),
It is clear that arginine aspartate (denoted as Arg · Asp in the table), hydroxypropylcellulose and crospovidone stabilize benzimidazole compounds.

Effect of Sodium Carbonate in Tablets Tablets having different amounts of sodium carbonate obtained in Examples 4 to 9 shown below were stored at 40 ° C. and 75% relative humidity for 1 week, and then measured by high performance liquid chromatography. Table 4 shows the rabeprazole sodium content in the tablets obtained.

[0024]

[Table 4]

Since the stability of rabeprazole sodium content in tablets is improved depending on the amount of sodium carbonate added, the effect of adding sodium carbonate in the present invention is clear.

Effect of Crospovidone in Tablets Tablets having different amounts of crospovidone powder obtained in Examples 10 to 12 shown below were added at 40 ° C. and 75% relative humidity.
After storage for one week, the rabeprazole sodium content in the tablets measured by high performance liquid chromatography is shown in Table 5. Regarding the change in the color of the tablet, the larger the amount of the crospovidone powder added, the smaller the change in the color of the tablet.

[0027]

[Table 5] It is clear that the addition of crospovidone improves the stability of the benzimidazole compound.

Effect of micronized crospovidone in tablets The thickness of the tablets to which crospovidone having different average particle sizes obtained in Examples 16 to 18 shown below were added was measured in a cold place and in a cold place.
Measured after each one month storage at 5 ° C and 75% relative humidity,
The swelling ratio of the tablets stored at 25 ° C. and a relative humidity of 75% relative to the tablets stored at a cold place was evaluated. As a result, the average particle size was 51 μm,
The swelling coefficients of the tablets containing crospovidone of 6 μm and 6 μm were 1.61, 1.48 and 1.43, respectively. As crospovidone is made into a fine powder having a smaller average particle size, the degree of swelling of the tablet is reduced, so that cracks and deformation due to the expansion of the tablet are reduced. Therefore, micronization of crospovidone
It is clear that it contributes to improving the stability of the tablet shape.

Effect of Moisture-Proof Coating Applied on Formulation Coated with Enteric Coating The enteric coating-coated tablets obtained in Examples 19 to 20 shown below and tablets coated with both the enteric coating and the moisture-proof coating were prepared. After storage at 25 ° C. and a relative humidity of 75% for one week, the amount of rabeprazole sodium-related substances in the tablets was measured by high performance liquid chromatography. As a result, the relative substance amounts of the enteric film-coated tablet and the tablet coated with both the enteric film and the moisture-proof film were 2.88% and 2.23%, respectively. It is clear that a preparation coated with both an enteric film and a moisture-proof film has the same or better stability than the enteric film-coated tablet.

The thickness of the placebo tablets obtained in Examples 21 to 23 shown below was measured after storage for one week in a cool place and at 40 ° C. and 75% relative humidity, respectively.
The swelling ratio of the stored tablet to the cold storage tablet was evaluated. As a result, enteric-coated tablets, enteric-coated tablets coated with a moisture-proof coating made of sucrose, enteric-coated tablets HA (Sankyo) (polyvinyl acetal diethylaminoacetate, hydroxypropylpyrmethylcellulose, macrogol, Talc), the swelling coefficients of the tablets coated with a moisture barrier coating of 1.15 and 1.0, respectively.
3, 1.12. It is clear that the preparation coated with both the enteric film and the moisture-proof film has a lower tablet swelling degree during storage than the enteric film-coated tablet, thereby improving the stability of the tablet shape. .

Effect of antioxidant added to core containing benzimidazole compound Examples 24 to 24 shown below
Using the tablets obtained in 26 to which crospovidone containing different amounts of peroxides were added, the amount of rabeprazole-related substances in the tablets was measured by high performance liquid chromatography. As a result, the peroxide content was 18 ppm, 190 ppm, 3 ppm.
The initial relative substance content of the tablets to which crospovidone was added at 10 ppm was 0.65%, 0.88%, and 1.13%, respectively.
The higher the amount of peroxide contained in crospovidone, the more the decomposition of rabeprazole sodium was promoted and the amount of related substances was increased.

Also, 1 g of crospovidone having a peroxide content of 201 ppm was precisely weighed, and sodium sulfite was added (addition amount: not added, 0.02%, 0.05%, 0.10%).
%, 4 levels) and mixed well, and the amount of peroxide in the mixture was measured according to the test method described in the Japanese Pharmacopoeia. As a result, the added amount of sodium sulfite was not added, 0.02
%, 0.05%, and 0.10%, the amount of peroxide in the composition was 201 ppm, 184 ppm, 108 ppm, and 0 ppm, respectively.
The peroxide amount was found to decrease as the amount of sodium sulfite added increased.

From the above, it is clear that the stability of the benzimidazole compound in the preparation is improved by adding an antioxidant to the core of the tablet containing the benzimidazole compound and crospovidone. is there.

[0034]

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 10 g of rabeprazole sodium and 10 g of sodium carbonate
g and 100 g of mannitol were added and mixed, and while mixing, hydroxypropylcellulose 2.5 dissolved in ethanol was added.
g of sodium stearate was added, and the mixture was granulated, dried and sieved. Calcium stearate was added, and the mixture was tableted to give one tablet of 120 mg containing 10 mg of rabeprazole sodium.

Example 2 The tablets obtained in Example 1 were mixed with hydroxypropyl methylcellulose phthalate 10 in a 2: 8 mixed solvent of water and ethanol.
The solution in which g was dissolved was sprayed using a fluidized bed granulator to produce enteric coated tablets.

Example 3 An ethanol solution of hydroxypropylcellulose was sprayed on the tablets obtained in Example 1 using a fluidized bed granulator, and the procedure was carried out in the same manner as in Example 2 to obtain enteric coated tablets.

Examples 4 to 9 Rabeprazole sodium (10 g) was mixed with sodium carbonate (0 to 0).
While adding 10 g and 15 to 90 g of mannitol and mixing, respectively, 0.7 to 2 g of hydroxypropylcellulose dissolved in ethanol was gradually added, followed by stirring and wet granulation to prepare main drug granules. Separately, 100 g of mannitol
The mixture was stirred and wet-granulated while gradually adding 2 g of hydroxypropylcellulose dissolved in ethanol to prepare placebo granules. Next, the main drug granules and the placebo granules are mixed, and crospovidone 5% and a small amount of magnesium stearate are powdered.
One tablet of 100.5 mg containing 0 mg was obtained. Each formulation is shown in Table 6.

[0039]

[Table 6]

Examples 10 to 12 Tablets were obtained in the same manner as in Examples 4 to 9 except that the amount of powdered crospovidone was set at three levels of 0, 2.5 and 5%.
The formulations are shown in Table 7.

[0041]

[Table 7]

Examples 13 to 14 According to the two prescription examples shown in Table 8, 0 to 50 g of sodium carbonate, 79.3 to 84.3 g of mannitol, 4.2 g of crospovidone and 1.5 g of magnesium stearate were added to 100 g of rabeprazole sodium. Add thoroughly, mix directly, and perform rabeprazole sodium 10mg
A tablet of 100 mg was obtained.

[0043]

[Table 8]

Example 15 100 g of rabeprazole sodium and sodium carbonate 5
0 g and 2 g of magnesium stearate were added, mixed well, and subjected to dry compression granulation to prepare granules of the main drug. Also,
Separately, 76.3 g of mannitol and crospovidone
2 g of each was added, mixed well, and stirred wet granulation was performed while gradually adding 2.3 g of hydroxypropyl cellulose dissolved in ethanol to prepare placebo granules. Next, the main drug granules and the placebo granules were mixed, a small amount of magnesium stearate was added to the powder, and the mixture was tableted to give 100 mg tablets each containing 10 mg of rabeprazole sodium as shown in Table 9.

[0045]

[Table 9]

Examples 16 to 18 To 100 g of rabeprazole sodium, 527 g of crospovidone having a different average particle size and 20 g of hydroxypropylcellulose were mixed, 3 g of magnesium stearate was added, and the mixture was compressed into tablets as shown in Table 10. One tablet of 65 mg containing 10 mg of rabeprazole sodium was obtained.
The crospovidone used was a product of BASF, and its average particle size was Kollidon CL (51 μm), Kollidon CLM (12 μm), and a hammer mill-crushed product of Kollidon CLM (6 μm).

[0047]

[Table 10] Examples 19 to 20 After cores containing rabeprazole sodium were granulated with ethanol, a water-insoluble intermediate film containing ethyl cellulose, crospovidone and magnesium stearate was coated. Next, a further coating was applied to obtain a tablet coated with both an enteric coating-coated tablet and both an enteric coating and a moisture-proof coating. The prescription is shown in Table 11.

[0048]

[Table 11]

Examples 21 to 23 As placebo tablets containing no benzimidazole compound, tablets having a water-soluble intermediate film made of hydroxypropyl cellulose on the core were prepared. An enteric film-coated tablet obtained by coating the tablet with an enteric film, and a moisture-proof film-coated preparation obtained by spraying a solution comprising sucrose or HA (Sankyo) on the enteric film-coated tablet were prepared. The prescription is shown in Table 12.

[0050]

[Table 12]

Examples 24-26 Tablets containing rabeprazole sodium and crospovidone having different peroxide amounts, sodium hydroxide and sodium carbonate were obtained by wet granulation according to the formulation in Table 13.

[0052]

[Table 13]

Example 27 To 30 g of rabeprazole sodium, 43.5 g of finely powdered crospovidone and 6 g of hydroxypropylcellulose were added and mixed well, and while thoroughly mixing, an ethanol solution of sodium hydroxide (a solution in which 1.5 g of sodium hydroxide was dissolved in ethanol) Is gradually added and granulated, dried, and sized with a small speed mill. To the sized granules, 3% of crospovidone and 1.6% of magnesium stearate are added, mixed and tableted, and one tablet containing 10 mg of rabeprazole sodium 7
0 mg tablets were obtained.

Example 28 The tablets obtained in Example 27 were coated with a hydrous ethanol solution containing hydroxypropylcellulose and a small amount of magnesium stearate using a fluidized bed granulator.
A tablet having 2 mg of the intermediate film laminated thereon was obtained. Next, an aqueous ethanol solution containing hydroxypropylcellulose phthalate, monoglyceride, talc, and titanium oxide was sprayed on the intermediate film-coated tablet using a fluidized bed granulator to obtain an enteric coated tablet coated with 10 mg of an enteric film. Obtained.

Example 29 Hydroxypropyl methylcellulose and Macrogol 60 were added to the enteric coated tablets obtained in Example 28 using a fluid bed granulator.
Purified water containing 00 and talc was sprayed to obtain tablets coated with 5 mg of moisture-proof coating.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/30 A61K 47/30 47/38 47/38 // C07D 401/12 C07D 401/12 (72) Inventor Yasuyuki Suzuki 2520-4 Joyokoba, Tsukuba City, Ibaraki Prefecture (72) Inventor Shigeru Aoki 2-15, Midoricho, Kawashima-cho, Hashima-gun, Gifu Prefecture (72) Inventor Akira Kato 5-2-27, Matsushiro, Tsukuba-shi, Ibaraki Prefecture (72) Inventor Masao Kawamura 67-13 Shimododo, Honjo City, Saitama Prefecture (72) Inventor Satoshi Fujioka 39-1 Funairi, Imari, Ichinomiya City, Aichi Prefecture F-term (reference) 4C063 AA01 BB08 CC26 DD12 EE01 4C076 AA45 BB01 CC16 DD25 DD30 DD37 DD38 DD41 DD51 EE13 EE32 FF25 4C086 AA01 BC39 GA07 GA08 MA03 MA05 MA34 MA52 NA03 ZA68 ZC41

Claims (14)

[Claims] 1. A benzimidazole compound represented by the following structural formula (formula 1) or an alkali metal salt thereof: sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate. , A composition comprising one or more substances selected from hydroxypropylcellulose and crospovidone. Embedded image 2. The composition according to claim 1, wherein the benzimidazole compound is rabeprazole, omeprazole, pantoprazole, lansoprazole or an alkali metal salt thereof. 3. A benzimidazole compound or an alkali metal salt thereof, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate,
The composition according to claim 1, wherein the mixing ratio with hydroxypropylcellulose and / or crospovidone is 0.01 to 20 parts by weight in total with respect to 1 part by weight of the benzimidazole compound. 4. A benzimidazole compound represented by the formula 1 or an alkali metal salt thereof, comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, and hydroxypropyl cellulose. And a nucleus comprising at least one substance selected from crospovidone and an enteric coating. 5. A benzimidazole compound represented by the formula 1 or an alkali metal salt thereof, comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, and hydroxypropyl cellulose. And a nucleus containing at least one substance selected from crospovidone and an intermediate film, and further coated with an enteric film. 6. A benzimidazole compound represented by the formula 1 or an alkali metal salt thereof, comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, aminoalkyl methacrylate copolymer E, arginine aspartate, and hydroxypropyl cellulose. And a nucleus comprising at least one substance selected from crospovidone and an intermediate coating, an enteric coating, and a moisture-proof coating. 7. A composition comprising rabeprazole or an alkali metal salt thereof mixed with sodium hydroxide, potassium hydroxide and / or sodium carbonate. 8. A composition comprising rabeprazole or an alkali metal salt thereof mixed with 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate. 9. A preparation comprising rabeprazole or an alkali metal salt thereof mixed with 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate, and a core coated with an enteric coating. 10. A core obtained by mixing 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole or an alkali metal salt thereof, and coating an intermediate film with an enteric film. Coated formulation 11. An intermediate film is coated on a core obtained by mixing 1) crospovidone and 2) sodium hydroxide, potassium hydroxide and / or sodium carbonate with rabeprazole or an alkali metal salt thereof, and further comprising an enteric film. A formulation coated and then coated with a moisture barrier coating. 12. A stable composition or preparation comprising crospovidone according to claim 8 or a nucleus according to claims 9 to 11 and an antioxidant. 13. A preparation comprising a nucleus containing a drug which is accelerated in the presence of moisture and is chemically unstable in stomach acid, coated with an enteric coating, and further coated with a moisture-proof coating. 14. A nucleus containing a drug which is decomposed in the presence of moisture and which is chemically unstable in gastric acid, is coated with an intermediate film, further coated with an enteric film, and then coated with a moisture-proof film. Formulation coated with.