JP2007091648A - Pharmaceutical composition containing benzimidazole-based proton pump inhibitor and h2 receptor antagonist - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable oral pharmaceutical composition containing both of a benzimidazole-based proton pump inhibitor and a histamine H2 receptor antagonist, and to provide a method for producing the pharmaceutical composition. <P>SOLUTION: The oral pharmaceutical composition contains both of the benzimidazole-based proton pump inhibitor and the histamine H2 receptor antagonist, wherein the benzimidazole-based proton pump inhibitor is protected with acid-resistant layer. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an oral pharmaceutical composition comprising a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist, and a method for producing the same.

Benzimidazole proton pump inhibitors such as rabeprazole are drugs that are generally prescribed and used as gastric ulcer and gastric acid secretion inhibitors, and have good therapeutic results when taken once or twice a day. Has been obtained.
In addition, histamine H2 receptor antagonists typified by famotidine are also widely used as drugs that suppress gastric acid secretion, but it is known that the gastric acid secretion inhibitory effect does not reach the effect of proton pump inhibitors.
However, recently, it has been reported that a stronger suppression of gastric acid secretion can be obtained by using a proton pump inhibitor in combination with an H2 receptor antagonist (Patent Documents 1 and 2). In order to obtain excellent results in such drug treatment, it is important to increase patient compliance. Thus, it is possible to administer two or more different formulations to a patient, but a combination of an H2 receptor antagonist and an acid sensitive proton pump inhibitor is used to increase the number of formulations taken. This is more desirable and leads to patient satisfaction.
In preparations containing benzimidazole proton pump inhibitors, benzimidazole proton pump inhibitors are generally susceptible to chemical degradation in acidic and neutral solvents, so contact with acidic gastric juice In order to protect, an enteric coating must be applied. Furthermore, it may be desired to provide a stable long-acting preparation by means such as applying a sustained-release coating layer to a benzimidazole proton pump inhibitor. In addition, in order to produce an oral preparation containing both a benzimidazole proton pump inhibitor and an H2 receptor antagonist, a medicinal component having a different physical property is stable without causing a physicochemical interaction. Need to be kept.
In particular, when preparing tablets containing multiple units such as granules containing benzimidazole proton pump inhibitors, for example, the granules containing benzimidazole proton pump inhibitors coated with an enteric coating layer are compressed and molded into tablets. In some cases, the enteric coating layer may be compressed, causing a part of the layer to break, and acidic gastric juice in the gastrointestinal tract may permeate through the cracking of the layer during administration. That is, the acid resistance of the enteric coating layer applied to the granules is not sufficient for tablets after compression, so that decomposition of benzimidazole proton pump inhibitors is promoted by the digestive fluid of the digestive tract after administration. become.

International Publication No. WO2004 / 037256 Chinese Patent Publication CN-1559612

As described above, development of a stable oral pharmaceutical composition comprising both a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist and a method for producing the same are eagerly desired.

  Accordingly, an object of the present invention is to provide a stable oral pharmaceutical composition comprising both a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist, and a method for producing the same.

  In view of the above situation, the present inventors have intensively studied a stable oral pharmaceutical composition comprising both a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist. As a result, the inventors have found that the initial object can be achieved by the following configuration, and completed the present invention.

The present invention relates to an oral pharmaceutical composition comprising a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist, wherein the benzimidazole proton pump inhibitor is protected by an acid resistant layer. An oral pharmaceutical composition characterized by

The benzimidazole proton pump inhibitor according to the present invention is not particularly limited. For example, rabeprazole, lansoprazole, omeprazole or pantoprazole, optical isomers thereof, and pharmacologically acceptable salts thereof (EP0005129, EP174726, EP166287, WO90 / 06925, WO91 / 19711, WO91 / 9712, WO95 / 01977, WO94 / 27988, etc.). Examples of the pharmacologically acceptable salt include Mg salt, Ca salt, Na salt, K salt or Li salt. It can also be used in the form of a racemate or a substantially pure enantiomer. Rabeprazole or a pharmacologically acceptable salt thereof is preferable, and rabeprazole sodium is particularly preferable.

  The histamine H2 receptor antagonist according to the present invention is not particularly limited, and is, for example, famotidine, ranitidine, cimetidine or a pharmacologically acceptable salt thereof, and particularly preferably famotidine.

The acid-resistant layer according to the present invention is an acid-resistant layer defined by the United States Pharmacopoeia, and granules or tablets containing a proton pump inhibitor are immersed in an aqueous 0.1 M HCl solution for 2 hours. It is a coating layer having a function that the weight of the proton pump inhibitor released into the HCl aqueous solution is sometimes 10% or less of the weight of the proton pump inhibitor contained in the original preparation. Examples of the acid resistant layer include an enteric coating layer and a sustained release coating layer.
In the present invention, the form of protecting the benzimidazole proton pump inhibitor with the acid resistant layer is not particularly limited, but the benzimidazole proton pump inhibitor is directly or directly connected to the benzimidazole proton pump inhibitor. The form etc. which coat | cover with the acid-resistant layer on the outer side of the powder layer to contain, or the outer side which further laminated | stacked the layer are mentioned. For example, granules containing a benzimidazole proton pump inhibitor may be coated with an acid resistant layer, or 1) a granule containing a benzimidazole proton pump inhibitor and 2) a histamine H2 receptor antagonist powder. Or you may coat | cover an acid-resistant layer on the tablet formed by compressing the granule containing H2 receptor antagonist.

The oral pharmaceutical composition in which the benzimidazole proton pump inhibitor is protected by an acid resistant layer may be present in any state of the benzimidazole proton pump inhibitor and the histamine H2 receptor antagonist, or Any solid dosage form may be used. The benzimidazole proton pump inhibitor and the histamine H2 receptor antagonist may be present separately in the preparation, or may be present in a mixed state. The dosage form is not particularly limited, but is preferably a tablet, an orally disintegrating tablet, a granule, or a capsule, and particularly preferably a tablet. The oral pharmaceutical composition according to the present invention includes, for example, a tablet containing multiple units coated with an acid resistant layer as a constituent element, a tablet coated with an acid resistant layer, and a benzimidazole proton pump inhibitor. And a multi-layer tablet in which an agent and a histamine H2 receptor antagonist are sequentially coated in layers, or a capsule filled with a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist.

An intermediate layer made of a water-soluble, water-insoluble, or water-dispersible film may be disposed between the benzimidazole proton pump inhibitor and the acid resistant layer. In particular, when the acid-resistant layer is an enteric coating layer, the benzimidazole proton pump inhibitor has the property of being easily decomposed in an acidic state, so avoid direct contact with the enteric base that is an acidic base. Is required. Therefore, it is desirable to arrange an intermediate layer composed of a water-soluble, water-insoluble or water-dispersible film between the benzimidazole proton pump inhibitor and the acid resistant layer.

The combination of the benzimidazole proton pump inhibitor and the histamine H2 receptor antagonist is not particularly limited, but the most preferred combination is that the benzimidazole proton pump inhibitor is rabeprazole and the histamine H2 receptor antagonist is famotidine. .
Moreover, the compounding quantity of a medicinal ingredient is not specifically limited, However, The compounding quantity of a benzimidazole type | system | group proton pump inhibitor is 5-80 mg normally in 1 formulation, Preferably it is 10-60 mg. Moreover, the compounding quantity of H2 receptor antagonist is 10-800 mg normally, Preferably it is 50-500 mg.

The present invention also relates to a tablet obtained by compressing together 1) a benzimidazole proton pump inhibitor-containing granule and 2) H2 receptor antagonist powder or H2 receptor antagonist-containing granule, An oral pharmaceutical composition characterized in that the pump inhibitor is protected by an acid resistant layer. As a manufacturing method, both 1) and 2) coated with an acid resistant layer may be compressed after mixing, or both normal granules 1) and 2) which are not coated with an acid resistant layer are mixed. The tablet obtained by subsequent compression may be coated with an acid resistant layer. Also, compress 1) covered with acid-resistant layer, then add 2) and compress again to make a dry-coated tablet, or compress normal granules 1) and then add 2) and compress again Then, it may be coated with an acid resistant layer as a dry-coated tablet. Alternatively, 2) may be compressed and then coated with an acid-resistant layer 1) and compressed again to form a dry-coated tablet, or 2) may be compressed and then normal granules 1) may be added and compressed again. Then, it may be coated with an acid resistant layer as a dry-coated tablet.
Furthermore, at least one or more water-soluble low-melting-point substances are blended in a powder state, and 1) benzimidazole proton pump inhibitor-containing granules and 2) H2 receptor antagonist powder or H2 receptor antagonist It may be compressed together with the contained granule, or may be blended in the H2 receptor antagonist-containing granule and compressed together with the benzimidazole proton pump inhibitor-containing granule to form a tablet. The water-soluble low melting point substance is not particularly limited as long as it is an additive having a melting point of 40 ° C. to 80 ° C., but preferably macrogol, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester and / or glycerin fatty acid. Esters, more preferably macrogol and sucrose fatty acid esters. The blending amount of the water-soluble low-melting substance is usually 5% to 40%, preferably 10 to 40%, more preferably 15 to 30% with respect to the tablet weight. The compression pressure at the time of tableting of the preparation usually needs to be performed at a low tableting pressure of 20 kg to 400 kg, preferably 50 kg to 300 kg, and more preferably 100 kg to 300 kg. Moreover, it is desirable to heat-process after tableting. The heat treatment is performed at a temperature equal to or higher than the melting point of the water-soluble low-melting substance, preferably 40 to 90 ° C., more preferably 60 to 80 ° C., usually 3 minutes to 120 minutes, preferably 5 to 60 minutes, more preferably 10 It is characterized by heating for ˜50 minutes. The tablet according to the present invention has outstanding tablet characteristics such as high hardness and low friability while being compressed with a low compression pressure. This is due to the following reason.
That is, the acid-resistant layer that coats each of the benzimidazole proton pump inhibitor-containing granules is an enteric coating layer or a sustained-release coating layer, and a normal tableting pressure (500 to 2000 kg) is applied. When loaded, compression during tableting tends to cause a crack in a part of the coating layer, and the acid resistance function of the coating layer is likely to be lost. Therefore, by blending the water-soluble low melting point substance according to the present invention and compressing with low tableting pressure so that the acid resistance of the individual granules coated with the acid resistant layer is not affected by compression, Once a tablet with low tablet strength is made, and then heat treatment is performed to melt the blended water-soluble low-melting substance, the water-soluble low-melting substance forms a net inside the tablet, providing sufficient tablet strength. Can be secured. The tablet according to the present invention can ensure excellent stability even during long-term storage. Furthermore, it may be coated with a film layer to form a film tablet.

Although the specific aspect which concerns on this invention is shown below, this invention is not necessarily limited to these.

Figure 1 shows a mixture of benzimidazole proton pump inhibitor-containing granule (1) and H2 receptor antagonist-containing granule (2) coated with an enteric coating layer, and a water-soluble low-melting substance added together and compressed at low pressure. A multi-unit tablet obtained by heat treatment is shown. This tablet may be covered with a film coating layer (4).

FIG. 2 shows a mixture of a benzimidazole proton pump inhibitor-containing granule (1) coated with an enteric coating layer, an H2 receptor antagonist-containing granule (2), and various excipients (3). A multi-unit tablet obtained by compressing and heat-treating at low pressure together with a low melting point substance is shown. This tablet may be covered with a film coating layer (4).

FIG. 3 has two separated layers, one of which is a benzimidazole proton pump inhibitor-containing granule (1) coated with an enteric coating layer, excipient (5), water-soluble low The other layer, which is mixed with a melting point material, consists of an H2 receptor antagonist powder (6) and represents a tablet compressed and heat treated at low pressure. The tablet may be coated with a film coating layer (4). First, the H2 receptor antagonist powder or H2 receptor antagonist-containing granule (6) is filled into a mortar of a tableting machine, lightly compressed with an upper punch and molded, and then coated with an enteric coating layer. Pills containing benzimidazole proton pump inhibitor-containing granules (1), excipient (5), and water-soluble low-melting substance are filled into a mortar and compressed and molded again at low pressure to produce a laminated tablet Can do.

Furthermore, the present invention provides an acid-resistant layer coated on a tablet obtained by compressing together 1) a benzimidazole proton pump inhibitor-containing granule and 2) H2 receptor antagonist powder or H2 receptor antagonist-containing granule. It is a tablet made.

Although the specific aspect which concerns on this invention is shown below, this invention is not necessarily limited to these.

FIG. 4 shows that an enteric coating layer was coated on a tablet obtained by mixing and tableting a granule (7) containing a benzimidazole proton pump inhibitor, a granule (8) containing an H2 receptor antagonist and an excipient (5). Tablets are shown. The tablet is coated with an enteric coating layer (9), and if desired, an intermediate layer (10) may be provided between the tablet core and the enteric coating layer.

FIG. 5 has two separated layers, one layer mixed with benzimidazole proton pump inhibitor (7) and excipient (5), the other layer is an H2 receptor antagonist The tablet which consists of the following powder (6) and which is compressed together is shown. The tablet is coated with an enteric coating layer (9). If desired, an intermediate layer (10) may be provided between the tablet core and the enteric coating layer.
First, H2 receptor antagonist powder or H2 receptor antagonist-containing granule (6) is filled into a die of a tableting machine, and after lightly compressing and molding with an upper punch, a benzimidazole proton pump inhibitor is further added. Produced by filling the containing granule (7) and excipient (5) into a mortar, recompressing and molding to form a laminated tablet, and then coating with an enteric coating layer (9) Can do.

FIG. 6 shows a tablet (11) obtained by subjecting a granule containing a benzimidazole proton pump inhibitor coated with an enteric coating layer to an appropriate excipient and a water-soluble low-melting substance, and tableting at low pressure and heat treatment. Next, a dry-coated tablet obtained by adding a suitable excipient and a water-soluble low-melting substance to the H2 receptor antagonist-containing granule (2) and compressing it at a low pressure and heat-treating it is shown. The tablet may be coated with a film coating layer (4).

An oral pharmaceutical composition comprising a benzimidazole proton pump inhibitor according to the present invention and a histamine H2 receptor antagonist, wherein the benzimidazole proton pump inhibitor is protected by an acid resistant layer. An oral pharmaceutical composition characterized by can be characterized and manufactured as follows.

(Granules containing benzimidazole proton pump inhibitor)
The benzimidazole proton pump inhibitor-containing granule can be produced by various methods. Specifically, water-insoluble seeds such as crystalline cellulose, or water-soluble seeds composed of various sugars, sugar alcohols, corn starches, etc., alone or as a mixture, may be coated with a proton pump inhibitor using a coating apparatus. Good. The proton pump inhibitor may be sprayed by mixing with other components, for example, spraying as a solution or suspension of water or an organic solvent together with a binder, a surfactant, a disintegrant, an alkaline additive, etc. Is mentioned. Examples of the binder include ethyl cellulose (EC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, and polyvinylpyrrolidone, and the surfactant is a pharmaceutically acceptable nonionic or ionic surfactant. For example, sodium lauryl sulfate is sufficient. Examples of the disintegrant include low-substituted hydroxypropylcellulose, crospovidone, and Ac-di-sol. Moreover, you may mix with an alkaline additive if desired, for example, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, sodium hydroxide etc. are mentioned, for example.
In addition, various excipients, binders, disintegrants, and alkaline additives are added to the benzimidazole proton pump inhibitor to produce granules by extrusion granulation, rolling granulation, fluidized bed granulation, and benzimidazole. Granules containing a proton pump inhibitor may be used.
Benzimidazole proton pump inhibitor-containing granules can be dispersed in water or ethanol by adding various excipients, binders, disintegrants, and alkaline additives to the benzimidazole proton pump inhibitor. Can be manufactured.

Next, before coating the benzimidazole proton pump inhibitor-containing granules with an acid-resistant layer such as an enteric coating layer, if desired, between the benzimidazole proton pump inhibitor and the acid-resistant layer, An intermediate layer composed of a water-insoluble or water-dispersible film can be provided. In particular, when the acid-resistant layer is an enteric coating layer, the benzimidazole proton pump inhibitor has the property of being easily decomposed in an acidic state, so avoid direct contact with the enteric base that is an acidic base. This is because it is required.
The intermediate layer can be coated with a coating apparatus or a fluidized bed granulator. The intermediate layer is made of sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, magnesium stearate, calcium stearate, titanium oxide, talc, etc. alone or as appropriate It can be used by combining.

(Granules containing benzimidazole proton pump inhibitor coated with acid resistant layer)
When an enteric coating layer is coated as the acid-resistant layer, water or an appropriate amount is applied to a granule containing an benzimidazole proton pump inhibitor-containing granule or an intermediate layer of a benzimidazole proton pump inhibitor-containing granule. An enteric base dispersed or dissolved in an organic solvent can be coated using a coating apparatus or a fluidized bed granulating apparatus. Examples of enteric bases include methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac. Or other suitable enteric coating polymer can be used. A plasticizer may be added to the enteric coating layer, and examples thereof include triethyl citrate, phthalate ester, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate and the like. The amount of the plasticizer is usually 7 to 40%, preferably 10 to 40%, based on the weight of the enteric coating base.
In the case of coating a sustained release base as the acid resistant layer, water or suitable for the granule containing the benzimidazole proton pump inhibitor-containing granule or the granule containing the benzimidazole proton pump inhibitor-containing granule and the intermediate layer A sustained release base dispersed or dissolved in an organic solvent can be coated using a coating apparatus or a fluidized bed granulating apparatus. Examples of sustained release bases include water-insoluble polymers, water-soluble polymers, lubricants, and the like, and these may be used alone or in combination of two or more.
Examples of water-insoluble polymers include cellulose ethers (cellulose alkyl ethers such as ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, and butyl cellulose, cellulose aralkyl ethers such as benzyl cellulose, and cellulose cyanoalkyl such as cyanoethyl cellulose. Ethers), cellulose esters (cellulose organic acid esters such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate), methacrylic acid / acrylic acid copolymer (trade name: Eudragit RS, Eudragit RL, Eudragit NE, manufactured by Rohm Pharma). Examples of the water-soluble polymer include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone and the like. Examples of the lubricant include magnesium stearate, calcium stearate, titanium oxide, talc and the like.

The acid-resistant coating layer described above can also be used to coat H2 receptor antagonist-containing granules, and also contains benzimidazole proton pump inhibitor-containing granules and H2 receptor antagonist powders or H2 receptor antagonists. It can also be used to coat tablets formed by compressing granules.

A tablet comprising a composition of a benzimidazole proton pump inhibitor-containing granule and an H2 receptor antagonist may be further coated with a water-soluble coating layer. The coating layer must be water soluble or readily disintegratable in water. The water-soluble coating layer is obtained by coating the granules or tablets coated with the enteric coating layer by dissolving or suspending them in water or an organic solvent using a coating apparatus. Examples thereof include sugar, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and the like. Also, plasticizers, colorants and antistatic agents such as titanium dioxide, talc and other additives can be included in the coating layer.

(Preparation of granules containing H2 receptor antagonist)
The H2 receptor antagonist may be mixed with various excipients and disintegrants and granulated by wet granulation or dry granulation. The loss on drying of the obtained granules is desirably less than 3%.

(Multi-unit tablet)
The benzimidazole proton pump inhibitor-containing granule coated with an enteric coating layer is mixed with a powder of H2 receptor antagonist or an H2 receptor antagonist-containing granule, an excipient, and a lubricant, and tableted. The lubricant is not particularly limited, and examples thereof include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc and the like. This mixture is compressed to produce multiple unit tablets. Furthermore, it can coat | cover with a film coating layer, and can improve the photostability of a H2 receptor antagonist. In addition, additives, such as a coloring agent and a lubricant, can be added to a film coating layer.
Preferably, a water-soluble low melting point substance is blended as a tablet component. That is, benzimidazole proton pump inhibitor-containing granules coated with an enteric coating layer are H2 receptor antagonist powders or H2 receptor antagonist-containing granules, excipients, lubricants, water-soluble low-melting substances And mixed with tablets. The water-soluble low-melting substance may be any of macrogol, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, glycerin fatty acid ester, and the like, and is characterized by blending one or more kinds. Suitable lubricants for tableting are, for example, sodium stearyl fumarate, magnesium stearate, talc. Tablets obtained by compressing this mixture are heat-treated at a temperature equal to or higher than the melting point of the water-soluble low-melting substance to produce multi-unit tablets. Furthermore, it can coat | cover with a film coating layer, and can improve the photostability of a H2 receptor antagonist. In addition, additives, such as a coloring agent and a lubricant, can be added to a film coating layer.

When manufacturing the above-mentioned multiple unit tablet, instead of the H2 receptor antagonist-containing granule, an H2 receptor antagonist-containing granule having an enteric coating layer may be used. This is because H2 receptor antagonists have a property of degrading under acidic conditions.

Moreover, when manufacturing the above-mentioned multiple unit tablet, it replaces with the mixing | blending of the powder of H2 receptor antagonist, or an H2 receptor antagonist containing granule, and the benzimidazole type proton pump inhibitor coat | covered with the enteric coating layer Granules obtained by coating the containing granules with a solution or suspension of an H2 receptor antagonist may be used.

(Capsules containing multiple granules)
The benzimidazole proton pump inhibitor-containing granule coated with an enteric coating layer may be mixed with a lubricant, excipient, etc., if desired, together with H2 receptor antagonist powder or H2 receptor antagonist-containing granule. The capsule may be filled.

According to the present invention, it is possible to provide a stable oral pharmaceutical composition comprising both a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist.
In particular, a benzimidazole proton pump inhibitor-containing granule coated with an acid-resistant layer, an H2 receptor antagonist powder or an H2 receptor antagonist-containing granule, a water-soluble low-melting substance, and heat-treated after compression In the tablet, it is possible to formulate a good multi-unit tablet having sufficient tablet strength and disintegration characteristics without losing the acid resistance function of the coating layer after tableting. The effect example is shown below.

1. Excellent tablet strength of tablets according to the present invention The tablets obtained in Examples 1 and 2 and Control Examples 1 and 2 were measured for hardness using a hardness meter. Formulation formulations are shown in Tables 1 and 2, and the results are shown in Table 3.

実施例１及び２は、表３に示したように高い硬度を有し、取り扱い上問題のない良好な硬度であった。一方、対照例１及び２は、脆弱すぎて硬度測定は不可能であり、５Ｎ以下であった。
本発明に係る酸抵抗性層で被覆されたベンズイミダゾール系プロトンポンプ阻害剤含有顆粒、Ｈ２受容体拮抗剤の粉末又はＨ２受容体拮抗剤含有顆粒、水溶性低融点物質を配合し圧縮後に熱処理してなる錠剤は、優れた錠剤強度を有することは明らかである。

Examples 1 and 2 had high hardness as shown in Table 3, and were good hardness with no problem in handling. On the other hand, Comparative Examples 1 and 2 were too weak to measure hardness, and were 5N or less.
A benzimidazole proton pump inhibitor-containing granule coated with an acid-resistant layer according to the present invention, an H2 receptor antagonist powder or an H2 receptor antagonist-containing granule, a water-soluble low-melting substance, and heat-treated after compression It is clear that the resulting tablet has excellent tablet strength.

2. Excellent disintegration characteristics of the tablet according to the present invention For the tablets produced in Examples 1 and 2, according to the disintegration test method of Japanese Pharmacopoeia XIII, disintegration test was conducted using 0.1M HCl, and the tablets The enteric granules exposed from the inside of the tablet due to the disintegration of were observed visually to confirm the presence or absence of cracks in the enteric coating layer (film). The results of the decay time are shown in Table 4.

実施例１及び２の錠剤が崩壊して放出された酸抵抗性層で被覆されたベンズイミダゾール系プロトンポンプ阻害剤含有顆粒には、腸溶性被覆層（皮膜）の亀裂や損傷は認められなかった。また、崩壊時間も良好であった。
本発明に係る酸抵抗性層で被覆されたベンズイミダゾール系プロトンポンプ阻害剤含有顆粒、Ｈ２受容体拮抗剤の粉末又はＨ２受容体拮抗剤含有顆粒、水溶性低融点物質を配合し圧縮後に熱処理してなる錠剤は、打錠後の被覆層の酸抵抗性機能が失われることなく、良好な崩壊特性を有することは、明らかである。

In the benzimidazole proton pump inhibitor-containing granules coated with the acid-resistant layer released by disintegrating the tablets of Examples 1 and 2, no enteric coating layer (film) was cracked or damaged. . The disintegration time was also good.
A benzimidazole proton pump inhibitor-containing granule coated with an acid-resistant layer according to the present invention, an H2 receptor antagonist powder or an H2 receptor antagonist-containing granule, a water-soluble low-melting substance, and heat-treated after compression It is apparent that the tablets obtained have good disintegration properties without losing the acid resistance function of the coating layer after tableting.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1
(I) Preparation of granules containing enteric rabeprazole sodium 150 g of rabeprazole sodium and 26.5 g of ethylcellulose were dissolved in 1599 g of absolute ethanol. Using a Wurster type fluidized bed granulation coating machine (trade name: multiplex, POWREC), 500 g of non-parel 108 as a core material was coated and dried to produce a rabeprazole sodium-containing granule (1).
Next, 69.3 g of ethyl cellulose and 424.2 g of hydroxypropyl cellulose were dissolved in 812.7 g of absolute ethanol, and further 199.1 g of magnesium stearate was dispersed and coated on the above-mentioned 400 g of rabeprazole sodium-containing granules (1). Thus, a rabeprazole sodium-containing granule (2) coated with an intermediate layer was obtained.
Further, 453.1 g of hydroxypropylmethylcellulose phthalate and 45.3 g of diacetylated monoglyceride were dissolved in 8700 g of an anhydrous ethanol aqueous solution, and further, 66.6 g of a blend dye consisting of titanium oxide, talc, and red iron oxide was dispersed. 400 g of beprazole sodium-containing granules (2) coated with an intermediate layer were obtained to obtain rabeprazole sodium-containing granules (3) coated with an enteric coating layer.
(Ii) Preparation of tablet according to the present invention Next, 37.3 g of the enteric-coated rabeprazole sodium-containing granule (3) prepared above was added to 1.25 g of famotidine, 20 g of macrogol 6000, 16 g of lactose (Flow Lac), low substitution Hydroxypropylcellulose (L-HPC, grade: LH-21) 25 g and magnesium stearate 0.5 g are added, mixed in a plastic bag, and tableted with a punching force of 150 to 200 kg with a 13 mm diameter mortar. A tablet containing 10 mg rabeprazole sodium and 10 mg famotidine in 800 mg was obtained. The tablet was heated in a constant temperature layer at 70 ° C. for 40 minutes and then cooled at room temperature to obtain a tablet according to the present invention.

Example 2
37.3 g of the enteric rabeprazole sodium-containing granule (3) obtained in Example 1 was added to 1.25 g of famotidine, 30 g of macrogol 6000, 16 g of lactose (flow rack), low-substituted hydroxypropylcellulose (L-HPC, grade) : LH-21) 25 g and 0.5 g of magnesium stearate were added, mixed in a plastic bag, tableted with a pressing force of 150 to 200 kg with a 13 mm diameter punch, and 10 mg of rabeprazole sodium and 10 mg of famotidine in 800 mg of each tablet. A primary tablet containing was obtained. The tablet was heated in a constant temperature layer at 70 ° C. for 40 minutes and then cooled at room temperature to obtain a secondary tablet according to the present invention.

In order to show the remarkable excellent effect of the dissolution control preparation according to the above examples, the following control examples are given.
In the control example, only the primary tablet was prepared by the normal tableting operation with the formulation shown in Table 2, and the heating and cooling operations were not performed after the preparation. That is, preparation was performed according to the following procedure.

Control Example 1
37.3 g of the enteric rabeprazole sodium-containing granule (3) obtained in Example 1 was added to 1.25 g of famotidine, 20 g of macrogol 6000, 16 g of lactose (Flowlac), low-substituted hydroxypropylcellulose (L-HPC, grade: LH-21) 25 g and 0.5 g of magnesium stearate were added, mixed in a plastic bag, tableted with a pressing force of 150 to 200 kg with a 13 mm diameter punch, and each tablet contained 800 mg rabeprazole sodium and 10 mg famotidine. To obtain a tablet.

Control Example 2
37.3 g of the enteric rabeprazole sodium-containing granules (3) obtained in Example 1 were added to 1.25 g of famotidine, 30 g of macrogol 6000, 16 g of lactose (Flowlac), low-substituted hydroxypropylcellulose (L-HPC, grade: LH-21) 25 g and 0.5 g of magnesium stearate were added, mixed in a plastic bag, tableted with a pressing force of 150 to 200 kg with a 13 mm diameter punch, and each tablet contained 800 mg rabeprazole sodium and 10 mg famotidine. To obtain a tablet.

It is an illustration of a cross-sectional view of a multi-unit tablet in which a benzimidazole proton pump inhibitor-containing granule (1) coated with an enteric coating layer is mixed with an H2 receptor antagonist-containing granule (2). The tablets are coated with a film coating layer (4). A cross-sectional view of a multi-unit tablet in which a granule (1) containing a benzimidazole proton pump inhibitor coated with an enteric coating layer is mixed with an H2 receptor antagonist-containing granule (2) and an excipient (3) It is an example. The tablets are coated with a film coating layer (4). It has two separated layers, one of which is a mixture of benzimidazole proton pump inhibitor-containing granules (1) coated with an enteric coating layer and an excipient (5). The layer is an illustration of a cross-sectional view of a tablet consisting of an incorporated H2 receptor antagonist powder (6). The separated layers are optionally separated by an intermediate layer (10) and the tablets are coated with a film coating layer (4). In the illustration of the sectional view of a tablet in which a benzimidazole proton pump inhibitor (7) is mixed with one or more H2 receptor antagonists (8) and excipient (5) and coated with an enteric coating layer is there. The tablets are coated with an enteric coating layer (9), and optionally an intermediate layer (10) is provided between the tablet core and the enteric coating layer. It has two separated layers, one layer of benzimidazole proton pump inhibitor (7) mixed with excipient (5) and the other layer of the included H2 receptor antagonist It is illustration of sectional drawing of the tablet which consists of powder (6). The tablets are coated with an enteric coating layer (9), and optionally an intermediate layer (10) is provided between the tablet core and the enteric coating layer. It is an illustration of a cross-sectional view of a tablet in which an acid-sensitive proton pump inhibitor (11) tablet coated with an enteric coating layer forms a dry-coated tablet with an H2 receptor antagonist-containing granule (2). The tablets are coated with a film coating layer (4).

Claims (17)

An oral pharmaceutical composition comprising a benzimidazole proton pump inhibitor and a histamine H2 receptor antagonist, wherein the benzimidazole proton pump inhibitor is protected by an acid resistant layer. Oral pharmaceutical composition. The oral pharmaceutical composition according to claim 1, wherein the benzimidazole proton pump inhibitor is rabeprazole, omeprazole, lansoprazole, pantoprazole, an optical isomer thereof, or a pharmacologically acceptable salt thereof. The oral pharmaceutical composition according to claim 1 or 2, wherein the histamine H2 receptor antagonist is famotidine, ranitidine, cimetidine or a pharmacologically acceptable salt thereof. The oral pharmaceutical composition according to any one of claims 1 to 3, wherein the acid resistant layer is an enteric coating layer or a sustained release coating layer. The oral layer according to any one of claims 1 to 4, wherein an intermediate layer comprising a water-soluble, water-insoluble or water-dispersible film is disposed between the benzimidazole proton pump inhibitor and the acid resistant layer. Pharmaceutical composition. The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of the benzimidazole proton pump inhibitor is 5 to 80 mg and the amount of the H2 receptor antagonist is 10 to 800 mg. The oral pharmaceutical composition is a tablet, orally disintegrating tablet, capsule or granule, according to any one of claims 1 to 6. The oral pharmaceutical composition is a tablet, and the oral pharmaceutical composition according to any one of claims 1 to 6. The oral pharmaceutical composition according to any one of claims 1 to 8, wherein the benzimidazole proton pump inhibitor is rabeprazole and the histamine H2 receptor antagonist is famotidine. 1) A tablet comprising both benzimidazole proton pump inhibitor-containing granules and 2) H2 receptor antagonist powder or H2 receptor antagonist-containing granules, wherein the benzimidazole proton pump inhibitor is acid resistant. An oral pharmaceutical composition characterized by being protected with a sex layer. Furthermore, the tablet of Claim 10 which mix | blends at least 1 or more types of water-soluble low melting-point substance in a powder state, or mix | blended in the granule containing an H2 receptor antagonist. The tablet according to claim 10 or 11, wherein the tablet is compressed with a low tableting pressure of 50 kg to 300 kg and heat-treated. The tablet according to claim 12, wherein the heat treatment is performed at a temperature equal to or higher than the melting point of the water-soluble low-melting substance. The water-soluble low-melting-point substance is macrogol, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester or glycerin fatty acid ester having a melting point of 40 ° C to 80 ° C. Tablets. Furthermore, the tablet of any one of Claims 10-14 formed by coat | covering with a film layer. A tablet formed by coating an acid-resistant layer on a tablet obtained by compressing 1) a benzimidazole proton pump inhibitor-containing granule and 2) H2 receptor antagonist powder or H2 receptor antagonist-containing granule. The oral pharmaceutical composition according to any one of claims 10 to 16, wherein the benzimidazole proton pump inhibitor is rabeprazole and the histamine H2 receptor antagonist is famotidine.

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