JPH01193215A - Coated composition containing agent suppressing secretion of acid in stomach - Google Patents

Abstract

PURPOSE:To obtain the title stable composition not exhibiting effects in the presence of an acid or in low acid, but showing effects only in high acid, by coating granules or tablets containing an acidic and unstable agent suppressing secretion of acid in the stomach with an enteric film and a coating film soluble in the stomach in this order. CONSTITUTION:Granules or tablets containing an acidic and unstable agent suppressing secretion of acid in the stomach {e.g., sodium salt of 2-[{4-(3- methoxypropoxy)-3-methylpyridin-2-yl) metlylsulfinyl-1H-benzimidazole]} are coated with an enteric film or a coating film soluble in the stomach. A material comprising a base such as hydroxypropylmethyl cellulose phthalate, etc., may be cited as the enteric film and a base comprising polyvinylacetal diethylamino acetate as the coating film soluble in the stomach.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a coated composition containing a gastric acid secretion inhibitor. Specifically, when an acidic and unstable gastric acid secretion suppressant is administered to a patient, and the patient's stomach is in a low or no acid state, the suppressant will not be effective and may cause damage to the gastrointestinal tract. The present invention relates to a composition containing a gastric acid secretion suppressant, which is designed to be excreted via the gastrointestinal tract and to exert its intended effect only when the patient's stomach is in a high acid state.

[Problems to be solved by conventional techniques and inventions] Currently,
Although many types of anti-ulcer drugs are used for treatment, one of the most commonly used is a class of drugs that reduce pain and heal ulcers by inhibiting gastric acid secretion. In particular, H”-K”ATP, which is being developed recently.
A series of compounds that have an inhibitory effect on gastric acid secretion have a strong and long-lasting effect.

However, special caution is required when using gastric acid secretion inhibitors that have a long duration of action.

That is, if a patient's gastric acid secretion is suppressed for a long period of time and the stomach is left in an acid-free or low-acid state, the main cells of the stomach may atrophy or the stomach wall may thicken.

Furthermore, there is a risk that bacteria may grow in the stomach and carcinogens may even be produced. Therefore, it is desirable to maintain a high acid state in the stomach at appropriate intervals. For this reason, when using gastric acid secretion inhibitors that have a long duration of action, it is necessary to check the gastric acid status using an intragastric probe, but this can cause great pain to the patient. This is practically impossible because it gives Alternatively, body medication may be administered for several days after taking the drug once, but this does not allow for confirmation of whether the stomach is in a high acid state and is also inconvenient for the patient. Therefore, it is necessary to design a formulation that suppresses gastric acid secretion, which has a long duration of action, so that it exerts its intended effect when the stomach is in a high acid state, and is excreted as is without exerting its effect in other cases. It becomes.

On the other hand, acidic gastric juices in the stomach generally result in chemical degradation of the administered drug. In particular, recently developed H”-ATP
Since gastric acid secretion inhibitors having anti-age effects are decomposed under acidic conditions, administration under highly acidic conditions results in a significant loss of their effectiveness. Therefore, in the case of acidic and unstable gastric acid secretion inhibitors, a special formulation design is required to stabilize them against high acid conditions.

[Means to solve the problem]

In view of these conditions, the present inventors have developed a gastric acid secretion suppressant that does not show its effect on patients in no-acid or low-acid states, but only in high-acid states, and is stable even in high-acid states. As a result of extensive research, we found that this objective could be achieved by coating an acidic and unstable gastric acid secretion inhibitor with an enteric coating agent, and then coating the enteric coating with a gastroinsoluble coating agent. The inventors have found that this can be achieved and have completed the present invention.

That is, the present invention is characterized in that granules or tablets containing an acidic and unstable gastric acid secretion inhibitor are coated with an enteric coating and a gastric coating in this order, and exhibit their effect only in acidic conditions. This invention relates to a coated composition containing a gastric acid secretion inhibitor.

In the present invention, known enteric coating agents are used to form the enteric coating, such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, methyl methacrylate, etc.
Examples include methacrylic acid copolymers, methyl acrylate/methacrylic acid copolymers, and the like. Hydroxypropyl methylcellulose phthalate has a pH value depending on the degree of substitution.
You can choose a base that dissolves at 5.0 to 5.5 or higher (Shin-Etsu Chemical: HP-50, HP-55).

Hydroxypropyl methylcellulose acetate succinate is also commercially available as a base that dissolves at pH 5.0 to 5.5 and can use water as a solvent (Shin-Etsu Chemical: AQOAT), and cellulose acetate phthalate dissolves at pH 7 or higher. Furthermore, methyl methacrylate/methacrylic acid copolymer and methyl acrylate/methacrylic acid copolymer are
It is known as a base that dissolves at H5-7 or higher (Röhm: Eudragitto L, S). In the present invention, any one or a combination of these bases can be used as the enteric coating agent.

In the present invention, a gastric soluble coating agent which is also known as a gastric soluble coating agent that forms a gastric soluble film is used. For example, polyvinyl acetal diethylamino acetate (Sankyo: A
EA) and dimethylaminoethyl methacrylate/methacrylate copolymer (Rehm: Eudragit)-E) are known as coating agents that dissolve only in acidic regions.
In the present invention, any of these gastric soluble coating agents can be selected and used.

Examples of the acidic and unstable gastric acid secretion inhibitor used in the present invention include 2N4-(3-methoxypropoxy)-3-methylpyridin-2-yl)methyl, which has a strong H"-K" ATPage inhibitory effect. sulfinyl)-1H
-benzimidazole sodium salt, 5-methoxy-2
Examples include, but are not limited to, compounds such as -[{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole; It can be applied to all unstable gastric acid secretion inhibitors.

In the present invention, granules or tablets containing a gastric acid secretion inhibitor that is unstable in an acidic region are coated with an enteric coating and a gastric coating in this order, so that the drug can be used in patients in no-acid or low-acid conditions. It was devised so that the drug would not be eluted and would only be eluted and effective in patients in a hyperacid state.

To obtain the coated composition containing the gastric acid secretion suppressant of the present invention, first, the enteric coating agent is dissolved as it is or in a solvent for dissolving it, such as ethanol, acetone, dichloromethane, isopropyl alcohol, water, etc. to form a liquid. If necessary, plasticizers, colorants, etc. are mixed and coated on granules, tablets, etc. containing acidic and unstable gastric acid secretion inhibitors by means such as spraying or kneading. The soluble coating agent can be used as it is or dissolved in a solvent such as ethanol, acetone, dichloromethane, etc. to make it liquid, and if necessary, a plasticizer or coloring agent can be mixed therein and the intestines can be treated by spraying or kneading. It is sufficient to coat granules, tablets, etc. with a soluble coating agent.

Furthermore, if necessary, an easily soluble coating agent such as hydroxypropyl methyl cellulose is applied between uncoated granules or tablets and the enteric coating, or between the enteric coating and the gastric coating to prevent substances with extremely different properties. You can also avoid contact.

Of course, the granules of the present invention can also be mixed with other substances to form capsules or tablets.

The usage ratio of enteric coating agent and gastrosoluble coating agent varies depending on the properties of the gastric acid secretion suppressant to be coated, the particle size of the granules, the size of the tablet, etc., but usually, the proportion of each coated drug is It is desirable that the amount is at least 5% by weight, preferably from 5 to 40% by weight. Generally, the amount of coating agent used increases as the particle size of the drug to be coated becomes smaller.

[Example] The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to these examples.
” Example 1 2- [{4-(3-methoxypropoxy)-3-methylpyridin-2-yl)methylsulfinyl]-1■-
Benzimidazole sodium salt 50g, mannitol 530g, low substituted hydroxypropyl cellulose 10
Mix 0g)-Fl:)xypropylcellulose 1
After granulation with 0 g of ethanol solution, the mixture was dried, sized, and tableted to obtain tablets with a diameter of 5 mm according to a conventional method (uncoated tablets). 700 g of this uncoated tablet was coated with a solution of 100 g of hydroxypropyl cellulose and 20 g of magnesium stearate dissolved and suspended in 2000 d of ethanol (lower tablet).

To 700 g of tablets, add 300 g of hydroxypropyl methyl cellulose phthalate, 30 g of monoglyceride (Mybaset 99-407), 30 g of talc, 15 g of titanium oxide, 4000 II of ethanol, and 11 of water.
! Tablets were coated with the solution dissolved and suspended in a mixture of (enteric-coated tablets).

50g of hydroxybrobyl cellulose in 700g of enteric coated tablets
1 Log of magnesium stearate to ethanol 150
Tablets were coated with the solution dissolved and suspended in 0d (inner-covered tablets).

Add 100 g of polyvinyl acetal diethylamino acetate (AEA) to 700 g of cored tablets and 150 g of ethanol.
Tablets were coated using the solution dissolved in 0d (final coated tablet).

A Blatt WSG-5 machine was used for all tablet coatings. The weights of these tablets were: plain tablet 70.4 mg, undercoated tablet 72.9n+g, enteric coated tablet 84.6a+g, inner coated tablet 87.5 mg, and final coated tablet 93.2 mg.

Example 2 100 g of hydroxypropyl methylcellulose was added to 700 g of uncoated tablets prepared in Example 1.) Liacetin 1
Tablets were coated with a solution of 0 g dissolved in a mixture of 1050 d of ethanol and 260 d of water (undercoat tablets).

A 700 g lower tablet was coated with 150 g of methyl acrylate/methacrylic acid copolymer (Eudragitto L), 15 g of triacetin, 15 g of talc, and 7.58 g of titanium oxide dissolved and suspended in 3500 g of ethanol (intestinal). (molten tablet).

100 g of hydroxypropyl methyl cellulose in 700 g of enteric-coated tablets, 10 g of lyacetin and 105 g of ethanol
〇-1 Wednesday 260 ad! Tablets were coated with the solution dissolved in a mixture of (inner-covered tablets).

Add 100g of AHA to 700g of tablet with 15% of ethanol.
Tablets were coated using the solution dissolved in 00d (final coated tablet).

The weight of these tablets is 70.4 mg for plain tablets and 7 for bottom tablets.
2.1mg, 111 melted tablet 83.3mg, medium-sized tablet 85
．． 9mg, fit final coated tablet 92.3mg.

〔Effect of the invention] The present invention will be explained in detail using experimental examples.

Experimental Example 1 <Sample> The final coated tablet obtained in Example 1 was used as a test sample.

Dissolution test> Perform a dissolution test on 2 tablets of the sample with a diurnal cycle of 1 liquid 900 m and a diurnal cycle of 2 liquid 900 m, respectively, or
Immediately after the 30-minute test with 900 d of solution, an elution test was conducted with 900 d of the two diurnal solutions (the temperature of the test solution was 37°C, the paddle method was 10,100 rpm, and the change in absorbance of the test solution was shown in Figure 1).

As is clear from Figure 1, the diurnal cycle of liquid 1 (marked with O) or liquid 2 (
・mark) alone does not elute the drug, but diurnal l
After a 30-minute test with the solution, the drug was quickly eluted when the second solution was tested (◎ mark).

That is, in the diurnal solution 1, the gastric coating and intermediate coating of the specimen sample dissolve, but the enteric coating applied underneath does not dissolve, so the drug does not elute. Since the dissolving film does not dissolve, the main drug does not elute. However, when performing a dissolution test with two liquids after testing with one liquid, the gastric dissolving film and the intermediate coating dissolve in the first liquid, and then in the second liquid. The drug is eluted because the enteric coating and underlayer coating dissolve.

Considering the elution behavior of the specimen sample as dissolution within the patient's gastrointestinal tract, if the stomach is in an acid-free or low-acid state, the gastric membrane of the specimen sample is sent to the duodenum without being dissolved. Since the pH inside the duodenum is high, the gastric membrane does not dissolve, and the drug is excreted from the body without being eluted. On the other hand, when the stomach is in a high acid state, the gastric coating and intermediate coating of the sample dissolve in the stomach, and after passing into the duodenum, the enteric coating and undercoat dissolve, and the drug is eluted. That will happen.

An animal study was conducted to confirm the above concept.

<Animal test> Peagle dogs were used as animals. The method of adjusting the acidity in the stomach is the method of Nakata et al. (Japan Pharmaceutical Society 2nd Annual Conference Abstracts,
p. 65) was used as a reference. That is, as a model of hypoacidity or noacidity in the stomach, the administration of 30 min.
The rats were forced to drink a 1% sodium bicarbonate solution every 15 minutes from 1 minute before administration until 2 hours after administration. In addition, pentagastrin was subcutaneously injected 10 minutes before administration as a model of a hyperacid state. Samples were forcibly administered to each of these three model animals, and the drug concentration in plasma was measured. The results are shown in Figure 2.

In dogs with low acid or no acid conditions (marked with *), almost no drug is detected in the plasma, whereas in dogs with high acidity (marked with O), a high concentration of the drug is detected, indicating that the coated tablets of the present invention can be used in vivo. It has become clear that the above concept works.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the elution of a drug from a specimen sample,
FIG. 2 is a graph showing the plasma drug concentration after administering a test sample to a Peagle-sized dog whose acidity in the stomach was controlled. Figure 1

Claims (1)

[Claims] 1. A coated gastric acid secretion characterized in that granules or tablets containing an acidic and unstable gastric acid secretion inhibitor are coated with an enteric coating and a gastric coating in this order. Inhibitor-containing composition. 2. The coated composition containing a gastric acid secretion inhibitor according to claim 1, wherein the composition is a tablet, granule, or capsule. 3. The enteric coating is hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate,
3. The coated gastric acid secretion inhibitor-containing composition according to claim 1, which comprises a base selected from methyl methacrylate/methacrylic acid copolymer and methyl acrylate/methacrylic acid copolymer. 4. The coated gastric acid secretion suppressor according to any one of claims 1 to 3, wherein the gastric coating is made of a base selected from polyvinyl acetal diethylaminoacetate and dimethylaminoethyl methacrylate/methacrylate copolymer. agent-containing composition. 5. An acidic and unstable gastric acid secretion inhibitor is 2-[{4-(
3-Methoxypropoxy)-3-methylpyridine-2-
yl}methylsulfinyl]-1H-benzimidazole sodium salt, or 5-methoxy-2-[{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl}
The coated gastric acid secretion suppressant-containing composition according to any one of claims 1 to 4, which is sulfinyl]-1H-benzimidazole.