WO1999048532A1

WO1999048532A1 - Medicinal compositions adhering to stomach/duodenum

Info

Publication number: WO1999048532A1
Application number: PCT/JP1999/001311
Authority: WO
Inventors: Toshio Inagi; Hiroyuki Shirai; Norikazu Yamaguchi; Takeshi Nishino
Original assignee: Kowa Co., Ltd.
Priority date: 1998-03-20
Filing date: 1999-03-17
Publication date: 1999-09-30
Also published as: JPH11269064A; BG104733A; BG64499B1

Abstract

Medicinal compositions adhering to the stomach/duodenum characterized by being obtained by coating a composition containing a drug acting in the stomach and/or duodenum and a component selected from among water-insoluble polymers, polyglycerol fatty acid esters, lipids and waxes with a polymer which is capable of adhering to the surface of the digestive tract mucosa under acidic conditions but strippable therefrom under neutral or alkaline conditions. Use of these compositions adhering exclusively to the gastroduodenal mucosae makes it possible to release drugs over a long period of time, thus achieving sufficient drug effects in a small dose.

Description

Description Gastric / duodenal adhesive pharmaceutical composition Technical field

The present invention relates to a pharmaceutical composition that adheres only to gastric mucosa and duodenal mucosa and that has a controlled drug release. Background art

Considering effective use of drugs, preparations with controlled release of the drug from the preparation, especially sustained-release preparations, can release the drug for a long time, reducing the number of doses and maintaining the blood concentration for a certain period of time There are great advantages such as being able to. Therefore, long-lasting preparations are being studied from various aspects.

Many of these long-acting preparations are designed to release the drug gradually as the preparation passes through the entire gastrointestinal tract, since the primary site of drug absorption is the intestinal tract. In contrast, few formulations are designed to exert their effects locally in the stomach and duodenum, rather than exhibiting their effects after being absorbed in the intestinal tract.

Drugs intended to allow the drug to act in the stomach include those with enhanced gastroretentivity by making the drug floatable (Da viss SS eta 1. Ph arm. R e s. 19 8 6: 2 0 8-2 13 3) Formulation with increased contact ratio to mucosal surface by increasing specific gravity (De Ver ereu XJE eta 1. Pharma col 199 0 0; 4 2: 5 0-5 0 1) has been reported. However, these formulations did not have sufficient retention.

In addition, a formulation has been proposed in which the blended polymer gels with water and adheres to the gastrointestinal mucosa (Japanese Patent Laid-Open No. 5-132416). Because of its strength and strength, this formulation has no selectivity for the gastrointestinal tract to adhere to and only adheres to the mucous membrane of the stomach and duodenum. I can't let it.

Accordingly, an object of the present invention is to provide a preparation which adheres only to the mucous membrane of the stomach and duodenum, controls the release of the drug, and has selectively excellent pharmacological action on the stomach and duodenum. Disclosure of the invention

In view of such circumstances, the present inventors have conducted intensive studies and have found that the release of a drug is controlled by a component selected from a water-insoluble polymer, a polyglycerin fatty acid ester, a lipid and a wax. If a polymer that adheres to the stomach and does not adhere under neutral or alkaline conditions imparts selective adhesion only to the mucosa of the stomach or duodenum, the drug will act on the gastric and duodenal membranes for a long time. The present inventor has found that a drug having a higher concentration and a higher pharmacological action can be obtained with a lower concentration of a drug because the drug is rapidly excreted from the intestinal tract, thereby completing the present invention.

That is, the present invention provides a composition containing a drug that acts on the stomach and Z or the duodenum and a component selected from a water-insoluble polymer, a polyglycerin fatty acid ester, a lipid and a wax on the surface of the gastrointestinal mucosa under acidic conditions. An object of the present invention is to provide a gastro-duodenal adhesive pharmaceutical composition characterized in that it is coated with a polymer having an adhesive ability and detachable from the gastrointestinal mucosa in neutral or alkaline conditions. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the relationship between the particle size and the adhesion rate of the preparation to cells. FIG. 2 is a diagram showing the relationship between PH and adhesiveness. FIG. 3 is a graph showing the transferability of a drug to gelatin. FIG. 4 is a diagram showing the eradication effect. FIG. 5 is a graph showing the bactericidal effect of formulations having different release times. BEST MODE FOR CARRYING OUT THE INVENTION Polymers that have an adhesive ability on the stomach and z or duodenal mucosa surface under acidic conditions used in the present invention, and which are detached from the gastrointestinal mucosa under neutral or alkaline conditions (hereinafter, referred to as

The “pH-dependent adhesive polymer” is not particularly limited, but is preferably one having a dissolution pH of 4 or more and having an anionic group. The following are examples of such a pH-dependent adhesive polymer.

(1) Natural polymer: purified shellac, white shellac. ,

(2) Synthetic polymer:

Cellulose derivative polymer:

Hydroxypropyl methylcellulose phthalate, hydroxypropylmethyl. Cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate trimellitate, cellulose acetate phthalate, etc.

Ataryl polymer:

A polymer obtained from acrylic acid and / or methacrylic acid,

Polymers obtained from ataryl acid and / or methacrylic acid and carboxylic acid esters.

Polyvinyl alcohol polymer:

Polyvinyl acetate rate.

Further, the pH-dependent adhesive polymer used in the present invention is particularly preferably a polymer having a carboxyl group, particularly preferably a polymer obtained from acrylic acid and / or methacrylic acid, and further, acrylic acid and Z or methacrylic acid, and a carboxylic acid ester. The polymers obtained from and are preferred. Examples of the carboxylate used herein include acrylic esters and methacrylic esters such as methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, T-butyl acrylate, 2-hydroquinethyl acrylate, 2-hydroquinpropyl acrylate, methyl methacrylate, methyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, methyl methacrylate Examples include 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, and t-butyl methacrylate.

As these polymers, a copolymer of methacrylic acid and methyl methacrylate is particularly preferred, especially those having a methacrylic acid content of 20 to 60%, such as Eudragit L100 or S100. Particularly preferred.

These pH-dependent adhesive polymers may be used alone or in combination of two or more. The component (water-insoluble component) selected from the water-insoluble polymer, polyglycerin fatty acid ester, lipid and wax used in the present invention (hereinafter sometimes referred to as “water-insoluble component”) is a component for controlling the release of the medicinal component.

The water-insoluble polymer used in the present invention is not particularly limited as long as it is generally used in pharmaceutical preparations as a sustained-release base. These polymers may be used alone or in combination of two or more. Examples of such polymers include the following.

Cellulosic polymers: crystalline cellulose, ethylcellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate fluorate, etc.

Of the above polymers, ethyl cellulose is particularly preferred.

The polyglycerin fatty acid ester used in the present invention is not particularly limited, and may be di-, tri- or higher polyglycerin fatty acid ester. The fatty acid portion of the polyglycerin fatty acid ester is preferably a fatty acid having 8 to 30 carbon atoms, and the polyglycerin portion is preferably from diglycerin to eicosaglycerin.

Specific examples of polyglycerin fatty acid esters include diglyceryl monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate, deglyceryl monostearate, tetraglyceryl tristearate, decaglyceryl tristearate, and pentane Tetraglyceryl stearate, pentaste Hexaglyceryl acrylate, hexaglyceryl monooleate, decaglyceryl monooleate, triglyceryl dioleate, tetraglyceryl dioleate, tetraglyceryl pentaoleate, hexaglyceryl penoleate, triglyceryl dilinoleate, dilinoleate Tetraglyceryl monophosphate, hexylglyceryl dilinoleate, tetraglyceryl monopalmitate, monono, hexaglyceryl hexylremitate, deglyceryl monopalmitate, tetraglyceryl tripalmitate, hexaglyceryl tripalmitate, etc. No.

Examples of the lipid used in the present invention include higher fatty acids or salts thereof, higher alcohols and fatty acid glycerin esters, and examples of the wax include waxes, hydrocarbons, and the like. Examples of higher saturated fatty acids or salts thereof include fatty acids having 8 to 30 carbon atoms or salts thereof, for example, stearic acid, magnesium stearate, and aluminum stearate. Examples of the higher alcohol include aliphatic alcohols having 10 to 24 carbon atoms, such as stearyl alcohol and cetyl alcohol. The fatty acid glycerin ester may be not only triglyceride with fatty acid but also monoglyceride or diglyceride. Examples of the waxes include carnapalow and beeswax. Examples of the hydrocarbon include microcrystalline wax, paraffin and the like.

The above-mentioned water-insoluble components, that is, the water-insoluble polymer, polyglycerol fatty acid ester, lipid and wax may be used alone or in combination of two or more. Further, in order to arbitrarily control the release of the drug from the preparation, a water-soluble polymer may be added to the water-insoluble component in any ratio. Examples of such a polymer include polyethylene glycol, hydroquinethyl cellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer, and polyvinyl acetate acetyl amino acetate.

In order to arbitrarily control the release in the present invention, the ratio of the water-soluble polymer to the water-insoluble component is preferably in the range of 0.1 to 60% by weight. The drug used in the present invention, the c Such drugs drugs acting in the stomach and duodenum are preferred, antacids, gastric mucosa protective agents, H ₂ blockers, Purotonpo Npuinhibi evening one (PPI), antibacterial Substances, protease inhibitors and the like. Examples of the antacid used in the present invention include magnesium hydroxide, magnesium aluminate and the like.

The gastric mucosa protective agent used in the present invention includes, for example, methylmethionine sulfonyl chloride (MMSC), vietnam sodium, sucralfate, and setraxate hydrochloride.

The H ₂ blockers used in the present invention, e.g., famotidine, cimetidine, mouth Kisachijinase evening one preparative and ranitidine, and the like.

Examples of PPI used in the present invention include Omebrabule and Lansobrasol.

Examples of the protease inhibitor used in the present invention include cetohydroxamic acid and caprihydroxamic acid.

Examples of the antibacterial substance used in the present invention include an anti-Helicobacter pylori active substance, a bismuth salt, and a quinolone compound. Among them, an anti-Helicobacter pylori active substance is preferable. Examples of anti-Helicobacter pylori active substances include penicillin antibiotics (such as moxicillin and ampicillin), macrolide antibiotics (such as erythromycin and clarithromycin), and tetracycline antibiotics (such as tetracycline). , Minocycline, streptomycin, etc.). The antibacterial substance used in the present invention is preferably a penicillin antibiotic, and particularly preferably is moxicillin (hereinafter referred to as “AMOX”) having high antibacterial properties against Helicobacter pylori.

In the composition of the present invention, the content of the drug may be appropriately determined depending on the type and preparation of the drug, but is generally preferably about 0.1 to 95% by weight, particularly preferably 0.1 to 90% by weight. Is preferable. The type of the water-insoluble component, the release time of the drug, etc. The amount used may be determined according to the formula, but generally it is preferably contained in the composition in an amount of 0.1 to 95% by weight, particularly preferably 1 to 60% by weight. Further, the pH-dependent adhesive polymer is preferably 0.1 to 95% by weight, more preferably 1 to 50% by weight in the composition.

In the composition of the present invention, conventional additives used in the production of solid pharmaceuticals may be used. The following are examples of such additives.

(1) Excipients: lactose, corn starch, talc, powdered sugar, light caffeic anhydride, carbonated magnesium, magnesium carbonate, etc.

(2) Binder: starch, sucrose, gelatin, gum arabic, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxydipropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.

(3) Plasticizer: polyethylene glycol, triethyl citrate, etc.

Other examples include a coloring agent; a flavoring agent; an adsorbent; a preservative; a wetting agent; The amounts of these additives are appropriately selected within a range that does not impair the pH-dependent adhesion to the gastric mucosa and does not affect the release of the drug.

The composition of the present invention is obtained by coating a composition containing a drug, an additive, if necessary, and the water-insoluble component with a pH-dependent adhesive polymer. Here, the drug, the necessary additive and the composition containing the water-insoluble component may be a drug or a mixture of this and an additive coated with the water-insoluble component, or may be a drug, a necessary additive and A matrix in which the water-insoluble components are mixed may be used, but the former is preferred. The term “coating” includes not only the case where the entire particle surface is uniformly coated with a coating agent but also the case where the particle surface is partially coated.

The release time of the drug from the preparation of the present invention may be arbitrarily set in consideration of the properties of the selected drug, etc. In order to fully demonstrate the quality, continuous and long time is desirable. In addition, considering the effects of gastrointestinal fluid and metabolism of gastric epithelial cells and the effects of diet, it is desirable that the release of the drug be completed within the time of adhering and staying on gastric mucosa. In consideration of the above points, the release time of the drug from the preparation is desirably 2 to 8 hours. The release time may be controlled by adjusting the ratio of the water-insoluble component to the water-soluble polymer, the amount of the water-insoluble component, and the like.

The particle size of the pharmaceutical composition of the present invention is preferably in the range of 30 to 300 μm, particularly 75 to 300 μm, from the viewpoint of adhesion to the stomach and Z or duodenal membrane. It is more preferably in the range of 100 to 250 m.

The pharmaceutical composition of the present invention comprises, for example, in the case of a preparation coated with the water-insoluble component, after preparing particles containing a drug using a conventional granulator or the like, the water-insoluble component and the pH-dependent adhesive polymer are mixed. It can be manufactured by sequentially performing coating. For the granulation, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method and the like can be adopted. Conventional coating methods such as a pan coating method and a fluidized bed coating method can be used for coating. When the coating agent is a solution or dispersion containing water or an organic solvent, a spray coating method can also be employed.

When the composition containing the drug and the water-insoluble component is a matrix, the water-insoluble component is dissolved in an appropriate organic solvent, and then kneaded with the drug, dried, and pulverized. Is dissolved in a suitable solvent, dispersed in a solution that is immiscible with the solvent, and the solvent is evaporated by heating to prepare particles. May be performed. The type of the organic solvent is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone; and halogenated hydrocarbons such as chloroform and dichloromethane. The coating agent and the matrix may contain the above-mentioned additives and the like. Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples.

Example 1

In accordance with the formulation in Table 1, a stomach and z or duodenal narrowing membrane adhesive preparation was prepared using a fluid bed coating machine. A solution prepared by dissolving 75 g of riboflavin phosphate in 3 L of water was sprayed on 300 g of anhydrous calcium hydrogen phosphate (average particle size: 150 urn) and dried. A solution obtained by dissolving 00 g in 4 L of ethanol was sprayed to perform coating. After drying, 500 g of methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L100) and 50 g of triethyl citrate dissolved in 5 L of ethanol are sprayed and coated. A yellow stomach and Z or duodenal mucosa adhesive preparation 1 was obtained.

Comparative Example 1

In the same manner as in Example 1 above, anhydrous calcium hydrogen phosphate (a solution of 75 g of riboflavin phosphate dissolved in 3 L of water in 300 g of an average particle diameter of 150 jm, 300 g) was sprayed and dried. After that, Comparative Formulation 1 was obtained, which was coated only with a solution of ethyl cellulose 400 g dissolved in ethanol 4 L. Table 1 Adhesive formulation 1 Comparative formulation 1 Anhydrous calcium hydrogen phosphate 3000 g 3000 g

(Product name: Fujikarin S G)

Riboflavin phosphate 75g 75g Ethyl cellulose 400g 400g Methacrylic acid-methyl methacrylate copolymer 500g

(Product name: Eudragit L100)

Triethyl citrate 50g Reference example 1

According to the formulation in Table 2, preparations for gastric and / or duodenal mucosa-adhesive preparations were prepared. After dissolving 20 g of methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L100) and 2 g of triethyl citrate in 5 OmL of ethanol, 25 g of drug and 75 g of excipient were added. The mixture was mixed well while heating to 60 ° C, and then dried. After drying, pulverization and classification are carried out to give products with an average particle size of about 30, 70, 100, 150, 200, 270, 325, 350 and 400 m. I got

Table 2

Example 2

Of the formulations shown in Table 3, 250 g of AMOX and 250 g of excipients were placed in a fluidized-granulation coating apparatus, and 40 g of ethyl cellulose was dissolved in 400 m of ethanol. The solution was sprayed and granulated. Subsequently, after coating with a solution prepared by dissolving 150 g of ethyl cellulose in 1.5 L of ethanol, 125 g of methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L100) was added. A formulation was prepared by coating with a solution of 25 g of triethyl citrate dissolved in 1.5 L of ethanol. Further, the obtained preparation was classified into particles that passed through 8 Omesh but did not pass through 15 Omesh (hereinafter abbreviated as 80/15 Omesh) to obtain spherical fine particles, which were designated as Preparation I. After adding excipient 4.58.1 g to AMOX4 1.9 g in a fluidized-granulation coating device and granulating, a coating similar to that of Formulation I was applied. The preparation was performed to obtain Formulation II. Furthermore, after excipient 4.58.1 g was added to 1.9 g of AM〇X4 in a fluidized-bed coating device and granulated in the same manner as in Preparation II, the release was controlled. After coating with a solution prepared by dissolving 112 g of ethyl cellulose and 600 g of polyethylene glycol in 1.5 L of ethanol, methacrylic acid / methacrylic acid was added in the same manner as in Preparations I and II. Coating of methyl copolymer (trade name: Eudragit L100) was performed to obtain preparation ③.

Further, 250 g of AMOX and 250 g of excipient were placed in a fluidized-granulation coating apparatus, granulated in the same manner as in ①, and coated with ethyl cellulose. Subsequently, methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L 100 93.7 g, trade name: Eudragit S 100 31.3 g) and triethyl citrate 25 g Was coated with a solution in which ethanol was dissolved in 1.5 L of ethanol to obtain Formulation I.

Table 3

① ② ③ ④

AMOX 250g 41.9g 41.9g 250g

Corn starch 250g 250g 250g 250g

Mannitol 208.lg 208.lg

Ethyl cellulose 190g 190g 152g 190g

PEG 6 0 0 0 38g

Methacrylic acid-methacrylic acid

Methyl copolymer

(Eudragit L 100) 125g 125g 125g 93.7g

(Eudragit S 100) 31.3g

Triethyl citrate 25g 25g 25g 25g Release time (hours) 6 6 2 6 Comparative Example 2

A preparation that adheres to the gastrointestinal mucosa was prepared using a polymer that gels with water, described in Japanese Patent Application Laid-Open No. 5-13234. That is, 85 g of stearic acid was dissolved in 70, and then 15 g of an atalylic acid-based polymer (trade name: Hibis @ KO 104) was added, mixed well for 10 minutes, and then cooled and solidified. After solidification, a preparation having a particle size of about 150; m was obtained by pulverization and classification.

Test example 1

Examination of gastric retention by polymer having pH-dependent adhesion

The preparations prepared in Example 1 and Comparative Example 1 were suspended in 10% (W / V) of 1 solution in Japan Pharmacopoeia and suspended in a 24-hour fasted rat (SD system, 8 weeks old). Was administered 2 mL, and 3 hours later, the stomach was removed and a formulation that remained in the stomach was examined. As a result, it was confirmed that the yellow preparation was retained in the stomach of the preparation of Example 1 for 1 and 3 hours, but the preparation of Comparative Example 1 was confirmed to be a yellow preparation in the stomach after 1 hour could not. From the results, it was confirmed that the retention of the drug in the gastric mucosa required the inclusion of methacrylic acid-methyl methacrylate copolymer.

Test example 2

Examination of adhesion by particle size

A solution in which each preparation with different particle size prepared in Reference Example 1 was suspended at a concentration of 10% (W / V) in 1 solution of JP to human fibroblasts cultured in a confluent state on a plastic slip. 2 mL was administered, the mixture was allowed to stand still for 1 minute, and the preparation was attached to the cells. After the adhesion, the plastic slip was washed in one solution of the Japanese Pharmacopoeia, and after washing, the weight of the formulation remaining on the plastic slip was measured to calculate the amount of the formulation attached. From the obtained amount of adhesion, the coated area of the preparation was calculated by the following formula, and the adhesion of the preparation to cells was determined. <Calculation formula>

Particle size: r, Specific gravity of preparation: d, Amount of coating: W

Weight of one particle: W = 4Z3 X7T X (r / 2) ³ xd Number of adhered particles: N = W / w

Covering area per particle: S = 7T X (r / 2) ²

Total coverage: S = Nx s

The results are shown in FIG. From these results, it was found that the adherence of the preparation to the cells did not show any change in the adhesion up to a particle diameter of 200 μm, but that the adhesion gradually decreased when the particle diameter exceeded 200 μm. Above m, no adhesiveness of the preparation was observed. From this, it can be seen that the pH-dependent adherence of the drug product is in the range up to a particle size of about 300 m, and that a certain high adherence can be obtained especially up to a particle size of about 200 / m. confirmed.

Test example 3

The pH is different between the preparation containing methacrylic acid-methyl methacrylate copolymer prepared in Reference Example 1 and having a particle size of 150 μm, and the comparison preparation containing an acrylic acid polymer prepared in Comparative Example 2 Adhesion to human fibroblasts in solution was examined. The results are shown in FIG.

From the results, the preparation containing methacrylic acid-methyl methacrylate copolymer shows good adhesion in JP 1 (pH 1.2), but no adhesion in saline adjusted to pH 6. Was. On the other hand, in the comparative preparation containing the acrylic acid-based polymer, no difference was observed in the adhesiveness depending on the pH. From this, it was confirmed that the adhesiveness of the methacrylic acid-methyl methacrylate copolymer was pH-dependent and had high local selectivity.

Test example 4

Drug transferability due to mucosal adhesion

A 20% gelatin solidified as a gastric mucosa model is placed in a solution, on which the gastric and / or duodenal mucoadhesive preparation prepared in Example 1 5 Omg (1 mg as lipoflavin phosphate) and riboflavin phosphate drug substance lmg each, and stirred at 25 rm to eliminate the concentration gradient. The physical quantity was measured. The results are shown in FIG.

From the results, it was confirmed that the administration of the stomach and Z or duodenal mucosa-adhesive preparations showed higher translocation than the drug substance administration. From this result, it was confirmed that more efficient pharmacological action can be obtained and the dose can be reduced by directly attaching the preparation and releasing the drug.

Test example 5

Effects of AMOX-containing gastric and / or duodenal mucoadhesive preparations

The AMO X-containing stomach and Z or duodenal mucosa-adherent preparations [①, ② and 中 in Table 3] produced in Example 2 were suspended in a 0.1% tragacanth solution to prepare a preparation administration solution. AMOX bulk powder was suspended in the same solution to prepare a drug substance administration solution. 2 (hereinafter abbreviated as HP) 4 hours fasted d dY mice Helicobacter one pylori the ATC C 43504 were infected in orogastric (1 0 ⁹ bacteria count X 3 / mouse) formulations and drug substance administered after 27 days The solutions were prepared so that AMOX was 0.1 mgZkg (using formulation I) and lmgZkg (using formulation I and II), respectively, and orally administered for 5 consecutive days. 24 hours after the final administration, the stomach was removed, and the stomach crushed solution was inoculated on an HP selection medium, cultured under microaerobic conditions for 8 days, and the number of viable bacteria was measured. Figure 4 shows the measured HP numbers. From the results, it was confirmed that the group to which the AMOX-containing stomach and Z or duodenal mucosa-adhesive preparations had a higher eradication effect than the group to which the drug was administered.

Test example 6

Eradication effect of AMOX-containing stomach and / or duodenal mucosa-adhesive preparations by release time Adhesion of AMOX-containing stomach and Z or duodenal mucosa produced in Example 2 to HP-infected dd Y mice by the same method as in Test Example 4. The active pharmaceutical preparations [1] and [3] in Table 3 were each suspended in a 0.1% tragacanth solution, adjusted to have an AMOX of 0.1 mg / kg, and administered continuously for 5 days. The number of viable bacteria was measured in the same manner as in Test Example 5, and the results are shown in FIG. The results showed that the two AMOX-containing stomach and / or duodenal mucosa-adhesive preparations that were administered had higher levels of eradication than those that were administered as the drug substance. Formulation (2), which had a longer release time of AMOX (6 hours), had a higher eradication effect than formulation (3), which had a shorter release time (2 hours). From this, it was recognized that more effective eradication can be achieved by controlling the release of the drug.

Example 3

In 20 mL of ethanol, 6 g of a methacrylic acid-methacrylic acid copolymer (trade name: Fludragit L100) and 1.2 g of triethyl citrate were added and dissolved well. Then, tetraglycerol monostearate was added. g, mixed and dried, and then crushed and classified to obtain a preparation of 150; m.

Example 4

In 20 mL of ethanol, 6 g of methacrylic acid-methacrylic acid copolymer (trade name: Hydrodite L100) and 1.2 g of triethyl citrate are dissolved, and 8 g of stearic acid is added. After mixing, drying, and pulverizing * classifying operation, a preparation of 150 m was obtained.

When the adhesion of the preparations obtained in Examples 3 and 4 was tested in the same manner as in Test Example 3, it was confirmed that the adhesion of these preparations was pH-dependent and had high local selectivity. Industrial applicability

The gastric / duodenal mucosa-adhesive pharmaceutical composition of the present invention has pH-dependent adhesive properties, and directly adheres to the gastrointestinal mucosa under acidic conditions, and has a high retention in the gastrointestinal tract. Therefore, the drug can be directly released from the drug product to the stomach and the Z or duodenal mucosa, and it also has controlled release, so that a sustained release can be obtained. It can be efficiently transferred into the intestinal mucosa. Therefore, a sufficient effect can be obtained with a low dose, so that the safety is high and the medicinal ingredient can be used effectively.

Claims

The scope of the claims

1. A composition containing a drug that acts on the stomach and z or the duodenum and a component selected from water-insoluble polymer, polyglycerin fatty acid ester, lipid and wax, has an ability to adhere to the gastrointestinal mucosal surface under acidic conditions. A stomach / duodenal adhesive pharmaceutical composition which is coated with a polymer which is neutral or alkaline and which is detached from the gastrointestinal mucosa.

2. A composition containing a drug that acts on the stomach and Z or duodenum, and a component selected from a water-insoluble polymer, a polyglycerol fatty acid ester, a lipid, and a box, comprises converting the drug into a water-insoluble polymer, a polyglycerin fatty acid ester, 2. The pharmaceutical composition according to claim 1, which is coated with a component selected from lipids and phenols.

3. A polymer that has an adhesive ability to the gastrointestinal mucosa surface under acidic conditions and is detached from the gastrointestinal mucosa in a neutral or neutral state and has a dissolution pH of 4 or more and has an anionic group. 3. The pharmaceutical composition according to claim 1, which is:

4. Claim drugs acting in the stomach and Z or duodenum, antacids, gastric mucosa protective agents, H ₂ blockers, proton bomb inhibitors evening one, in which Bareru selected from antimicrobials and Urea Ichize inhibitor The pharmaceutical composition according to any one of claims 1 to 3.