MXPA00008147A - Medicinal compositions adhering to stomach/duodenum - Google Patents

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

MEDICINAL COMPOSITIONS THAT ADHERE TO THE STOMACH / DUODENUM TECHNICAL FIELD The present invention relates to a pharmaceutical composition that adheres only to a gastric mucosa and a duodenal mucosa and controls the release of its medication.

PREVIOUS TECHNIQUE When considering the effective use of a medicament, a controlled preparation in the release of the medicament therefrom, particularly a sustained release preparation, has great advantages, such as decreasing the frequency of administration, maintaining the blood level by a predetermined time and the like, because you can continuously release the medication for long hours. Therefore, sustained release preparations have been investigated in several aspects. Since the medication of a sustained-release preparation is absorbed primarily in the intestine, many of the preparations are designed to gradually release the medication, while passing through the entire digestive system. On the contrary, preparations designed to exhibit their effectiveness not after being absorbed by the intestine, but topically in the stomach or duodenum, are not many. As a preparation designed to make the drug act in the stomach, a preparation having intragastric retention that is enhanced by imparting a floating property has been reported (Daviss SS et al., Pharm.Recom 208-213 (1986)), preparation whose contact ratio to the surface of a mucosa has been improved by increasing the specific gravity thereof (Devereux JE et al., Pharmacol, 42, 500-501 (1990)) and the like. These preparations are not sufficient, however, in terms of retention. In addition, a preparation which adheres to the mucosa of a digestive apparatus has been proposed by gelation of a polymer, which has been incorporated into the preparation, with water (Japanese Laid-Open Patent Application No. Hei 5-132416). However, this preparation lacks the selectivity of adhesion to a specific digestive system, so that it is impossible to adhere this preparation only to the gastric and duodenal mucosa. An object of the present invention is therefore to provide a preparation that adheres only to the gastric or duodenal mucosa, is controlled in the release of its medicament and has excellent pharmacological effects selectively for the stomach and duodenum.

BRIEF DESCRIPTION OF THE INVENTION With the above in mind, the inventors of the present have carried out extensive research. As a result, it has been found that by controlling the release of a medicament with an ingredient selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, and imparting to the medicament selective adhesion capability only to the gastric and duodenal mucosa, using a polymer that adheres to the mucosal surface of a digestive system under acidic conditions, but does not adhere to neutral or alkaline conditions, the drug acts on the gastric and duodenal mucosa for long hours, but is quickly excreted from the intestine, which makes it possible to provide a preparation exhibiting high pharmacological action at a low concentration of the drug, leading to compliance with the present invention. The present invention therefore provides a gastric and / or duodenal adhesive pharmaceutical composition which is obtained by coating a composition containing a medicament that exhibits action in the stomach and / or duodenum and an ingredient selected from water-soluble polymers, esters of fatty acids of glycerin, lipids and waxes, with a polymer that has the capacity to adhere to the mucosal surface of a digestive system under acidic conditions, but is separated from the mucosa of the digestive system under neutral or alkaline conditions.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the relationship between the particle size of a preparation and its adhesion ratio to cells Figure 2 illustrates the relationship between pH and adhesion Figure 3 illustrates the transition from a drug to gelatin Figure 4 illustrates the effects of eradication Figure 5 illustrates the effects of eradication of preparations of different release time BEST MODALITIES FOR CARRYING OUT THE INVENTION Although no particular limitation is imposed on the polymer having adhesive capacity to the surface of a gastric and / or duodenal mucosa under acidic conditions and it is separated from the mucosa of a digestive apparatus under neutral or alkaline conditions (said polymer will be called successively in the present "pH-dependent adhesive polymer"), polymers which are soluble in a solution of at least pH 4 and have an anionic group are preferred. Examples of such pH-dependent adhesive polymer include (1) natural polymers, purified lacquer and white lacquer, and (2) synthetic polymer polymers derived from cellulose hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate-tnmelitate, cellulose acetate phthalate, etc. Polymer acrylic polymers obtained from acrylic acid and / or methacrylic acid, and a carboxylic ester, etc., and polymers of the type of the alcohol with vinyl acetate acetate-phthalate, etc. As the pH-dependent adhesive polymers used in the present invention, those having a carboxyl group are particularly preferred, those which are obtained from acrylic acid and / or methacrylic acid being preferred and preferred still more those obtained from acrylic acid and / or methacrylic acid and a carboxylic ester Examples of the carboxylic esters used herein include acrylic esters and methacrylic esters, such as methyl acrylate, ethyl acrylate, n-acplate propyl, isopropyl acrylate, n-butyl acnlate, isobutyl acrylate, t-butyl acplate, acnla 2-H? drox? et? lo, 2-hydroxypropyl acyl, methyl metacuplate, ethyl metacplato, n-propyl metacplato, isopropyl metaplatto, 2-h? drox metacplato? ethanol, 2-hydroxy-propyl methanolate, n-butyl metaccate, isobutyl meta-platelet and t-butyl meta-plate Among them, a copolymer of methacrylic acid-methyl methaclet is preferred, this having a methacrylic acid content of 20 to 60%, particularly preferred, for example, Eudragit L100 or S100 These pH-dependent adhesive polymers can be used either individually or in combination. In the present invention, the ingredient selected from water-soluble polymers, polyglycerin fatty acid esters, lipids and waxes (which may be referred to hereinafter as the present invention). "water-insoluble ingredient") is an ingredient to control the release of active ingredients. No particular limitation is imposed on the water-insoluble polymers used in the present invention to the extent that they are sustained release bases ordinarily employed for the preparations. These polymers can be used either individually or in combination. As such polymers, the following may be mentioned by way of example. Polymers of the cellulose type: crystalline cellulose, ethylcellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate-succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc. Among them, ethylcellulose is particularly preferred. No particular limitation is imposed on the polyglycerin fatty acid esters in the present invention and polyglycerin fatty acid esters, such as di-, tri- or higher glycerin can be used. As the fatty acid portion of polyglycerin fatty acid esters, CM fatty acids are preferred, while as the polyglycerin portion, they are preferred from diglycerin to icosaglycerin. The specific examples of the fatty acid esters of polyglycrylics include diglyclen monostearate, tetraglycope monostearate, hexagon-ceposyl monostearate, decagliceplo monostearate, Tetraglyceroltenestearate, tetraglyceryltetearate, decagliceplopenteteate, tetraglycopepentastearate, hexaglopentanostearate, hexagloheleneoleate, decaghele monooleate, glycerol dioleate, tetraglycol pentaoleate, hexagonhexyl pentoleate, tngliceplo noleate , tetra-tetracephalic noleate, hexagrohexolelate, tetraglycollo monopalmitate, hexaglopella monopalmitate, decagliceplo monopalmitate, tetraglycollopalpramitate and hexagyl cerylpapillate The examples of the lipids used in the present invention include higher fatty acids and salts of the same, higher alcohols and glycine esters of fatty acids and those of the waxes include hydrocarbon waxes. Examples of the higher saturated fatty acids or salts thereof include C8 fatty acids and salts thereof, such as stearic acid. , magnesium stearate and aluminum stearate The examples of higher alcohols i C1024 aliphatic alcohols such as alcohol stearate and alcohol are included. As fatty acid esters of fatty acids, not only are they used with a fatty acid, but also monoglycerides and dig cements with the same. Examples of the waxes include carnauba wax and beeswax, while that of hydrocarbons include microcpstalin wax and paraffin The water insoluble ingredients described can be used above, ie water-insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, either individually or in combination. For the purpose of freely controlling the release of the drug from a preparation, a water soluble polymer can be added in any ratio to the water-insoluble ingredient described above. Examples of such polymers include polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, copolymers of aminoalkyl methacrylate and polyvinylacetal diethylaminoacetate. In order to freely control the releasability in the present invention, the water-soluble polymer is preferably added in an amount ranging from 0.1 to 60% by weight to the water-soluble ingredient described above. As the drugs used in the present invention, drugs that act on the stomach or duodenum are suitable. Examples of such medications include antacids, gastric mucosal protectors, H blockers, proton pump inhibitors (PPIs), antibiotics and urease inhibitors. Examples of the antacids used in the present invention include magnesium hydroxide and aluminum magnesium silicate. Examples of the gastric mucosa protectants used in the present invention include methylmethionine sulfonylchloride (M SC), calcium-sodium, sucralfate and cetraxate-hydrochloride.

Examples of the H2 blockers used in the present invention include famotidine, cimetidine, roxatidine acetate, and ranitidine. Examples of the PPIs used in the present invention include omeprazole and lansoprazole. Examples of the urease inhibitors used in the present invention include acetohydroxamic acid and capplohydroxamic acid Examples of the antibiotics used in the present invention include anti--He // active substances, pylop, bismuth salts and compounds of the quinolone type, of which the active substances are preferred to h-Helicobacter pylop Examples of the anti-Hehcobacter pylon substances include antibiotics of the penicillin type (such as amoxicillin and ampicillin), macrolides (such as eptromycin and claptromycin) and tetracycline-type antibiotics (such as tetracycline, minocycline and streptomycin). ) Among these antibiotics, antibiotics of the penicillin type, pr particularly amoxicillin (hereinafter abbreviated as "A OX") having a highly antibacterial property against Helicobacter pylop. In the compositions of the present invention, the content of the medicament can be determined, as needed, depending on the the nature of the medicament or the preparation Usually, a content of 0 to 95% by weight or more or less is preferred, with a range of 0 to 90% by weight being particularly preferred. The amount of use of the insoluble ingredient in the water depending on the nature of the ingredient, the time of release of the drug or the like. It is however preferred to incorporate it in an amount of 0.1 to 95% by weight in the composition, with 1 to 60% by weight being particularly preferred. The pH-dependent adhesive polymer incorporated is preferably incorporated in an amount of 0.1 to 95% by weight in the composition, with 1 to 50% by weight being particularly preferred. Additives ordinarily employed, used for the preparation of a solid pharmaceutical product, can be added to the compositions of the present invention. Examples include the following: (1) Excipients: lactose, corn starch, talc, powdered sugar, light anhydrous silicic acid, calcium carbonate, magnesium carbonate, etc. (2) Binders: starch, sucrose, gelatin, powdered acacia, carboxymethylcellulose, carboxymethylcellulose-sodium, hydroxypropylcellulose, hydroxypropylmethylcellose, polyvinylpyrrolidone, pullulan, dextin, etc. (3) Plasticizers: polyethylene glycol, triethyl citrate, etc. In addition, they can be used as additives, colorants, correctors, absorbers, antiseptics, humectants and antistatic agents. The amount of such additive can be determined, as needed, within a limit that does not impair the pH-dependent addition to the gastric mucosa or have adverse effects on the release of the drug. The compositions of the present invention comprise a medicament, an additive if necessary, and the insoluble ingredient described above and has been coated with a pH-dependent adhesive polymer. Here, the composition comprising a medicament, a necessary additive and the water-insoluble ingredient described above can be a composition having a medicament or a medicament-additive mixture coated with the water-insoluble ingredient described above or a matrix containing the medicament, a necessary additive and the water-insoluble ingredient described above as a mixture. However, the first is preferred. The term "coating" as used herein means not only the uniform coating of the entire surface of a particle, but also the partial coating of the surface of the particle. Although the time of release of the drug from the preparation can be freely determined, in consideration of the properties of the drug to be selected or the like, longer and longer release time is needed in order to fully exhibit the properties of the preparation, that is, to adhere to the gastric mucosa and allow the medication to act directly on it. In addition, the release of the drug is desirably completed, while the preparation has still been adhered and retained in the gastric mucosa. The influences of the gastric juice, the metabolism of the gastric epitheliocytes, the food and the like must be taken into consideration. It is necessary that the time of release of the drug from the preparation is from 2 to 8 hours, judging from the factors described above. The time of Release can be controlled by a ratio of the water-insoluble ingredient to a water-soluble polymer, the amount of the water-insoluble ingredient or the like. It is preferred that the particle size of the pharmaceutical composition of the present invention fall within a range of 30 to 300 μm from the point of view of adhesion to the gastric and / or duodenal mucosa, with a range of 75 to 300 μm, more preferably 100 to 250 μm, being particularly preferred. In the case in which the pharmaceutical composition of the present invention is a preparation coated with the water-insoluble ingredient described above, it is prepared, for example, by forming medicament-containing particles with a conventionally employed granulator or the like and then coating the particles with the water-insoluble ingredient described above and the pH-dependent adhesive polymer, successively. For granulation, fluidized bed granulation, high shear granulation, extrusion granulation and the like can be adopted. For the coating, a conventionally employed method may be adopted, such as a copper coating or fluidized bed coating. For the coating agent in the form of a solution or dispersion containing water or an organic solvent, spray coating can also be adopted. In the case where the composition containing a medicament and the water-insoluble ingredient described above is in the form of a matrix, it can be prepared by dissolving the water-insoluble ingredient described above in a suitable organic solvent, kneading the resulting solution with the medicament, and then drying and pulverizing the softened dough, or dissolving the water-insoluble ingredient previously described which contains the drug in a suitable solvent, dispersing the resulting solution in a solution immiscible with the solvent and then evaporating the solvent by heating to form particles, and then coating the particles with pH-dependent adhesive polymer. There is no particular limitation imposed on the nature of the solvent Organic Examples include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and halogenated hydrocarbons such as chloroform and dichloromethane. In the coating agent or matrix, the additive described above or the like can be incorporated.

EXAMPLES The present invention will be described hereinafter herein more specifically by examples and tests. It should be noted however that the present invention is not limited by these examples.

EXAMPLE 1 In accordance with the formulation shown in Table 1, an adhesive preparation was prepared to the gastric and / or duodenal mucosa using a fluidized bed coater. Namely, at 3000 g of anhydrous calcium phosphate acid (average particle size: 150 μm), a solution of 75 g of riboflavin phosphate was sprinkled in 3 liters of water and dried, followed by the spraying and drying. coating a solution of 400 g of ethylcellulose in 4 liters of ethanol. After drying, a solution of 500 g of a copolymer of methacrylic acid-methyl methacrylate ("Eudragit L100", trade name) and 50 g of triethyl citrate in 5 liters of ethanol was sprayed for coating, whereby prepared a yellow adhesive preparation to the gastric and / or duodenal mucosa 1.

COMPARATIVE EXAMPLE 1 In a manner similar to that of Example 1, a solution of 75 g of riboflavin phosphate in 3 liters of water to 3000 g of anhydrous calcium phosphate acid (average particle size: 150 μm) and dried, followed by coating only with a solution of 400 g of ethyl cellulose in 4 liters of ethanol, whereby the comparative preparation 1 was obtained.

TABLE 1 REFERENCE EXAMPLE 1 According to the formulation shown in Table 2, adhesive compositions were prepared to the gastric and / or duodenal mucosa. Namely, 20 g of methacrylic acid-methyl methacrylate copolymer ("Eudragit L100", trade name) and 2 g of triethyl citrate were dissolved in 50 ml of ethanol, followed by the addition of 25 g of a medicament and 75 g of an excipient. The resulting mixtwas mixed thoroughly under heating at 60 ° C and then dried. The dried mixtwas sprayed, followed by sorting, whereby preparations were obtained with average particle sizes of about 30, 70, 100, 150, 200, 270, 325, 350 and 400 μm, respectively.

TABLE 2 EXAMPLE 2 In a fluidized bed granulator, 250 g of A OX and 250 g of an excipient were charged, of the ingredients shown in Table 3, followed by spraying thereto a solution of 40 g of ethyl cellulose in 400 ml of Ethanol and granulation. Then, the resulting granules were coated with a solution of 150 g of ethylcellulose in 1.5 liters of ethanol and then with a solution of 125 g of methacrylic acid-methyl methacrylate copolymer ("Eudragit L100", trade name) and 25 g of triethyl citrate in 1.5 liters of ethanol, whereby a preparation was formed. The resulting preparation was then classified, whereby spherical fine particles not passing through the 150 mesh, but from the 80 mesh (which will be abbreviated hereinafter as "80 mesh") were obtained as preparation (1). 150"). Then, 41.9 g of AMOX and 458.1 g of a excipient in a fluidized bed granulator, followed by granulation. The resulting granules were coated in a manner similar to that described for preparation (1), whereby preparation (2) was obtained. In the third place, 41.9 g of AMOX and 458.1 g of an excipient in a fluidized bed granulator were charged and granulated in a manner similar to that described for preparation (2), followed by coating with a solution of 112 g. of ethylcellulose and 38 g of polyethylene glycol 6000 in 1.5 liters of ethanol for the control of the releasability. The copolymer of methacrylic acid-methyl methacrylate ("Eudragit L100", trade name) was coated in a manner similar to that described for preparation (1) or (2), whereby preparation (3) was obtained. Fourth, 250 g of AMOX and 250 g of an excipient were loaded into a fluidized bed granulator, followed by the granulation in a manner similar to that of (1). The resulting granules were coated with ethylcellulose and then with a solution of methacrylic acid-methyl methacrylate copolymers ("Eudragit L100", trade name: 93.7 g, "Eudragit S100", trade name: 31.3 g) and 25 g of ethyl acetate. triethyl in 1.5 liters of ethanol, whereby the preparation (4) was obtained.

TABLE 3 COMPARATIVE EXAMPLE 2 Using a polymer forming a gel with water, said polymer being described in Japanese Laid-open Patent Application No. Hei 5-132416, an adhesive preparation was prepared to the mucosa of a digestive apparatus. Specifically described, 85 g of stearic acid was dissolved at 70 ° C, followed by the addition of 15 g of a polymer of the acrylic acid type ("Hibiswako 104", trade name). After mixing thoroughly for 10 minutes, the resulting mixture was cooled and solidified. The resulting solid was subjected to sputtering and classification, whereby a preparation having a particle size of about 150 μm was prepared.

TEST 1 Investigation of intragastric retention produced by a pH-dependent adhesive polymer Each of the preparations obtained in Example 1 and Comparative Example 1 was suspended in an amount of 10% (P?) In the first liquid JP. They were administered to rats (SD rats, eight weeks old) fasting for 24 hours, 2 ml of the resulting suspension. After one hour and three hours respectively of the administration, the stomach was excised and the retention of the preparation in the stomach was investigated. As a result, the retention of the yellow preparation of Example 1 in the stomach was confirmed after one hour and three hours respectively of the administration, whereas the retention of the yellow preparation of Comparative Example 1 was not confirmed after one hour. From the results, it has been confirmed that the addition of a copolymer of methacrylic acid-methyl methacrylate is necessary for the retention of the preparation in the gastric mucosa.

TEST 2 Investigation of adhesion dependent on particle size Each of the preparations obtained in reference example 1, which deviated in particle size, was suspended in an amount of 10% (P / V) in the first liquid JP. 2 ml of the resulting suspension was administered to human fibroblasts that had been grown on a plastic slide to the confluent condition. Leaving it in total rest for one minute, the preparation adhered to the cells. After adhesion, the plastic slide was washed in the first JP liquid. Then, the weight of the preparation remaining on the plastic slide was measured and the amount of the preparation was calculated. In addition, from the adhered amount, the covered area of the preparation was calculated according to the following formula as an indication of the adhesion of the preparation to the cells.

Calculation formula Particle size: r, specific gravity of preparation: d, adhered quantity: W. Weight per particle: w = 4/3 xpx (r / 2) 3 xd Number of particles adhered: N = W / w Area covered by a particle: s = px (r / 2) 2. Total covered area: S = N x s.

The results are shown in Figure 1. From the results, with respect to the adhesion of the preparation to the cells, no change in the adhesion of the particles having a particle size up to 200 μm was recognized, the gradual deterioration of adhesion on particles having a particle size greater than 200 μm and adhesion was not recognized on particles having a particle size of 350 μm or greater. From the above finding, it has been confirmed that the pH-dependent adhesion of the preparation takes place within a particle size of up to 300 μm or more or less and that consistently high adhesion is obtainable when the particle size is up to 200. μm or more or less.

PROOF 3 Adhesion to human fibroblasts was studied in each of the solutions of different pH using the preparation of reference example 1 containing a copolymer of methacrylic acid-methyl methacrylate and having a particle size of 150 μm and the comparative preparation which contained a polymer of the acrylic acid type and prepared in Comparative Example 2. The results are shown in Figure 2.

For the results, the preparation containing a copolymer of methacrylic acid-methylmathacrylate exhibited good adhesion in JP1 (pH 1.2), but no adhesion was observed in a physiological saline solution adjusted to pH 6. The comparative preparation containing a polymer of the acrylic acid type exhibited, on the other hand, no pH-dependent adhesion difference. From the above finding, it has been recognized that the adhesion produced by the copolymer of methacrylic acid-methyl methacrylate depends on the pH and has high topical selectivity.

TEST 4 Transition of the drug by mucoadhesion A 20% solidified gelatin was placed in a solution as a model of gastric mucosa. Gelatin was administered 50 ml (1 mg in terms of rivoflavin phosphate) of adhesive preparation for the gastric and / or duodenal mucosa prepared in example 1 and 1 mg of rivoflavin phosphate, followed by stirring at 25 rpm. to eliminate a concentration gradient. After one hour and three hours, amounts of the drug transferred to the gelatin were measured, respectively. The results are shown in Figure 3. From the results, the highest transition in the gelatin administered with the adhesive preparation for the gastric and / or duodenal mucosa compared to that administered with the solution was confirmed, indicating that action can be achieved more effective pharmacological and dosage can be reduced by adhering the preparation directly to the stomach and / or deudeno and releasing the drug from the preparation.

TEST 5 Effects of the adhesive preparation containing AMOX for the gastric mucosa v / o deodenal Each of the adhesive compositions to the gastric and / or deodenal mucosa containing AMOX [(1), (2) and (4) in Table 3] prepared in Example 2 was suspended in a 0.1% tragacanth solution for its use as a solution to administer the preparation. In a similar tragacanth solution, the AMOX powder was suspended for use in a dispensing solution. A fasting ddY mouse for 24 hours was infected orally and endogastrically with Helicobacter pylori ATCC 43504 (hereinafter abbreviated as "HP", 109 viable count per 3 / mouse). After 27 days, the respective preparation solutions and the solution were adjusted so that they contained AMOX in amounts of 0.1 mg / kg (preparation (2)) and 1 mg / kg (preparations (1) and (4)) and were administered then orally for 5 full days. From the mouse, its stomach was excised 24 hours after the final administration and a solution of the disintegrated stomach was inoculated onto an HP selective medium. After incubation for 8 days under microaerophilic conditions, the viable count was measured. The viable HP count is shown in Figure 4. From the results, it has been confirmed that, compared to the group administered with the solution administration group, the group administered with the gastric and / or deodenal adhesive preparation containing AMOX exhibited effects of highest eradication.

TEST 6 Effects of eradication of the adhesive preparation of the gastric mucosa v / o duodenal which contains AMOX depending on the time of release.

Each of the adhesive preparations of the gastric and / or duodenal mucosa containing AMOX [(2) and (3) in Table 3] prepared in Example 2 was suspended in a suspension of 0.1% tragacanth. The resulting suspension was adjusted to contain AMOX in an amount of 0.1 mg / kg, followed by administration for 5 full days to a ddY mouse infected with HP in a manner similar to that of test 4. The viable count was measured as in test 5 and the results are shown in figure 5. From the results, it was recognized that adhesive preparations of gastric and / or duodenal mucosa containing AMOX had higher eradication effects than the solution. In addition, it was recognized that preparation (2) with a longer release time of AMOX (6 hours) had higher eradication effects than preparation (3) with a shorter AMOX release time (2 hours). From the above finding, it has been recognized that effective eradication can be carried out by controlled release of a drug.

EXAMPLE 3 In 20 ml of ethanol, 6 g of a copolymer of methacrylic acid-methyl methacrylate ("Eudragit L100", trade name) and 1.2 g of triethyl citrate were charged and completely dissolved. To the resulting solution was added 8 g of tetraglyceride monostearate. After drying, the resulting mixture was subjected to granulation and classification, whereby a preparation having an average particle size of 150 μm was obtained.

EXAMPLE 4 In 20 ml of ethanol, 6 g of a copolymer of methacrylic acid-methyl methacrylate ("Eudragit L100", trade name) and 1.2 g of triethyl citrate were charged and dissolved. The resulting solution was mixed with 8 g of stearic acid. After drying, the mixture was granulated and classified, whereby a preparation having an average particle size of 150 μm was obtained. The adhesion of the preparations obtained from Examples 3 and 4 was tested in a manner similar to that of Test 3. As a result, it has been recognized that the adhesion of those preparations depends on the pH and has high topical selectivity.

Operational capacity in the industry The adhesive pharmaceutical composition of the gastric and / or duodenal mucosa according to the present invention exhibits pH-dependent adhesion, so that it adheres directly to the mucosa of the digestive system under acidic conditions and has high retention in the digestive system, which makes it possible to release the drug from the preparation directly to the mucosa of the stomach and / or the duodenum; and it also exhibits a controlled release property, which allows the continuous release of the drug and the effective transition of the active ingredients to the gastric and / or duodenal mucosa. Sufficient effects can be achieved with a smaller dosage, so that the preparation has high safety and allows the effective use of the active ingredients.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - A gastric and / or duodenal adhesive pharmaceutical composition obtained by coating a composition, comprising a medicament that acts in the stomach and / or duodenum and one or more ingredients selected from water-insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, with a polymer that has adhesive capacity on the mucosal surface of a digestive system under acidic conditions and separates the mucosa from the digestive system under neutral or alkaline conditions.

2. A pharmaceutical composition according to claim 1, further characterized in that the drug has been coated with one or more of the ingredients selected from water-insoluble polymers, fatty acid esters of polyglycerin, lipids and waxes.

3. A pharmaceutical composition according to claim 1 or 2, further characterized in that the polymer that has adhesive capacity on the mucosal surface of a digestive system under acidic conditions and that separates from the mucosa of the digestive apparatus in neutral conditions or alkaline is soluble in a solution of at least pH 4 and has an anionic group.

4. - A pharmaceutical composition according to any of claims 1 to 3, further characterized in that the drug is selected from antacids, gastric mucosa protectors, H2 blockers, proton pump inhibitors, antibiotics and urease inhibitors.