BG64499B1 - Pharmaceutical adhesive compositions to stomach and/or duodenum - Google Patents

Abstract

The invention relates to a composition adhering to the stomach-duodenum mucous membrane wherein release of the active substance is possible for a long period of time. Sufficient effect is attained of the active substance using a small dose. The composition contains active substance acting in the stomach and/or the duodenum, and a component selected from among water-insoluble polymers, polyglycerol fatty acid esters, lipids and waxes; it is covered by a polymer which is capable of adhering to the surface of the mucous membrane of the digestive tract under acidic conditions and to be reduced under neutral or alkaline conditions.

Description

(54) PHARMACEUTICAL ADHESIVE COMPOSITION FOR STOMACH AND / OR DODENUM

Technical field

The invention relates to a pharmaceutical composition which adheres only to gastric mucosa and duodenal mucosa and is controlled upon release of its drug.

BACKGROUND OF THE INVENTION

When considering the effective use of a drug, a drug-controlled drug, especially a sustained-release drug, has great advantages, such as reducing the frequency of administration, maintaining blood levels for a predetermined time, and others, since it may be prolonged. releases the drug for a long time. The maintenance of drug release has been investigated from various aspects.

Because sustained release medicine is predominantly absorbed in the gut, many of the formulations are intended as a gradual release drug as they pass through the entire digestive tract. In contrast, preparations designed to be effective not after adsorption by the intestine but locally into the stomach or duodenum are not many.

As a drug intended to cause a drug to act on the stomach, it is known that there is a drug that has an increased retention within the stomach by transmitting it with a changing property (Daviss SS et al. Pharm. Res. 208-213 (1986)) , a preparation whose contact with respect to the mucosal surface is enhanced by increasing its specific attraction (Devereux JE et al. Pharmacol., 42,500-501 (1990)) and others. However, these preparations are not sufficient to contain them.

In addition, a preparation which adheres to the mucosa of the digestive tract by gelation of a polymer incorporated in the preparation is supplied with water (Japanese Patent Application Laid Open No. Hei 5 -132416). This preparation has no adhesive selectivity for the intended digestive tract, so it is impossible to adhere only to the gastric and duodenal mucosa.

It is an object of the invention to provide a formulation which adheres only to the gastric and duodenal mucosa, to control its release upon release of the drug, and to have improved pharmacological effects selective for the stomach and duodenum.

This objective is achieved by establishing that by controlling drug release by a component selected from water-insoluble polymers, polygspiceric fatty acid esters, lipids and waxes, and transmitting the drug with selective adhesion only to the gastric and duodenal mucosa by use of a polymer that adheres to the surface of the mucosa of the digestive tract under acidic conditions but does not adhere under neutral or alkaline conditions, the drug acts on the stomach and duodenum mucosa for a long time, but is quickly excreted from the intestine, which makes it possible to provide a drug exhibiting high pharmacological action at low drug concentration.

The invention provides a pharmaceutical adhesive composition for the stomach and / or duodenum, obtained by coating a composition comprising a medicament exhibiting effects on the stomach and / or duodenum and a component selected from water-insoluble polymers, polystyrene fatty acid esters, lipids and waxes, with a polymer which has an adhesive capacity to the surface of the digestive tract mucosa under acidic conditions but is separated from the mucosa of the digestive tract under neutral or alkaline conditions.

Explanation of the annexed figures

Figure 1 represents the relationship between the particle size of the preparation and its adhesion to cells;

Figure 2 shows the relationship between pH and adhesion;

Figure 3 - conversion of the drug into gelatin;

figure 4 - removal of effects;

Figure 5 - elimination of effects of preparations that differ in release time.

SUMMARY OF THE INVENTION

Although no particular restriction is required on a polymer which has an adhesive ability to the surface of gastric and / or duodenal mucosa under acidic conditions and is separated from the mucosa of the digestive tract under neutral or alkaline conditions (this polymer is hereinafter referred to as "pH" -dependent adhesive polymer ”), polymers that are soluble in solution with at least pH 4 and have an anionic group are preferred. Examples of such a pH-dependent adhesive polymer include (1) Natural polymers: purified shellac and white shellac; and (2) Synthetic polymers:

Cellulose derivatives polymers: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethyl cellulose, cellulose acetate trimethylate, cellulose acetate phthalate and others.

Acrylic polymers:

polymers derived from acrylic acid and / or methacrylic acid, polymers obtained from acrylic acid and / or methacrylic acid and carboxylic ester, and others, and

Polyvinyl alcohol type polymers: polyvinyl acetate phthalate and others.

As the pH-dependent adhesive polymers used in the invention, those having a carboxyl group are particularly preferred, those derived from acrylic acid and / or methacrylic acid are more preferred and those obtained from acrylic acid and / or methacrylic acid and carboxylic ester are even more preferred. Examples of the carboxyl ester used herein include acrylic esters and methacrylic esters, such as methyl acrylate, ethyl acrylate, η-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, t -bugyl acrylase; 2-hydroxyethyl acrylase; 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, η-propyl methacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butyl methacrylate; isobutyl methacrylate and t-butyl methacrylate.

Among them, the methacrylic acid-methyl methacrylate copolymer is preferred, with a methacrylic acid content of 20 to 60%, for example Eudragit LIOOmjihSIOO is particularly preferred.

These pH-dependent adhesive polymers can be used alone or in combination.

In the invention, the component selected from water-insoluble polymers, polyglycerol fatty acid esters, lipids and waxes (hereinafter referred to as water-insoluble component) is a component for controlling the release of the active components.

There is no particular restriction on the water-insoluble polymers used in the invention as they are maintained to release bases commonly used for the formulations. These polymers can be used both alone and in combination. As such polymers, the following may be mentioned by way of example.

Cellulose type polymers: crystalline cellulose, ethyl cellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate, and the like. Among them, ethyl cellulose is particularly preferred.

There is no particular restriction on the polyglycerol fatty acid esters used in the invention and the polyglycerol fatty acid esters as such as di-, tri- or higher glycerol may be used. Such as fatty acid forming part of the polyglycerin fatty acid esters are preferred Cg_ ₃₀ fatty acids, while as polyglycerin portion is preferred to diglycerin eykozaglitserin.

Specific examples of polyglycerol fatty acid ester include diglyceryl monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate; Decaglyceryl monostearate, tetraglitseril tristearate, Decaglyceryl tristearag, tetraglitseril pentastearat, hexaglyceryl pentastearat, hexaglyceryl monooleate, Decaglyceryl monooleate, triglyceryl dioleate, tetraglitseril dioleate, tetraglitseril pentaoleate, hexaglyceryl pentaoleate, triglyceryl dilinoleat, tetraglitseril dilinoleat, hexaglyceryl dilinoleat, tetraglitseril monopalmitate, hexaglyceryl monopalmitag, Decaglyceryl monopalmitate , tetraglyceryl tripalmitate and hexaglyceryl tripalmitate.

Examples of the lipid used in the invention include higher fatty acids and their salts, higher alcohols and glycerol esters of fatty acids and those for wax include waxes and hydrocarbons. Examples of the higher saturated fatty acid or its salt include C ₈ - _iso fatty acids and salts thereof such as stearic acid, magnesium stearate and aluminum stearate. Examples of higher alcohols include C _{| 0-24} aliphatic alcohols, such as stearyl alcohol and cetyl alcohol. Not only fatty acid triglycerides but also monoglycerides and diglycerides can be used as the fatty acid glycerol ester. Examples of waxes include carnauba wax and beeswax, while those for hydrocarbons include microcrystalline wax and paraffin.

The water-insoluble components described, such as water-insoluble polymers, polyglycerol fatty acid esters, lipids and waxes, may be used alone or in combination.

With the intention of freely controlling the release of the drug from the preparation, a water-soluble polymer may be added in any ratio to the water-insoluble component described. Examples of such a polymer include polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, aminoalkyl methacrylic copolymers and polyvinyl acetal diethylaminoacetate.

It is possible for the free control of the release of the invention that the water-soluble polymer is preferably added to the water-insoluble component described in an amount ranging from 0.1 to 60% by weight.

As a medicament used in the invention are suitable drugs that act on the stomach or duodenum. Examples of such drugs include antacids, gastric mucosa protectors, Hj blockers, proton inhibitor inhibitors (PPIs), antibiotics, and urease inhibitors.

Examples of the antacid used in the invention include magnesium hydroxide and aluminum-magnesium silicate.

Examples of the gastric mucosa protector used in the invention include methyl methionine sulfonyl chloride (MMSC), ecabet sodium, sucralfare and cetraxate hydrochloride.

Examples of H ₂ blockers used in the invention include famotidine, cimetidine, roxatidine acetate and ranitidine.

Examples of PPIs used in the invention include omeprazole and lansoprazole.

Examples of the urease inhibitor used in the invention include acetohydroxamic acid and caprylohydroxamic acid.

Examples of the antibiotic used in the invention include anti-Helicobacter pyroli active substances, bismuth salts and quinoline type compounds, of which anti-Helicobacter pyroli active agents are preferred. Examples of anti-Helicobacter pyroli active substance include penicillin-type antibiotics (such as amoxicillin and ampicillin), macrolides (such as erythromycin and clarithromycin) and tetracycline-type antibiotics (such as tetracycline, minocycline and streptomycin). Among these antibiotics, a penicillin-type antibiotic is preferred, with amoxicillin (which will hereinafter be abbreviated as "AMOX") having a strong antibacterial property against Helicobacter pyroli, which is particularly preferred.

In the composition of the invention, the content of the drug may be determined as necessary depending on the nature of the drug or preparation. Typically, a content of 0.01 to 95% by weight is preferred, but particularly preferably 0.1 to 90% by weight. The amount of water-insoluble component used can be determined depending on the nature of the component, the release time of the drug, and others. However, it is preferred to introduce in an amount of from 0.1 to 95% by weight in the composition, but particularly preferably from 1 to 60% by weight. The pH-dependent adhesive polymer is preferably introduced into the composition in an amount of 0.1 to 95% by weight, with a particular preference of 1 to 50% by weight.

Commonly used additives for the preparation as a solid pharmaceutical substance may be added to the composition of the invention, for example:

(1) Inert filler: lactose, corn starch, talc, powdered sugar, loose anhydrous silicic acid, calcium carbonate, magnesium carbonate and others;

(2) Binder: starch, sucrose, gelatin, acacia powder, carboxymethyl cellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, pullulan, dextrin and the like;

(3) Plasticizer: polyethylene glycol, triethyl citrate and others.

In addition, colorants, pharmaceutical modifiers, adsorbents, antiseptics, humectants and antistatic agents may be used. The amount of such an additive can be determined as necessary in an amount that neither weakens the pH-dependent adhesion to the gastric mucosa nor has adhesive effects on the drug for release.

The composition of the invention includes a drug, an additive, if necessary, and the insoluble component described and is coated with a pH-dependent adhesive polymer. The composition includes a drug, a necessary additive, and the water-insoluble component described may be a composition having a drug or drug-additive mixture coated with the water-insoluble component described or a bulk containing the drug, the required additive, and the water-insoluble component described as a mixture. However, the guideline is preferred. The term "coating" as used herein means not only uniform coverage of the entire surface of the particle, but also partial coverage of the surface of the particle.

Although drug release time may be freely determined in accordance with the properties of the drug to be selected, and the like, a longer and longer release time is desirable, if possible, to exhibit the properties of the drug. of the preparation so that it adheres to the gastric mucosa and allows the drug to act directly on it. In addition, release of the drug is desirable to complete while the preparation is still adhered to and retained in the gastric mucosa. The effects of gastric juice, the metabolism of gastric epitheliocytes, food and others, of course, should be taken into account. The release time of the drug from the preparation is preferably 2 to 8 hours, depending on the assessment of the factors described. The release time can be controlled by the ratio of the water-insoluble component to the water-soluble polymer, the amount of the water-insoluble component, or the like.

The particle size of the pharmaceutical composition of the invention is preferably reduced in the range from 30 to 300 µm in terms of adhesion to the gastric and / or duodenal mucosa, and more preferably from 75 to 300 µm, in particular from 100 to 250 µm .

In the case where the pharmaceutical composition of the invention is a preparation coated with the water-insoluble component described above, it is prepared, for example, by forming a drug comprising particles of a conventionally used granulator or the like and subsequently sequentially coating the particles with the water-insoluble component described and pH-dependent adhesive polymer. For granulation, fluidized bed granulation, high shear granulation, extrusion granulation, and the like may be considered. A conventional method, such as mold coating or fluidised bed coating, may be adopted for coating. For the coating agent, the form of a solution or dispersion containing water or an organic solvent may also be taken.

In the case where the composition contains a drug and the water-insoluble component described is in the form of a base mass, it can be prepared by dissolving the water-insoluble component described in a suitable organic solvent, mixing the resulting solution with the drug, and then drying and atomizing the mixed mass, or dissolving the described water-insoluble component containing 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 a pH-dependent adhesive polymer.

There is no particular limitation of the organic solvent. Examples include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and halogenated hydrocarbons such as chloroform and dichloromethane. The described additive or the like may be introduced into the coating agent or base.

Examples of carrying out the invention

The invention is illustrated by the following non-limiting examples and tests.

Example 1. In accordance with the formulation shown in Table 1, an adhesive preparation for gastric and / or duodenal mucosa was prepared using a fluidized bed coating machine. A solution of 75 g of riboflavin phosphate in 3 L of water was sprayed onto 3000 g of anhydrous calcium hydrogen phosphate (average particle size: 150 pm) and dried, followed by spray and coating with a solution of 400 g of ethyl cellulose in 41 ethanol. After drying, a solution of 500 g of methacrylic acid-methyl methacrylate (trademark “Eudragit L100”) and 50 g of triethyl citrate in 5 l of ethanol was sprayed to coat to give a yellow adhesive preparation 1 for gastric and / or duodenal mucosa.

Comparative Example 1. Similarly to Example 1, a solution of 75 g of riboflavin phosphate in 31 water was sprayed into 3000 g of anhydrous calcium hydrogen phosphate (average particle size of 150 µm) and dried, followed by coating with only a solution of 400 g of ethyl cellulose in 4 L of ethanol to give comparative preparation 1.

Table 1

Adhesive preparation 1 Comparative preparation 1 Anhydrous calcium hydrogen phosphate (“FujikarinSG”, trade name) 3000 g 3000г Riboflavin phosphate 75g 75g Ethyl cellulose 400g 400 g Methacrylic acid copolymer methyl methacrylate (“Eudragit L 100”, trade name) 500 g - Triethyl citrate 50g -

Reference Example 1. In accordance with the formulation shown in Table 2, adhesive compositions for gastric and / or duodenal mucus goat are prepared. 20 g of methacrylic acid-methyl methacrylate copolymer ("Eudragit L 100", trade name) and 2 g of triethyl citrate are dissolved in 50 ml of ethanol, followed by the addition of 25 g of drug and 75 g

Table 2 excipient. The resulting mixture was thoroughly stirred at 60 ° C and then dried. The dried mixture was transformed into a powder followed by a classification to give preparations having an average particle size of about 30,70,100,150,200,270,325,350 and 400 µm.

Barium sulphate 25 g Cornstarch 75 g Methacrylic acid-methyl copolymer methacrylate ("Eudragit L 100", commercial name) 20 g Triethyl citrate 2 g (Ethanol) 50 ml

Example 2. A fluidized bed granulator was fed 250 g of AMOX and 250 g of excipient, outside the components shown in Table 3, followed by sprayed with a solution of 40 g of ethyl cellulose in 400 ml of ethanol and granulation. The resulting granules were then coated with a solution of 150 g ethyl cellulose in 1.51 ethanol and then with a solution of 125 g methacrylic acid copolymer methyl methacrylate ("Eudragit L 100", trade name) and 25 g triethyl citrate in 1.51 ethanol, whereby the preparation is formed. The resulting preparation is classified by which spherical fine particles pass through a sieve with mesh sizes of not more than 150 mesh but not less than 80 mesh (hereinafter abbreviated as "80/150 mesh") to form a preparation (1). Next, 41.9 g of AMOX and 458.1 g of excipient were fed into the fluidized bed granulator followed by granulation. The resulting granules are coated similarly to that described for preparation (1), thereby producing preparation (2). Thirdly, 41.9 g of AMOX and 458.1 g of inert filler were introduced into the fluidized bed granulator and similarly granulated to that described for preparation (2), followed by coating with a solution of 112 g of ethyl cellulose and 38 g of polyethylene glycol 6000 in 1.51 ethanol to control release. It is coated with a methacrylic acid-methyl methacrylate copolymer ("Eudragit L100", trade name) in a similar manner to that described for preparation (1) or (2), thereby producing preparation (3). Fourth, 250 g of AMOX are fed into the fluidized bed granulator and

250 g of excipient, followed by granulation in a similar manner to preparation (1). The resulting granules were coated with ethyl cellulose and then with a solution of methacrylic acid-methyl methacrylate copolymers ("Eudragit L 100", trade name: 93.7 g, "Eudragit S 100", trade name: 31.3 g) and 25 g of trigyl citrate in 1.51 ethanol to give preparation (4).

Table 3

(1) (2) (3) (4) AMOX 250 g 41.9 g 41.9 g 250 g Cornstarch 250 g 250 g 250 g 250 g Mannitol - 208.1 g 208.1 g - Ethyl cellulose 190 g 190 g 152 g 190 g PEG 6000 - - 38g - Methacrylic acid copolymers methyl methacrylate: (“Eudragit L100”, auction, name) 125 g 125 g 125 g 93.7 g (“Eudragit S100”, auction, name) - - - 31.3 g Triethyl citrate 25g 25 g 25g 25 g Release Time (hours) 6 6 2 6

Comparative Example 2. By using a gel-forming polymer with water, said polymer exists described in Japanese Patent Description Hei 5 -132416, an adhesive preparation for the digestive tract mucosa is prepared. It is specifically described that 85 g of stearic acid are dissolved at 70 ° C, followed by the addition of 15 g of an acrylic acid polymer ("Hibiswako 104", trade name). After perfect mixing for 10 minutes, the resulting mixture was cooled and solidified. The solid obtained is sprayed and graded to form a preparation; which has a particle size of about 150 μιη.

Test 1. Investigation of intra-gastric retention induced by pH-dependent adhesive polymer

All preparations prepared in Example 1 and Comparative Example 1 were suspended in an amount of 10% (W / V) in the first liquid JP. Rats (SD rats, 8 weeks of age) were fasted for 24 h, and 2 ml of the resulting suspension was added. Every 1 h and 3 h after administration, the stomach is removed by surgery and the retention of the preparation in the stomach is examined. As a result, the retention of the yellow preparation of Example 1 in the stomach is confirmed every 1 h and 3 h after administration, whereas the retention of the yellow preparation of Comparative Example 1 is not confirmed after 1 h. From the results, it was confirmed that until the copolymer was delayed, methacrylic acid - methyl methacrylate was required to retain the preparation in gastric mucosa.

Test 2. Study of adhesion depending on the particle size

All preparations obtained in Reference Example 1, which differ in particle size, were suspended in an amount of 10% (W / V) in the first JP liquid. 2 ml of the resulting suspension was introduced into human fibroblasts grown on a plastic case until fused. By leaving it stationary for 1 minute, the preparation adheres to the cells. After adhesion, the plastic case is washed in the first liquid JP. The remaining weight of the preparation on the plastic case is then measured and the amount of the adhesive attached is calculated. In addition, from the adhered amount, the coated surface of the preparation is calculated in accordance with the following formula as an indication of adhesion of the preparation to the cells.

Formula for calculating particle size: d, specific attraction of the preparation: d, adhesive quantity: W

Particle Weight: w = 4 / 3xttx (r / 2) ³ xd

Number of adhered particles: N = W / w Coated surface of one particle: β = πχ (»2) ³ Total coated surface: S = N x s

The results are shown in FIG. 1. From the results regarding the adhesion of the preparation to the cells, no change in the adhesion of particles up to 200 µm was observed, a gradual deterioration of adhesion was observed in particles larger than 200 µm and no adhesion was observed. observed for particles having a size of 350 µm or larger. From the foregoing, it is confirmed that the pH-dependent adhesion of the preparation occurs at a particle size of more than 300 µm or also a persistently high adhesion is present when the particle size is greater than 200 µm or so.

Test 3. The adhesion of human fibroblasts to each of the solutions with different pH was examined using the preparation of Reference Example 1 containing the methacrylic acid-methyl methacrylate copolymer and having a particle size of 150 µm and a comparative preparation containing an acrylic acid type polymer and prepared in Comparative Example 2. The results are shown in FIG. 2.

From the results, the preparation containing the methacrylic acid-methyl methacrylate copolymer showed good adhesion in JP1 (pH 1.2), but no adhesion was observed with saline up to pH 6. The comparative preparation containing an acrylic acid-type polymer, on the other hand, exhibited no difference in pH-dependent adhesion. From the above, it is recognized that the adhesion induced by the copolymer methacrylic acid methyl methacrylate is pH dependent and has high local selectivity.

Test 4. Transition of the drug by mucoadhesion

Hardened 20% gelatin is put into solution as a model of gastric mucosa. Gelatin was administered 50 mg (1 mg with respect to riboflavin phosphate) of gastric and / or duodenal mucosa adhesive prepared in Example 1 and 1 mg of riboflavin phosphate, followed by stirring at 25 g to remove a concentration gradient. After 1 hour and 3 hours, respectively, the quantities of the drug converted to gelatin were measured. The results are shown in FIG. 3.

From the results, a higher transition is confirmed with gelatin introduced with an adhesive for gastric and / or duodenal mucosa compared to that introduced with the solution, indicating that more effective pharmacological action can be achieved and the dose can be reduced by adhering the preparation directly to the stomach and / or duodenum, releasing the drug from the preparation.

Test 5. Effects of an adhesive composition containing AMOX for gastric and / or duodenal mucosa Each of the adhesive compositions containing AMOX for gastric and / or duodenal mucosa [(1), (2) and (4) in Table 3] prepared in Example 2 was suspended in 0.1% tragacanth solution for use as a preparative solution. In such a tragacanth solution, AMOX powder is suspended for use as an introductory solution. The 24 h starved ddY mouse was infected orally and endomastically with Helicobacter pyroli ATCC 43504 (abbreviated as "HP"; 10 ⁹ viable microorganisms x 3 / mice). After 27 days, the respective solutions of the preparations and the solution were adjusted to the content of AMOX in amounts of 0.1 mg / kg (preparation (2)) and 1 mg / kg (preparations (1) and (4)) and then administered orally accurately. for 5 days. The mouse was excised from its stomach 24 h after the last injection and the solution of the destructed stomach was inoculated onto HP selective medium. After incubation for 8 days under microaerobic conditions, the amount of viable microorganisms is measured. The determination of the amount of viable microorganisms per RP is shown in FIG. 4. From the results, it is confirmed that, compared to the group administered with the solvent group, the group introduced with an admixture containing AMOX for the stomach and / or duodenum exhibits higher removal effects.

Test 6. Effects of removal of AMOX-containing adhesive preparation for gastric and / or duodenal mucosa, dependent on release time.

Each of the AMOX-containing gastric and / or duodenal mucosa adhesive preparations [(2) and (3) in Table 3] obtained in Example 2 was suspended in 0.1% tragacanth solution. The resulting suspension was adjusted to an AMOX content of 0.1 mg / kg, followed by administration for exactly 5 days in ddY mice infected with HP in a manner similar to test 4. Measure the amount of viable microorganisms as in test 5 and the results are shown in FIG. 5. Results from two AMOX-containing adhesives for gastric and / or duodenal mucosa were recognized to have higher removal effects than the solution. In addition, preparation (2) with a longer release time for AMOX (6 b) was recognized to have higher removal effects than preparation (2) with a shorter release time for AMOX (2 h). ). From the foregoing, it can be seen that effective removal can be achieved by controlled release of the drug.

Example 3 6 g of methacrylic acid-methyl methacrylate (“Eudragit L100”) copolymer and 1.2 g of triethyl citrate were added to 20 ml of ethanol and completely dissolved. To the resulting solution was added 8 g of tetraglyceryl monostearate. After drying, the resulting mixture was subjected to granulation and grading to give a preparation having an average particle size of 150 µm.

Example 4. 6 g of methacrylic acid-methyl methacrylate (“Eudragit L100”) copolymer and 1.2 g of triethyl citrate were added to 20 ml of ethanol and completely dissolved. The resulting solution was mixed with 8 g of stearic acid. After drying, the mixture was granulated and graded to give a preparation having an average particle size of 150 µm.

The adhesion of the preparations obtained in Examples 3 and 4 was examined in a manner similar to that of Test 3. As a result, it is recognized that the adhesion of these preparations is pH dependent and that they have high local selectivity.

Use of the invention

The adhesive pharmaceutical composition for gastric and / or duodenal mucosa according to the invention exhibits pH-dependent adhesion such that it adheres directly to the mucosa of the digestive tract under acidic conditions and has a high retention rate in the digestive tract, which makes it possible to release the drug from preparation directly on the mucosa of the stomach and / or duodenum. In addition, it exhibits a controlled-release property that permits sustained release of the drug and effective conversion of the active components into gastric and / or duodenal mucosa. Sufficient effects can be achieved by a lower dose so that the preparation is of high safety and allows the active ingredients to be used effectively.

Claims (4)

Claims A pharmaceutical adhesive composition for the stomach and / or duodenum, obtained by coating a composition comprising a medicament acting on the stomach and / or duodenum and one or more components selected from: water-insoluble polymers selected from the group , comprising crystalline cellulose, ethyl cellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate succinate, carboxymethyl cellulose and cellulose acetate phthalate; polyglycerol fatty acid esters selected from the group consisting of diglycerip monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate; decaglyceryl monostearate, tetraglyceryl tristearal; decaglyceryl tristearate; tetraglitseril pentastearat, hexaglyceryl pentastearat, hexaglyceryl monostearate, Decaglyceryl monooleate, triglyceryl dioleate, tetraglitseril diodeat, tetraglitseril pentaoleate, hexaglyceryl pentaoleag, triglyceryl dilinoleat, tetraglitseril dilinoleat, hexaglyceryl dilinoleat, tetraglitseril monopalmitate, hexaglyceryl monopalmitate Decaglyceryl monopalmitate tetraglitseril tripalmitate and hexaglyceryl tripalmitate; lipids selected from the group consisting of stearic acid, magnesium stearate, aluminum stearate, stearic alcohol and cetyl alcohol; and waxes selected from the group comprising carnauba wax, beeswax, microcrystalline wax and paraffin, with a polymer having an adhesive ability on the surface of the digestive tract mucosa under acidic conditions and separated from the mucosa of the digestive tract under neutral, alkaline or alkaline conditions selected from the group consisting of purified shellac, white shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimellate, cellulose acetate phthalate; polymers derived from acrylic acid and / or methacrylic acid, polymers obtained from acrylic acid and / or methacrylic acid and a carboxylic ester and polyvinyl acetate phthalate. Pharmaceutical composition according to claim 1, characterized in that the drug is coated with one or more components selected from: water-insoluble polymers selected from the group consisting of crystalline cellulose, ethyl cellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate succinate, succinate, succinate, succinate; cellulose acetate phthalate; polyglycerol fatty acid esters selected from the group consisting of diglyceryl monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate, decaglyceryl monostearate, tetraglyceryl tristearate, decaglyceryl tristearal; tetraglyceryl pentasterate, hexaglyceryl pentasterate, hexaglyceryl monostearate, decaglyceryl monooleate, triglyceryl dioleate, tetraglyceryl dioleate, tetraglyceryl pentoolate, hexaphtyrillate, triglylate, triglycerate tetraglyceryl monopalmitate, tetraglyceryl tripalmitate and hexaglyceryl tripalmitate; lipids selected from the group consisting of stearic acid, magnesium stearate, aluminum stearate, stearic alkali and cetyl alcohol, and waxes selected from the group comprising carnauba wax, beeswax, microcrystalline wax and paraffin. Pharmaceutical composition according to claim 1 or 2, characterized in that the polymer 5 having an adhesive ability on the surface of the digestive tract mucosa under acidic conditions and the ability to separate from the digestive tract mucosa under neutral or alkaline conditions selected from the group comprising tannery, white shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimethylate, cellulose acetate phthalate, polymers derived from acrylic acid and / or methacrylic acid acid, polymers derived from acrylic acid and / or methacrylic acid and a carboxylic ester, and polyvinyl acetate phthalate, is soluble in the solution at a pH of at least 4 and has an anionic group. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that the medicament is selected from antacids, gastric mucosa protectors, H ₂ blockers, proton injection inhibitors, antibiotics and urease inhibitors.