JPH11269064A - Medicine composition for adhering to stomach and duodenum - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition adhering only to the mucosa of the stomach and duodenum, controlling the release of a medicine, showing excellent pharmacological action selectively on the stomach and duodenum, by coating a composition containing the medicine acting in the stomach/ duodenum and a specific medicine release controller with a prescribed pH- dependent polymer. SOLUTION: This composition is obtained by coating a composition containing (A) a medicine acting in the stomach and duodenum (preferably amoxigillin which is a penicillin-based antibiotic and has high antibacterial activity against Helicobactor pylori) and (B) a polyglycol fatty acid ester and/or a lipid is coated with (C) a polymer which has adhesiveness on the surface of mucosa of digestive tract under acidic conditions and releases from the mucosa of digestive tract in neutrality or alkalinity. A methacrylic acid-methyl methacrylate copolymer having 20-60% methacrylic acid content is preferable as the component C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition which adheres only to gastric mucosa and duodenal mucosa and has a controlled drug release.

[0002]

2. Description of the Related Art In consideration of effective use of drugs, preparations in which the release of the drug from the preparation is controlled, especially sustained-release preparations, can be released for a long period of time, so that the number of doses can be reduced and the blood concentration can be reduced. There is a great advantage such that can be maintained for a certain time. Therefore, a long-lasting preparation has been studied from various aspects.

[0003] Many of these long-acting preparations are designed to gradually release the drug while the preparation passes through the entire digestive tract, since the main absorption site of the drug is the intestinal tract. . On the other hand, there are few preparations designed to exert a medicinal effect locally in the stomach and duodenum instead of exerting a medicinal effect after being absorbed in the intestinal tract.

[0004] As a preparation intended to cause a drug to act in the stomach, a preparation (Daviss SS et al. P.) which has enhanced gastroretentivity by imparting floating properties to the preparation.
harm. Res. 1986: 208-213) and a preparation (D) in which the contact ratio to the mucosal surface was improved by increasing the specific gravity.
evereux JE et al. Pharmaco
l 1990; 42: 500-501). However, these formulations did not have sufficient retention. Also, a formulation has been proposed in which the compounded polymer gels with water and adheres to the gastrointestinal mucosa (Japanese Patent Laid-Open No. 5-132416). However, this formulation has no selectivity for the gastrointestinal tract to adhere to and cannot be adhered only to the mucosa of the stomach and duodenum.

[0005]

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

[0006]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies, and as a result, have controlled the release of drugs by polyglycerin fatty acid esters and / or lipids, and have been able to control the surface of the gastrointestinal mucosa under acidic conditions. If a polymer that adheres to the stomach or duodenal mucosa only is selectively attached by a polymer that does not adhere under neutral or alkaline conditions, the drug will act on the stomach and duodenal mucosa for a long time and quickly in the intestinal tract. The present inventors have found that a drug having a higher pharmacological action can be obtained with a lower concentration of a drug because the drug is excreted, and completed the present invention.

That is, the present invention relates to a drug acting on the stomach and / or duodenum, a fatty acid ester of polyglycerin and / or
Or a composition containing a lipid and a gastrointestinal / duodenal adhesion, characterized in that it is coated with a polymer that has an adhesive ability on the gastrointestinal mucosal surface under acidic conditions and is detached from the gastrointestinal mucosa in neutral or alkaline conditions. It provides a pharmaceutical composition.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION A polymer having an adhesive ability to the gastric and / or duodenal mucosa surface under acidic conditions used in the present invention and detachable from the gastrointestinal mucosa under neutral or alkaline conditions (hereinafter referred to as "pH-dependent adhesive") The polymer is not particularly limited, but preferably has a dissolution pH of 4 or more and has 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: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimellitate,
Cellulose acetate phthalate and the like. Acrylic polymer: a polymer obtained from acrylic acid and / or methacrylic acid, a polymer obtained from acrylic acid and / or methacrylic acid, and a carboxylic acid ester. Polyvinyl alcohol-based polymer: polyvinyl acetate phthalate and the like.

[0010] The pH-dependent adhesive polymer used in the present invention is particularly preferably one having a carboxyl group, particularly preferably a polymer obtained from acrylic acid and / or methacrylic acid. Polymers obtained from carboxylic esters are preferred. Examples of the carboxylic acid ester used here include acrylic acid esters and methacrylic acid esters such as methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, and t-acrylate. Butyl, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, methacrylic acid n-butyl,
Isobutyl methacrylate, t-butyl methacrylate and the like.

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

The polyglycerin fatty acid ester used in the present invention is not particularly limited, and may be di-, tri- or higher polyglycerin. Specific examples of polyglycerin fatty acid esters include diglyceryl monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate, decaglyceryl monostearate, tetraglyceryl tristearate, decaglyceryl tristearate, tetrapentastearate Glyceryl, hexaglyceryl pentastearate, hexaglyceryl monooleate, decaglyceryl monooleate, triglyceryl dioleate, tetraglyceryl dioleate, tetraglyceryl pentaoleate, hexaglyceryl pentaoleate, triglyceryl dilinoleate, tetra dilinoleate Glyceryl, hexaglyceryl dilinoleate, tetraglyceryl monopalmitate, hexaglyceryl monopalmitate, monopal Chinsan decaglyceryl tetraglyceryl tripalmitate, and the like tripalmitate hexaglyceryl it is. Examples of the lipid used in the present invention include higher alcohols, fatty acid glycerin esters, waxes and hydrocarbons. Specific examples of lipids include, as saturated fatty acids or salts thereof, for example, stearic acid, magnesium stearate, aluminum stearate, and higher alcohols, such as stearyl alcohol, cetyl alcohol, and fatty acid glycerin esters. Not only triglyceride but also monoglyceride and diglyceride may be used. Examples of waxes include carnauba wax and beeswax, and examples of hydrocarbons include microcrystalline wax and paraffin.

In order to arbitrarily control the release of the drug from the preparation, a polymer which can be dissolved under water-soluble or acidic conditions is used as a polyglycerin fatty acid ester and / or polyglycerol fatty acid ester.
Or you may mix | blend with an arbitrary ratio with a lipid. Examples of such polymers include the following. (1) Water-soluble polymer: polyethylene glycol, hydroxyethylcellulose, hydroxypropylcellulose, etc. (2) Acid-soluble polymer: aminoalkyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, etc.

In the present invention, the ratio of the water-soluble polymer to be added to the polyglycerol fatty acid ester and / or lipid for arbitrarily controlling the release property is from 0.1 to 0.1.
A range of 60% by weight is preferred.

The drug used in the present invention is preferably a drug that acts on the stomach and duodenum. Such drugs, antacids, gastric mucosa protective agents, H ₂ blockers, PP
I, antibacterial substances, urease inhibitors and the like, among which antibacterial substances are most suitable.

The antibacterial substance used in the present invention includes, for example, an anti-Helicobacter pylori active substance, a bismuth salt,
And quinolone compounds. Of these, anti-Helicobacter pylori active substances are preferred. Examples of the anti-Helicobacter pylori active substance include penicillin antibiotics (amoxicillin, ampicillin, etc.), macrolide antibiotics (erythromycin, clarithromycin, etc.), tetracycline antibiotics (tetracycline, minocycline, streptomycin, etc.). No. The antimicrobial substance used in the present invention is preferably
Amoxicillin (hereinafter referred to as “AM”) is a penicillin antibiotic that has high antibacterial activity against Helicobacter pylori.
OX ") is particularly preferred.

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 0.01 to 95% by weight, particularly preferably 0.1 to 9% by weight.
A range of 0% by weight is preferred. The amount of the polyglycerin fatty acid ester and / or lipid (hereinafter referred to as “polyglycerin fatty acid ester or the like”) may be determined according to the type thereof, the release time of the drug, and the like. , Preferably in the range of 1 to 95% by weight.
It is preferable to contain 60% by weight. Further, the content of the pH-dependent adhesive polymer in the composition is preferably 0.1 to 95% by weight, particularly preferably 10 to 90% by weight.

In the composition of the present invention, conventional additives used for the production of solid pharmaceuticals may be used. Examples of such additives include the following. (1) Excipients: lactose, corn starch, talc, powdered sugar,
(2) Binder: starch, sucrose, gelatin, gum arabic powder, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc. (3) Plasticity Agents: polyethylene glycol, triethyl citrate, etc. In addition, coloring agents; flavoring agents; adsorbents; preservatives;
And an antistatic 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, a polyglycerol fatty acid ester and the like with a pH-dependent adhesive polymer. Here, the drug, the necessary additives and the composition containing the polyglycerin fatty acid ester and the like, the drug or a mixture of the additive and the additive may be coated with polyglycerin fatty acid ester and the like, or the drug, the necessary additive and A matrix in which polyglycerin fatty acid ester or the like is mixed may be used, but the former is preferred. The “coating” is not limited to the case where the entire particle surface is uniformly coated with the coating agent, but also includes the case where the particle surface is partially coated.

The release time of the drug from the preparation in the present invention may be arbitrarily set in consideration of the properties of the selected drug and the like, but it is sufficient that the preparation adheres to the gastric mucosa and directly acts on the drug. In order to exert the effect, it is desirable to be continuous and for a long time. Also, taking into account the effects of gastrointestinal fluid and metabolism of gastric epithelial cells, diet, and the like, it is desirable that the release of the drug be completed within the time of adhering and staying on the 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 is controlled by the ratio of polyglycerin fatty acid ester and the like to the water-soluble polymer,
It may be adjusted by the amount of polyglycerin fatty acid ester and the like.

[0021] The particle size of the pharmaceutical composition of the present invention may be stomach and / or stomach.
Alternatively, the thickness is preferably in the range of 30 to 300 µm, particularly preferably in the range of 75 to 300 µm, and more preferably in the range of 100 to 250 µm, in terms of adhesion to the duodenal mucosa.

In the case of a preparation coated with a polyglycerol fatty acid ester or the like, the drug of the present invention is prepared by preparing a particle containing a drug using a conventional granulator or the like, and then preparing the polyglycerin fatty acid ester or the like and a pH-dependent adhesive. The polymer can be produced by successive coating. For granulation, a fluidized granulation method, a tumbling granulation method and the like can be adopted. For the coating, a conventional method, for example, a pan coating method, a fluid coating method, a tumbling coating method and the like can be adopted. When the coating agent is a solution or a dispersion containing water or an organic solvent, a spray coating method can also be employed. Further, when the composition containing a drug or the like and polyglycerin fatty acid ester or the like is a matrix, after dissolving a water-insoluble polymer containing the drug or the like in an appropriate organic solvent,
It may be prepared by kneading and pulverizing, or may be dispersed in a solution that is immiscible with the solvent, and after preparing the particles by evaporating the solvent by heating, the pH-dependent adhesive polymer may be coated. . 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.

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following Examples and Experimental Examples, but the present invention is not limited to these Examples.

Example 1 In 20 mL of ethanol, 6 g of a methacrylic acid-methacrylic acid copolymer and 1.2 g of triethyl citrate were added and dissolved well, and then tetraglyceryl monostearate 8 g was dissolved.
g, mixed and dried, and then pulverized and classified to obtain a 150 μm preparation.

Comparative Example 1 12 g of tetraglyceryl monostearate was heated at 85 ° C. to dissolve, then 4 g of carboxyvinyl polymer was added and mixed well, followed by solidification, pulverization and classification, and a 150 μm preparation was obtained. Obtained.

Example 2 In 20 mL of ethanol, 6 g of a methacrylic acid-methacrylic acid copolymer and 1.2 g of triethyl citrate were added and dissolved well. Then, 8 g of stearic acid was added, mixed, dried, and then crushed and classified. Was performed to obtain a preparation of 150 μm.

Comparative Example 2 After heating and dissolving 7.5 g of stearic acid at 85 ° C.,
After adding 2.5 g of a carboxyvinyl polymer and mixing well, the mixture was solidified, and crushed and classified to obtain a preparation of 150 μm.

Test Example 1 A preparation containing the methacrylic acid-methyl methacrylate copolymer prepared in Example 1 and a preparation containing the acrylic acid-based polymer prepared in Comparative Example 1 were mixed in a solution having different pH to 10% (W). / V), 2 mL was administered to human fibroblasts cultured in a confluent state on a plastic slip, allowed to stand for 1 minute, and the preparation was allowed to adhere to the cells. After attaching,
The plastic slip was washed with the solution, and after washing, the weight of the formulation remaining on the plastic slip was measured to calculate the amount of the formulation adhered. The results are shown in FIG. From the results, the preparation containing the methacrylic acid-methyl methacrylate copolymer shows good adhesion in JP1 (pH 1.2),
Adhesion in physiological saline adjusted to pH 6 was not observed. On the other hand, in the preparation containing the acrylic acid-based polymer, no significant difference in the adhesion due to the pH was observed.
From this, it was confirmed that the adhesiveness of the preparation containing the methacrylic acid-methyl methacrylate copolymer was pH-dependent and the local selectivity was high.

Test Example 2 Using the preparation prepared in Example 2 and the preparation prepared in Comparative Example 2, the amount of adhesion to human fibroblasts was examined in the same manner as in Test Example 1. The results are shown in FIG. From the results, the adhesion of each preparation was the same as in Test Example 1.

[0030]

Industrial Applicability The gastric / duodenal mucosa-adhering pharmaceutical composition of the present invention has pH-dependent adhesion, adheres directly to the gastrointestinal mucosa under acidic conditions, and has high retention in the gastrointestinal tract. Therefore, the drug can be directly released from the preparation to the stomach and / or duodenal mucosa, and also has a controlled release, so that a sustained release can be obtained, and the active ingredient can be efficiently introduced into the stomach and / or duodenal mucosa. Can be migrated. Therefore, since a sufficient effect can be obtained with a low dose, the safety is high and the medicinal component can be effectively used.

[Brief description of the drawings]

FIG. 1 is a drawing showing the relationship between pH and adhesiveness.

FIG. 2 is a diagram showing the relationship between pH and adhesiveness.

Claims (2)

[Claims] 1. A composition containing a drug acting on the stomach and / or the duodenum and a polyglycerol fatty acid ester and / or lipid, which is capable of adhering to the gastrointestinal mucosal surface under acidic conditions and having a neutral or alkaline property. A pharmaceutical composition adherent to the stomach and duodenum, which is coated with a polymer detachable from the gastrointestinal mucosa. 2. A composition comprising a drug acting on the stomach and / or duodenum and a polyglycerin fatty acid ester and / or lipid, wherein the drug is coated with a polyglycerin fatty acid ester and / or lipid. 1
The pharmaceutical composition according to any one of the preceding claims.