Patent 6,582,720

The present invention provides a gastric and/or duodenal adhesive pharmaceutical composition obtained by coating a composition, which comprises a medicament acting at the stomach and/or duodenum and one or more of ingredients selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, with a polymer having adhesive capacity onto the surface of the mucosa of a digestive tract under acid conditions and separates from the mucosa of the digestive tract in neutral or alkaline conditions. This composition adheres only to the mucosa of the stomach and/or duodenum and releases the medicament over long hours so that sufficient effects are available by a small amount of the medicament.

DISCLOSURE OF THE INVENTION

With the foregoing in view, the present inventors have carried out an extensive investigation. As a result, it has been found that by controlling the release of a medicament by an ingredient selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, and imparting the medicament with selective adhering capacity only to the gastric and duodenal mucosae by using a polymer which adheres to the surface of the mucosa of a digestive tract under acid conditions but does not adhere under neutral or alkali conditions, the medicament acts on the gastric and duodenal mucosa over long hours but quickly excreted from the intestine, which makes it possible to provide a preparation exhibiting high pharmacological action at a low concentration of the medicament, leading to the completion of the present invention.

The present invention therefore provides a gastric and/or duodenal adhesive pharmaceutical composition obtained by coating a composition, which contains a medicament exhibiting action in the stomach and/or duodenum and an ingredient selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, with a polymer which has adhering capacity to the surface of the mucosa of a digestive tract under acid conditions but separates from the mucosa of the digestive tract under neutral or alkaline conditions.

BEST MODES FOR CARRYING OUT THE INVENTION

Although no particular limitation is imposed on the polymer which has adhering capacity to the surface of a gastric and/or duodenal mucosa under acid conditions and separates from the mucosa of a digestive tract under neutral or alkaline conditions (said polymer will hereinafter be called "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 a pH-dependent adhesive polymer include:

(1) Natural polymers: purified shellac and white shellac; and

(2) Synthetic polymers:

Cellulose derivative polymers: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate trimellitate, cellulose acetate phthalate, etc.,

Acrylic polymers: polymers obtained from acrylic acid and/or methacrylic acid, polymers obtained from acrylic acid and/or methacrylic acid and a carboxylic ester, etc. and

Polyvinyl alcohol type polymers: polyvinyl acetate phthalate, etc.

As the pH dependent adhesive polymers used in the present invention, those having a carboxyl group are particularly preferred, with those obtained from acrylic acid and/or methacrylic acid being more preferred and those obtained from acrylic acid and/or methacrylic acid and a carboxylic ester being still more preferred. Examples of the carboxylic ester 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-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate and t-butyl methacrylate.

Among them, a methacrylic acid-methyl methacrylate copolymer is preferred, with that having a methacrylic acid content of 20 to 60%, for example, Eudragit L100 or S100 being particularly preferred.

These pH dependent adhesive polymers may be used either singly or in combination.

In the present invention, the ingredient selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes (which may hereinafter be called "water-insoluble ingredient") is an ingredient for controlling the release of active ingredients.

No particular limitation is imposed on the water insoluble polymers used in the present invention insofar as they are sustained release bases ordinarily employed for preparations. These polymers may be used either singly or in combination. As such polymers, following ones may be mentioned by way of example.

Cellulose type polymers: crystalline cellulose, ethyl cellulose, hydroxymethylcellulose phthalate, hydroxymethylcellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate, [etc.] Among them, ethyl cellulose is particularly preferred.

No particular limitation is imposed on the polyglycerin fatty acid esters used in the present invention and fatty acid esters of polyglycerin such as di-, tri- or higher-glycerin may be used. As the fatty acid portion of the polyglycerin fatty acid esters, C_8-30 fatty acids are preferred, while as the polyglycerin portion, diglycerin to eicosaglycerin are preferred.

Specific examples of the polyglycerin fatty acid ester include diglyceryl monostearate, tetraglyceryl monostearate, hexaglyceryl monostearate, decaglyceryl monostearate, tetraglyceryl tristearate, decaglyceryl tristearate, tetraglyceryl pentastearate, hexaglyceryl pentastearate, hexaglyceryl monooleate, decaglyceryl monooleate, triglyceryl dioleate, tetraglyceryl dioleate, tetraglyceryl pentaoleate, hexaglyceryl pentaoleate, triglyceryl dilinoleate, tetraglyceryl dilinoleate, hexaglyceryl dilinoleate, tetraglyceryl monopalmitate, hexaglyceryl monopalmitate, decaglyceryl monopalmitate, tetraglyceryl tripalmitate and hexaglyceryl tripalmitate.

Examples of the lipid used in the present invention include higher fatty acids and salts thereof, higher alcohols and fatty acid glycerin esters and those of the wax include waxes and hydrocarbons. Examples of the higher saturated fatty acid or salt thereof include C_8-30 fatty acids and salts thereof such as stearic acid, magnesium stearate and aluminum stearate. Examples of the higher alcohol include C_10-24 aliphatic alcohols such as stearyl alcohol and cetyl alcohol. As the fatty acid glycerin ester, not only triglycerides with a fatty acid but also monoglycerides and diglycerides therewith may be used. Examples of the waxes include carnauba wax and bees wax, while those of the hydrocarbon include microcrystalline wax and paraffin.

The above-described water-insoluble ingredients, that is, water-insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, may be used either singly or in combination.

With a view to freely controlling the releasability of the medicament from a preparation, a water soluble polymer may be added in any ratio to the above-described water-insoluble ingredient. Examples of such a polymer include polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymers 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 wt. % to the above-described water-insoluble ingredient.

As the medicament used in the present invention, medicaments which act in the stomach or duodenum are suited. Examples of such medicaments include antiacids, gastric mucosa protectors, H₂ blockers, proton pump inhibitors (PPIs), antibiotics and urease inhibitors.

Examples of the antiacid used in the present invention include magnesium hydroxide and aluminum magnesium silicate.

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

Examples of the H₂ blocker 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 inhibitor used in the present invention include acetohydroxamic acid and caprylohydroxamic acid.

Examples of the antibiotic used in the present invention include anti-Helicobacter pylori active substances, bismuth salts and quinolone type compounds, of which anti-Helicobacter pylori active substances are preferred. Examples of the anti-Helicobacter pylori 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, penicillin type antibiotics are preferred, with amoxicillin (which will hereinafter be abbreviated as "AMOX") having high antibacterial property against Helicobacter pylori being particularly preferred.

In the composition of the present invention, the content of the medicament may be determined as needed depending on the nature of the medicament or preparation. Usually, a content of 0.01 to 95 wt. % or so is preferred, with a range of from 0.1 to 90 wt. % being particularly preferred. The using amount of the water-insoluble ingredient may be determined depending on the nature of the ingredient, release time of the medicament or the like. It is however preferred to incorporate it in an amount of 0.1 to 95 wt. % in the composition, with 1 to 60 wt. % being particularly preferred. The pH-dependent adhesive polymer is preferably incorporated in an amount of 0.1 to 95 wt. % in the composition, with 1 to 50 wt. % being particularly preferred.

To the composition of the present invention, ordinarily employed additives used for the preparation of a solid pharmaceutical may be added. Examples include following ones:

(1) Excipient: lactose, corn starch, talc, powdered sugar, light anhydrous silicic acid, calcium carbonate, magnesium carbonate, etc.

(2) Binder: starch, sucrose, gelatin, powdered acacia, carboxymethyl cellulose, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, pullulan, dextrin, etc.

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

In addition, colorants, corrigents, adsorbents, antiseptics, humectants and antistatic agents can be used as additives. The amount of such an additive may be determined as needed within an extent neither impairing pH-dependent adhesion to the gastric mucosa nor having adverse effects on the releasability of the medicament.

The composition of the present invention comprises a medicament, an additive if necessary, and the above-described insoluble ingredient and it has been coated with a pH-dependent adhesive polymer. Here, the composition comprising a medicament, a necessary additive and the above-described water-insoluble ingredient may be a composition having a medicament or medicament-additive mixture coated with the above-described water-insoluble ingredient or a matrix containing the medicament, necessary additive and the above-described water-insoluble ingredient as a mixture. The former one is however preferred. The term "coating" as used herein means not only the uniform coating of the whole surface of a particle but also partial coating of the surface of the particle.

Although the release time of the medicament from the preparation may be determined freely in consideration of the properties of the medicament to be selected or the like, continuous and longer release time is desired in order to fully exhibit the properties of the preparation, that is, to adhere to the gastric mucosa and allow the medicament to directly act thereon. In addition, the release of the medicament is desirably completed while the preparation has still adhered to and retained in the gastric mucosa. Influences of gastric juice, metabolism of the gastric epitheliocytes, meal and the like must of course be taken into consideration. The release time of the medicament from the preparation is desired to be 2 to 8 hours, judging from the above-described factors. The release time may be controlled by a ratio of the water-insoluble ingredient to a water soluble polymer, amount of the water-insoluble ingredient or the like.

The particle size of the pharmaceutical composition of the present invention is preferred to fall within a range of 30 to 300 .mu.m from the viewpoint of adhesion to the gastric and/or duodenal mucosa, with a range of 75 to 300 .mu.m, moreover 100 to 250 .mu.m being particularly preferred.

In the case where the pharmaceutical composition of the present invention is a preparation coated with the above-described water-insoluble ingredient, it is prepared, for example, by forming medicament-containing particles by a conventionally employed granulator or the like and then coating the particles with the above-described water-insoluble ingredient and pH dependent adhesive polymer successively. For granulation, fluidized bed granulation, high shear granulation, extrusion granulation or the like can be adopted. For coating, conventionally employed method such as pan coating or fluidized bed coating can be adopted. 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 above-described water-insoluble ingredient is in the form of a matrix, it can be prepared by dissolving the above-described water-insoluble ingredient in a suitable organic solvent, kneading the resulting solution with the medicament, and then drying and pulverizing the kneaded mass, or dissolving the above-described water-insoluble ingredient containing the medicament 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.

Claim 1 of 14 Claims

What is claimed is:

1. An adhesive pharmaceutical composition obtained by coating a composition, which comprises a medicament acting at the stomach or duodenum and a water insoluble cellulose polymer (I), with a second composition consisting essentially of a polymer (II) having an adhesive capacity onto the surface of the mucosa of a digestive tract under acid conditions and separates from the mucosa of the digestive tract in neutral or alkaline conditions, wherein said polymer (II) is obtained from an acrylic acid, a methacrylic acid or a mixture thereof, and a carboxylic ester.

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