# US 8,784,885 B2 · Controlled release preparation

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- Number: US 8,784,885 B2
- Document ID: US8784885B2
- Status: Granted
- Kind: B2
- Application number: 12/839,054
- Filed: 2010-07-19
- Published: 2010-11-11
- Granted: 2014-07-22
- Earliest claimed: 2002-10-16
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Yohko Akiyama; Takashi Kurasawa; Hiroto Bando; Naoki Nagahara
- Inventors: Yohko Akiyama; Takashi Kurasawa; Hiroto Bando; Naoki Nagahara
- Web page: https://patentgrep.com/patent/US8784885B2

## CPC

- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 9/5078: {with drug-free core}
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A controlled release preparation wherein the release of active ingredient is controlled, which releases an active ingredient for an extended period of time by staying or slowly migrating in the gastrointestinal tract, is provided by means such as capsulating a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. Said tablet, granule or fine granule has a release-controlled coating-layer formed on a core particle containing an active ingredient.

## Claims

### Claim 1

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
wherein the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 2 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the pH-dependently soluble release-controlled coating layer comprises one polymeric substance or more than one polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac.

### Claim 3 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the composition is a capsule containing the tablet, the granules, or the fine granules.

### Claim 4 (depends on 3)

The pharmaceutical composition according to claim 3, wherein the composition is a capsule containing the granules.

### Claim 5 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the composition releases the active ingredient from the first component and the second component so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 6 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level in the mammal to at least 300 ng/ml.

### Claim 7

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core article containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac,
the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof.

### Claim 8

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8,
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component, and
wherein the one polymeric substance or more than one polymeric substances having different release properties are selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate, and shellac,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the active ingredient contained in the first component and the second component is released in a pulsatile manner, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 9 (depends on 8)

The pharmaceutical composition according to claim 8, wherein the composition is a capsule containing the tablet, the granules, or the fine granules.

### Claim 10 (depends on 9)

The pharmaceutical composition according to claim 9, wherein the composition is a capsule containing the granules.

### Claim 11 (depends on 8)

The pharmaceutical composition according to claim 8, wherein the composition releases the active ingredient from the first component and the second component so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 12 (depends on 8)

The pharmaceutical composition according to claim 8, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 300 ng/ml.

### Claim 13

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac,
the active ingredient contained in the first component and the second component is released in a pulsatile manner, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 14

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the amount of the active ingredient in the first component is at least 50% more than an amount of the active ingredient in the second component, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 15 (depends on 14)

The pharmaceutical composition according to claim 14, wherein an amount of the active ingredient in the first component is at least twice of an amount of the active ingredient in the second component.

### Claim 16 (depends on 14)

The pharmaceutical composition according to claim 14, wherein an amount of the active ingredient in the first component is at least three times an amount of the active ingredient in the second component.

### Claim 17 (depends on 14)

The pharmaceutical composition according to claim 14, wherein the pH-dependently soluble release-controlled coating layer comprises one polymeric substance or more than one polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac.

### Claim 18 (depends on 14)

The pharmaceutical composition according to claim 14, wherein the composition is a capsule containing the tablet, the granules, or the fine granules.

### Claim 19 (depends on 18)

The pharmaceutical composition according to claim 18, wherein the composition is a capsule containing the granules.

### Claim 20 (depends on 14)

The pharmaceutical composition according to claim 14, wherein the composition releases the active ingredient from the first component and the second component so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 21 (depends on 14)

The pharmaceutical composition according to claim 14, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 300 ng/ml.

### Claim 22

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac,
the amount of the active ingredient in the first component is at least 50% more than an amount of the active ingredient in the second component, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 23

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the total amount of the active ingredient in the first component and the second component is between 5 mg and 150 mg, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 24 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the total amount of the active ingredient in the first component and the second component is between 30 mg and 90 mg.

### Claim 25 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the pH-dependently soluble release-controlled coating layer comprises one polymeric substance or more than one polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac.

### Claim 26 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the composition is a capsule containing the tablet, the granules, or the fine granules.

### Claim 27 (depends on 26)

The pharmaceutical composition according to claim 26, wherein the composition is a capsule containing the granules.

### Claim 28 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the composition releases the active ingredient from the first component and the second component so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 29 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 300 ng/ml.

### Claim 30

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac,
the total amount of the active ingredient in the first component and the second component is between 5 mg and 150 mg, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 31

A method to treat a gastrointestinal disorder in a mammal in need thereof comprising administering to the mammal a pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one polymeric substance or more than one polymeric substances selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the gastrointestinal disorder is caused by at least one selected from the group consisting of ulcer, gastric juice secretion, mucosa damage, and Helicobacter pylori, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 32 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31,
wherein the gastrointestinal disorder is at least one selected from the group consisting of digestive ulcer, Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD) with no esophagitis, non-ulcer dyspepsia (NUD), gastric cancer, and gastric MALT lymphoma.

### Claim 33 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31, wherein the mammal is human.

### Claim 34 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31,
wherein the pH-dependently soluble release-controlled coating layer comprises one polymeric substance or more than one polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac.

### Claim 35 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31, wherein the composition is a capsule containing the tablet, the granules, or the fine granules.

### Claim 36 (depends on 35)

The method to treat a gastrointestinal disorder according to claim 35, wherein the composition is a capsule containing the granules.

### Claim 37 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31, wherein the composition releases the active ingredient from the first component and the second component of the pharmaceutical composition so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 38 (depends on 31)

The method to treat a gastrointestinal disorder according to claim 31, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 300 ng/ml.

### Claim 39

A method to treat a gastrointestinal disorder in a mammal in need thereof comprising administering to the mammal a pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled by a release-controlled coating layer formed on the core particle containing the active ingredient,
the release-controlled coating layer comprises a pH-dependently soluble polymer, which comprises one polymeric substance or more than one polymeric substances having different release properties from each other,
wherein the elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8, and
wherein the release-controlled coating layer comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component,
the release of the active ingredient in the second component is controlled by an enteric coating layer,
wherein the enteric coating layer is formed on an intermediate layer formed on the core particle containing the active ingredient in the second component, and
wherein the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac,
the gastrointestinal disorder is caused by at least one selected from the group consisting of ulcer, gastric juice secretion, mucosa damage, and Helicobacter pylori, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof, and
wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 40

A pharmaceutical composition containing a tablet, granules, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first component and the second component comprises a core particle containing the active ingredient, which is at least one benzimidazole proton pump inhibitor (PPI) or a salt thereof,
the release of the active ingredient in the first component is controlled for delivery at an elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8,
the first component comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component under the coating layer,
a release of the active ingredient in the second component is controlled for delivery,
the second component comprises an enteric coating layer formed on an intermediate layer formed on the core particle containing the active ingredient in the second component,
the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxyethylcellulose acetate succinate, ethyl acrylate-methyl methacylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml.

### Claim 41 (depends on 40)

The pharmaceutical composition according to claim 40, wherein the composition releases the active ingredient from the first component and the second component so that the plasma level of at least 100 ng/ml in the mammal continues for at least 8 hours.

### Claim 42 (depends on 40)

The pharmaceutical composition according to claim 40, wherein the first component and the second component individually contain a sufficient amount of the active ingredient to raise the plasma level in the mammal to at least 300 ng/ml.

### Claim 43

A pharmaceutical composition containing a tablet, granule, or fine granule, in which a release of an active ingredient is controlled,
wherein the pharmaceutical composition comprises a first component and a second component, each of which has different release properties of the active ingredient relative to the other component,
each of the first and second components comprises a core particle containing the active ingredient,
the release of the active ingredient in the first component is controlled for delivery at an elution rate of the active ingredient from the first component is 10% or less for 5 hours in a solution of pH 6.0, and 5% or less for one hour and 60% or more for 8 hours in a solution of pH 6.8,
the first component comprises a coating layer, which covers at least about 80% of a surface of the core particle or a layer formed in the first component under the coating layer,
the release of the active ingredient in the second component is controlled for delivery,
the second component comprises an enteric coating layer formed on an intermediate layer formed on the core particle containing the active ingredient in the second component,
the enteric coating layer comprises one or more polymeric substances selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, carboxymethyl ethylcellulose, methacrylic acid-ethyl acrylate copolymer, and shellac, and
the first component and the second component individually contain a sufficient amount of the active ingredient to raise a plasma level of the active ingredient in a mammal to whom the pharmaceutical composition is administered to at least 100 ng/ml, and
the active ingredient is represented by formula (I′):
wherein ring C′ is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocyclic ring, R0 is a hydrogen atom, an optionally substituted aralkyl group, acyl group or acyloxy group, R1, R2 and R3 are the same or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH; or a salt thereof or an optically active isomer thereof.