Controlled release preparation

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.