Formulation having improved ph-dependent drug-release characteristics containing esomeprazole or pharmaceutically acceptable salt thereof

Abstract

Disclosed is a pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation, based on considerably improved pH-dependent drug release characteristics, starts to release the esomeprazole or a pharmaceutically acceptable salt thereof at a target delay time after oral administration, continues the release for a predetermined time, and finishes the release after a predetermined time, thereby providing excellent patient convenience and excellent therapeutic effects, as compared to conventional other formulations.

What is claimed is: 
     
         1 . A pharmaceutical formulation comprising:
 (a) a core containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient;   (b) an endothelial coated layer formed on the core; and   (c) a release-control coated layer formed on the endothelial coated layer,   wherein the endothelial coated layer comprises at least one selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC-L), starch, gelatin and ethyl cellulose (EC),   the release-control coated layer comprises a polymer in which a methacrylic acid copolymer S and a methacrylic acid copolymer L are mixed in a ratio of 1.5:1 to 3.5:1 (w/w) as release-control coating base materials, and   wherein the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L, as the release-control coating base material, is 15 to 40% (w/w), with respect to a weight of an endothelial coated tablet.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein a content ratio of at least one substance selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC-L), starch, gelatin and ethyl cellulose (EC) present in the endothelial coated layer, with respect to the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L, as the release-control coating base materials, is 3.5 to 8.0 (w/w), and
 a content of at least one substance selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), low-substituted hydroxypropyl cellulose (HPC-L), starch, gelatin and ethyl cellulose (EC), contained in the endothelial coated layer, is 4.4 to 5.2% (w/w), with respect to the weight of the endothelial coated tablet.   
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein the esomeprazole or a pharmaceutically acceptable salt thereof is an esomeprazole magnesium salt or an esomeprazole strontium salt. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein the esomeprazole or a pharmaceutically acceptable salt thereof is an anhydride or hydrate. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein the core containing esomeprazole or a pharmaceutically acceptable salt thereof further comprises at least one excipient selected from diluents, binders, disintegrants, lubricants, surfactants, antioxidants, preservatives and stabilizers. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein, in a release test using an artificial intestinal fluid having a pH of 6.7 to 6.9, a number of revolutions of 75 rpm and 37° C. in accordance with the USP paddle method, 5% or less of the esomeprazole or a pharmaceutically acceptable salt thereof is eluted at up to 2 hours, and at least 90% of the esomeprazole or a pharmaceutically acceptable salt thereof is eluted after 6 hours. 
     
     
         7 . The pharmaceutical formulation of  claim 1 , wherein the pharmaceutical formulation is selected from the group consisting of a pellet, a mini-tablet, a tablet, a mixture of a pellet and a mini-tablet, and a capsule. 
     
     
         8 . A method of preventing and treating gastric and esophageal reflux diseases of reflux esophagitis, and diseases associated with gastric hyperproliferation including gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer by administering the pharmaceutical formulation of  claim 1  to a subject in need thereof. 
     
     
         9 . A method of preparing a pharmaceutical formulation of  claim 1 , comprising:
 (a) mixing esomeprazole or a pharmaceutically acceptable salt thereof with a diluent;   (b) adding a disintegrant, a binder and a lubricant to a mixture of step (a), followed by mixing;   (c) obtaining a mini-tablet or tablet by dry-granulating the mixture of step (b) and then tableting;   (d) endothelially coating a tableted mini-tablet or tablet obtained in step (c) using a fluidized bed dryer (FBG) and a coater; and   (e) forming a release-control coated layer using a mixture containing a methacrylic acid copolymer S and a methacrylic acid copolymer L in the endothelially coated mini-tablet or tablet obtained in step (d).