HK40006385A - Formulation having improved ph-dependent drug-release characteristics, containing esomeprazole or pharmaceutically acceptable salt thereof - Google Patents

Description

Formulation with improved pH-dependent drug release profile comprising esomeprazole, or a pharmaceutically acceptable salt thereof

Technical Field

The present invention relates to a novel formulation having improved pH-dependent drug release characteristics comprising esomeprazole or a pharmaceutically acceptable salt thereof, and a preparation method thereof.

Background

Esomeprazole [ (S) -5-methoxy-2- [ (4-methoxy-3, 5-dimethylpyridin-2-yl) methylsulfinyl ] -3H-benzimidazole) ] is a Proton Pump Inhibitor (PPI) having the structure shown in formula 2, which can be used as the (S) -enantiomer of omeprazole having the structure shown in formula 1. Of the two optical isomers of omeprazole, the (R) -enantiomer is metabolized to the inactive metabolite (not the active metabolite) more rapidly than the (S) -enantiomer and has a greater metabolic rate difference between individuals. Therefore, the (R) -enantiomer has more side effects, poorer therapeutic effects and more heterogeneous therapeutic rate than the (S) -enantiomer, and the (S) -enantiomer has the advantage of less influence on liver metabolism than the (R) -enantiomer and the omeprazole racemate.

[ Table 1] Structure of omeprazole and Esomeprazole

The proton pump inhibitor to which esomeprazole belongs has the following advantages: gastric acid secretion in mammals, including humans, is inhibited by modulating gastric acid secretion at the final stages of the acid secretion pathway. Therefore, proton pump inhibitors are useful for the prevention and treatment of gastric and esophageal reflux diseases (e.g., reflux esophagitis) and diseases associated with gastric hyperproliferation (including gastritis, duodenitis, gastric ulcer, duodenal ulcer, and peptic ulcer).

On the other hand, esomeprazole is easily decomposed or converted under acidic conditions. Thus, oral formulations comprising esomeprazole should not contact acidic gastric juices, but should be delivered to the gastrointestinal site where pH is near neutral and rapid absorption can occur. Therefore, a preparation obtained using a method such as forming an enteric coating layer has been actively developed.

However, research into esomeprazole formulations has so far focused only on the development of enteric coatings for intestinal absorption while preventing exposure to gastric acid in the stomach. Based on the study of pH-dependent release profiles, the development of the following formulations is still insufficient and unsatisfactory: the formulation begins to release at a specified time after the target delay time following oral administration, continues to release for a desired period of time, and completes after the specified time. Under such circumstances, there is an urgent and increasing need for new formulations comprising esomeprazole and pharmaceutically acceptable salts thereof having such improved pH-dependent release characteristics.

In these technical backgrounds, the inventors have found that the pH-dependent release characteristics of esomeprazole, or a pharmaceutically acceptable salt thereof, can be significantly improved when an inner coating layer is formed on a core comprising esomeprazole, or a pharmaceutically acceptable salt thereof, on which a controlled-release coating layer comprising a polymer composed of methacrylic acid copolymer S and methacrylic acid copolymer L mixed in a specific ratio is present, and methacrylic acid copolymer S and methacrylic acid copolymer L contained in the controlled-release coating layer are present in a certain ratio with respect to the weight of an inner coating tablet or an inner coating layer, thereby completing the present invention.

Summary of The Invention

Accordingly, it is an object of the present invention to provide a novel pharmaceutical preparation having improved pH-dependent drug release characteristics comprising esomeprazole or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

The above and other objects can be accomplished by the provision of a pharmaceutical preparation comprising (a) a core comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, (b) an inner coating layer formed on the core, and (c) a controlled-release coating layer formed on the inner coating layer, wherein an inner coating material contained in the inner coating layer and methacrylic acid copolymer S and methacrylic acid copolymer L contained in the controlled-release coating layer as a controlled-release coating base material are present at a content ratio.

The pharmaceutical formulation may be selected from the group consisting of pellets, mini-tablets (MUST), tablets, a mixture of pellets and mini-tablets, and capsules, but the present invention is not limited thereto. The pellets and/or mini-tablets may be incorporated into capsules.

According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical formulation comprising esomeprazole, or a pharmaceutically acceptable salt thereof, the method comprises (a) mixing esomeprazole or a pharmaceutically acceptable salt thereof with a diluent, (b) adding a disintegrant, a binder and a lubricant to the mixture of step (a), then mixing, (c) dry granulating and then tabletting the mixture of step (b) to obtain mini-tablets (MUST) or tablets, (d) endotheli-coating the tabletted mini-tablets or tablets obtained in step (c) using a fluid bed dryer (FBG) and a coating machine, and (e) forming a controlled release coating layer in the endothelial coated mini-tablet or tablet obtained in step (d) using a mixture comprising methacrylic acid copolymer S and methacrylic acid copolymer L.

Brief Description of Drawings

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

fig. 1 shows the results of the test on the release characteristics of the pharmaceutical formulation according to the present invention, in which the mixing ratio between the methacrylic copolymer S and the methacrylic copolymer L present as the controlled-release coating base material in the controlled-release coating layer is 2:1 to 3:1(w/w), and the weight of the methacrylic copolymer S and the methacrylic copolymer L present as the controlled-release coating base material in the controlled-release coating layer is 20% to 35% (w/w) with respect to the weight of the endothelial coated tablet; and

fig. 2 shows the results of the test on the release characteristics of the comparative pharmaceutical preparations, in which the mixing ratio between the methacrylic copolymer S and the methacrylic copolymer L present as the controlled-release coating base material in the controlled-release coating layer is 6:1(w/w), or the weight of the methacrylic copolymer S and the methacrylic copolymer L present as the controlled-release coating base material in the controlled-release coating layer is 10% to 40% (w/w) relative to the weight of the endothelial-coated tablet.

Best Mode for Carrying Out The Invention

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein is well known and commonly employed in the art.

In one aspect, the present invention provides a pharmaceutical composition comprising esomeprazole, or a pharmaceutically acceptable salt thereof, comprising:

(a) a core comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient;

(b) an inner skin coating layer formed on the core; and

(c) a controlled-release coating layer formed on the inner coating layer, the controlled-release coating layer comprising a polymer composed of a methacrylic copolymer S and a methacrylic copolymer L mixed at a specific ratio,

wherein the endothelial coating layer comprises at least one selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC),

the controlled-release coating layer comprises a mixture of methacrylic acid copolymer S and methacrylic acid copolymer L in a ratio of 1.5:1 to 3.5:1, preferably 2:1 to 3:1, and

the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L as the base material of the controlled-release coating is 15% to 40% (w/w), preferably 20% to 35% (w/w), relative to the weight of the endothelial-coated tablet.

The pharmaceutical formulation according to the present invention is preferably provided in the form of pellets, mini-tablets (MUST), tablets, a mixture of pellets and mini-tablets, or capsules, but is not limited thereto, and the provided pellets or mini-tablets may be incorporated into capsules.

The pharmaceutical preparation according to the present invention hardly degrades in the stomach and starts to dissolve esomeprazole or a pharmaceutically acceptable salt thereof in the gastrointestinal tract at a pH range of 6.5 to 7.0. In particular, the pharmaceutical preparation starts dissolving esomeprazole or a pharmaceutically acceptable salt thereof at pH 6.7 to 6.9 after a delay time of 2 hours and then completes dissolving after 6 hours, thus having advantages of obtaining high convenience for patients and excellent therapeutic effect.

In the pharmaceutical preparation according to the present invention, any pharmaceutically acceptable salt of esomeprazole may be used without limitation as long as it is generally used in the art, and preferred examples of the pharmaceutically acceptable salt of esomeprazole include, but are not limited to, metal salts of esomeprazole (such as magnesium (Mg), strontium (Sr), lithium, sodium, potassium or calcium salts of esomeprazole) and ammonium salts of esomeprazole. Most preferably, a magnesium or strontium salt of esomeprazole is used.

Further, in the pharmaceutical preparation according to the present invention, esomeprazole or a pharmaceutically acceptable salt thereof may be used in the form of an anhydride or hydrate thereof.

In the pharmaceutical preparation according to the present invention, the core containing esomeprazole or a pharmaceutically acceptable salt thereof may further contain an appropriate amount of a generally acceptable excipient in addition to esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, the core may include one or more excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, surfactants, antioxidants, preservatives, and stabilizers, but is not limited thereto.

The diluent which may be comprised in the core of the pharmaceutical preparation according to the present invention may comprise at least one selected from the group consisting of: mannitol, microcrystalline cellulose, lactose, cellulose and its derivatives, calcium hydrogen phosphate or tribasic calcium phosphate, erythritol (erythritol), low-substituted hydroxypropylcellulose, pregelatinized starch, sorbitol and xylitol. However, mannitol and/or microcrystalline cellulose are preferably used.

The binder may be selected from the group consisting of: hydroxypropyl cellulose (HPC), copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (povidone), pregelatinized starch, and low-substituted hydroxypropyl cellulose (HPC-L), but are not limited thereto. Hydroxypropyl cellulose is preferably used.

The disintegrant may comprise at least one selected from the group consisting of: croscarmellose sodium, corn starch, crospovidone, low substituted hydroxypropyl cellulose (HPC-L), or pregelatinized starch, but is not limited thereto. Preferably, croscarmellose sodium is used.

The lubricant may include at least one selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, talc, polyethylene glycol, calcium behenate, calcium stearate, and hydrogenated castor oil, but are not limited thereto. Preferably, sodium stearyl fumarate is used.

In the pharmaceutical preparation according to the present invention, the endothelial coating layer formed on the core comprising esomeprazole or a pharmaceutically acceptable salt thereof includes at least one selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC). Preferably, Hydroxypropylmethylcellulose (HPMC) is used.

As used herein, the term "endothelial coated tablet" refers to a mini-tablet (MUST) having an endothelial coating layer formed on a core comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient.

At least one substance selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC) is contained in the endothelial coating layer preferably at a content ratio of 4.4% to 5.2% (w/w), preferably 4.7% to 4.9% (w/w), with respect to the weight of the endothelial coated tablet.

In the pharmaceutical preparation according to the present invention, the controlled-release coating layer formed on the inner coating layer, which may be used interchangeably with the "enteric coating layer" herein, comprises a mixture of methacrylic acid copolymer S and methacrylic acid copolymer L as a base material of the controlled-release coating, in a ratio of 1.5:1 to 3.5:1(w/w), preferably 2:1 to 3:1 (w/w).

Methacrylic copolymer S is an anionic copolymer comprising methacrylic acid and methyl methacrylate (ratio about 1:2) sold under the trade name Eudragit S-100, and methacrylic copolymer L is an anionic copolymer comprising methacrylic acid and methyl methacrylate (ratio about 1:1) sold under the trade name Eudragit L-100.

As used herein, the term "release-controlled coated tablet" refers to a mini-tablet (MUST) or tablet having a controlled release coating layer formed on an inner coating layer.

In the pharmaceutical formulation according to the present invention, the controlled-release coating base material (i.e., methacrylic acid copolymer S and methacrylic acid copolymer L) included in the controlled-release coating layer is present in an amount of 15% to 40% (w/w), preferably 20% to 35% (w/w), relative to the weight of the endothelial coated tablet.

The content ratio of at least one substance present in the endothelial coating layer, selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC), with respect to the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L, is 3.5 to 8.0(w/w), preferably 4.2 to 7.4 (w/w).

Further, the pharmaceutical preparation according to the present invention is characterized in that 5% or less (preferably 2% or less) of esomeprazole or a pharmaceutically acceptable salt thereof is eluted after 2 hours and 90% or more (preferably 98% or more) of esomeprazole or a pharmaceutically acceptable salt thereof is eluted after 6 hours in a release (dissolution) test using an artificial intestinal fluid (medium) having a pH of about 6.7 to 6.9 and at a rotation number of 75rpm at 37 ℃ according to the USP paddle method.

When the content ratio of at least one selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin, and Ethylcellulose (EC) present in the inner skin coating layer with respect to the weight of methacrylic acid copolymer S and methacrylic acid copolymer L as the base material of the controlled-release coating according to the present invention is less than 3.5(w/w) or more than 8.0(w/w), esomeprazole or a pharmaceutically acceptable salt thereof starts to be eluted before the desired delay time according to the present invention, or esomeprazole or a pharmaceutically acceptable salt thereof cannot be sufficiently eluted until the desired dissolution time.

When the amount of at least one substance selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin, and Ethylcellulose (EC) is less than 4.4(w/w) or more than 5.2(w/w) relative to the weight of the endothelial-coated tablet, the esomeprazole, or a pharmaceutically acceptable salt thereof starts to be eluted before the desired delay time or the esomeprazole, or a pharmaceutically acceptable salt thereof cannot be sufficiently eluted until the desired dissolution time.

In another aspect, the present invention provides a method for preparing a pharmaceutical preparation comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Specifically, a method for preparing a pharmaceutical preparation comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient will be described according to an example in which the preparation is a mini tablet (MUST) or a tablet. Specifically, the pharmaceutical formulation may be prepared by processes including, but not limited to:

(a) mixing esomeprazole, or a pharmaceutically acceptable salt thereof, with a diluent;

(b) adding a disintegrant, a binder, and a lubricant to the mixture of step (a) and then mixing;

(c) dry granulating the mixture of step (b) and then tabletting to obtain mini-tablets or tablets;

(d) endothelialising the tabletted mini-tablets or tablets obtained in step (c) using a fluid bed dryer (FBG) and a coating machine; and is

(e) Forming a controlled release coating layer in the endothelial coated mini-tablet or tablet obtained in step (d) using a mixture comprising methacrylic acid copolymer S and methacrylic acid copolymer L.

In another aspect, the present invention provides the use of a pharmaceutical preparation comprising esomeprazole, or a pharmaceutically acceptable salt thereof, as an active ingredient for the prevention and treatment of gastric and esophageal reflux diseases (such as reflux esophagitis) and diseases associated with gastric hyperproliferation (including gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer), and a method for the prevention and treatment of gastric and esophageal reflux diseases (such as reflux esophagitis) and diseases associated with gastric hyperproliferation (including gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer) comprising administering the pharmaceutical preparation according to the present invention to a patient in need of treatment.

Examples

Hereinafter, the present invention will be described in more detail with reference to examples. However, it will be apparent to those skilled in the art that these examples are provided only for illustrating the present invention and should not be construed as limiting the scope of the present invention.

[ examples ]

Examples 1 to 4: preparation of tablets comprising a magnesium salt of esomeprazole

The esomeprazole magnesium salt and mannitol were mixed and granulated through a 30 mesh round sieve. The resulting mixture was blended with microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and sodium stearyl fumarate in an empty blender for 15 minutes to prepare a final blend. The final mixture was dry granulated in a roller mill and the resulting granules obtained were granulated through a 20 mesh round sieve.

Then, mini tablets (MUST) having a hardness of about 1-2kp and a predetermined weight of 7.5mg were prepared by tabletting with a tabletting machine by using MUST punches having a diameter of 2.0 mm.

The composition of the final core comprising the magnesium salt of esomeprazole is shown in table 2.

[ Table 2] composition of core containing magnesium salt of esomeprazole

The tablets were then coated in a fluid bed coater according to the composition of table 3 to obtain endothelial coated tablets with a weight of 7.88 mg.

HPMC is present in the endothelial coated tablets at a content ratio of 4.82(w/w) relative to the weight of the endothelial coated tablets.

[ Table 3] composition of endothelial-coated tablet

Subsequently, the above-described endothelial-coated tablets were coated in a fluidized-bed coater in accordance with the composition of table 4 to prepare coated tablets (controlled-release coated tablets) having a controlled-release coating layer (enteric coating layer), as shown in examples 1 to 4.

TABLE 4 composition of controlled-release coating layer according to examples of the present invention

Examples 1 and 2 in table 4 relate to a table in which ewing S-100 and ewing L-100 as base materials of a controlled release coating are mixed at a ratio of 2:1, and the controlled release coating layer is coated at a content ratio of 25% to 35% (w/w) with respect to the weight of the endothelial coated tablet. Examples 3 and 4 relate to a table in which the ewter S-100 and the ewter L-100 as controlled release coating base materials were mixed at a ratio of 3:1, and the controlled release coating base materials were coated at a content ratio of 20% to 30% (w/w) with respect to the weight of the endothelial coated tablet. Further, the content ratio of HPMC included in the inner coating layer to the total weight of the controlled-release coating base material (i.e., methacrylic acid copolymer S and methacrylic acid copolymer L included in the controlled-release coating layer) is 4.21 to 7.37 (w/w).

In summary, table 5 summarizes content ratios of the respective components in the pharmaceutical preparations according to the embodiments of the present invention, and the like.

TABLE 5 composition and content ratio of pharmaceutical preparations according to examples of the present invention

Comparative examples 1 to 6: preparation of tablets of esomeprazole magnesium salt

Tablets of comparative examples 1 to 6 were prepared, wherein the mini-tablets, which were subjected to the endothelial coating according to the production methods of examples 1 to 4, had a controlled-release coating layer formed according to the composition of table 6.

Comparative examples 1 and 2 in table 6 are compositions in which ewing S-100 and ewing L-100 are mixed at a ratio of 2:1, and a controlled-release coating base material is coated at a content ratio of 10% to 40% (w/w) with respect to the weight of the endothelial coated tablet. Further, comparative examples 3 and 4 relate to tablets in which ewing S-100 and ewing L-100 are mixed at a ratio of 3:1, and a controlled-release coating base material is coated at a content ratio of 10% to 40% (w/w) with respect to the weight of the endothelial coated tablet.

Comparative examples 5 and 6 relate to tablets in which ewing S-100 and ewing L-100 are mixed at a ratio of 6:1, and a controlled-release coating base material is coated at a content ratio of 10% to 20% (w/w) with respect to the weight of the endothelial-coated tablet.

TABLE 6 composition of controlled-release coating layer according to comparative example of the present invention

In summary, content ratios of the respective components of the pharmaceutical preparations according to comparative examples of the present invention and the like are summarized in table 7.

TABLE 7 composition and content ratio of pharmaceutical preparations according to comparative examples of the present invention

Test example 1

The dissolution rate of the magnesium salt of esomeprazole was measured over time under the conditions shown in table 8 using the formulations of examples 1 to 4 and the formulations of comparative examples 1 to 6.

[ Table 8] conditions for measuring dissolution rate of esomeprazole magnesium salt

The results of the measurement of the dissolution rate are shown in tables 9 and 10 and fig. 1 and 2. As can be seen from table 9 and fig. 1, in examples 1 to 4, the delay of drug release in the artificial intestinal juice may be 2 hours or more, and the release may be accelerated once the release is started.

That is, it can be seen that, when the controlled-release coating layer comprises a polymer composed of methacrylic acid copolymer S and methacrylic acid copolymer L mixed at a ratio of 1.5:1 to 3.5:1(w/w), preferably 2:1 to 3:1(w/w) as a controlled-release coating base material, the weight of the controlled-release coating base material is 15% to 40% (w/w), preferably 20% to 35% (w/w), relative to the weight of the tablet comprising the inner coating layer, the weight ratio of the controlled-release coating base material and HPMC in the inner coating layer is 3.5 to 8.0(w/w), preferably 4.2 to 7.4(w/w), and the weight of HPMC in the inner coating layer is 4.4% to 5.2% (w/w), preferably 4.7% to 4.9% (w/w), the esomeprazole is hardly released within 2 hours, the rapid release started after 2 hours and after 6 hours it was 99% or more, which means a very excellent release profile.

As can be seen from the comparison of example 1 and example 3, although a relatively small amount of the controlled-release coating base material was used, there may be a sufficient delay in drug release due to the increased ratio of Ewing S-100, which is relatively insoluble in artificial intestinal fluid.

On the other hand, as can be seen from comparative example 1 and comparative example 3, when the amount of the controlled-release coating agent used was lower than that of the controlled-release coating agent used in examples (wherein 10% or less of the controlled-release coating base material relative to the endothelial coated core tablet was used), the effect of delaying the release of the drug in the artificial intestinal fluid was poor, and as can be seen from comparative example 2 and comparative example 4, when the amount of the controlled-release coating agent used was higher than that of the controlled-release coating agent used in examples (wherein 40% or more of the controlled-release coating base material relative to the endothelial coated core tablet was used), rapid drug release delay was difficult, and the drug was not completely released even after 6 hours, and thus the drug was likely to be discharged before being absorbed in vivo.

Furthermore, considering comparative example 5 and comparative example 6 having a high proportion of relatively insoluble yutex S-100 in the artificial intestinal juice, when 10% or less of the controlled release coating base material is used relative to the endothelial coated core tablet, the release delaying effect is poor, and when 20% or more of the controlled release coating base material is used, disadvantageously, the drug is slowly released over a long period of time after the delayed release, and the final dissolution rate is also less than 100%.

TABLE 9 dissolution rates of magnesium esomeprazole (examples)

TABLE 10 dissolution rates of magnesium esomeprazole (comparative example)

The invention has been described on the basis of its preferred embodiments. Those skilled in the art to which the invention pertains will appreciate that the invention can be implemented in modified forms without departing from the spirit and scope of the invention.

The embodiments disclosed above are therefore to be considered in all respects as illustrative and not restrictive. The scope of the invention is defined by the appended claims rather than the foregoing disclosure, and all differences which fall within the range of equivalents are intended to be construed as being included in the present invention.

Industrial applicability

The present invention relates to a pharmaceutical formulation comprising esomeprazole, or a pharmaceutically acceptable salt thereof. Based on the significantly improved pH-dependent drug release profile, the pharmaceutical formulation according to the present invention 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 completes the release at a predetermined time, thereby providing superior patient convenience and superior therapeutic effects compared to conventional other formulations.

While specific configurations of the present invention have been described in detail, it will be appreciated by those skilled in the art that this description is provided as a preferred embodiment for illustrative purposes and is not to be construed as limiting the scope of the invention. Accordingly, the substantial scope of the present invention is defined by the appended claims and equivalents thereof.

Claims (9)

1. A pharmaceutical formulation, comprising:

(a) a core comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient;

(b) an inner skin coating layer formed on the core; and

(c) a controlled-release coating layer formed on the inner coating layer,

wherein the endothelial coating layer comprises at least one selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC),

the controlled-release coating 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 a controlled-release coating base material, and

the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L as the controlled-release coating base material is 15% to 40% (w/w) with respect to the weight of the endothelial-coated tablet.

2. The pharmaceutical preparation of claim 1, wherein at least one substance present in the endothelial coating layer is selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin and Ethylcellulose (EC) in a content ratio of 3.5 to 8.0(w/w) with respect to the weight of the methacrylic acid copolymer S and the methacrylic acid copolymer L as the base material of the controlled-release coating, and

the content of at least one selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose (HPC-L), starch, gelatin, and Ethylcellulose (EC) contained in the endothelial coating layer is 4.4% to 5.2% (w/w) relative 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 a magnesium esomeprazole salt or a strontium esomeprazole 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 comprising esomeprazole, or a pharmaceutically acceptable salt thereof, further comprises at least one excipient selected from the group consisting of diluents, binders, disintegrants, lubricants, surfactants, antioxidants, preservatives, and stabilizers.

6. The pharmaceutical formulation of claim 1, wherein 5% or less of the esomeprazole, or a pharmaceutically acceptable salt thereof, is eluted within 2 hours at most in a release (dissolution) test using an artificial intestinal fluid (medium) having a pH of 6.7 to 6.9 at a rotation number of 75rpm at 37 ℃ according to USP paddle method, 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 pellets, mini-tablets (MUST), tablets, a mixture of pellets and mini-tablets, and capsules.

8. Use of a pharmaceutical preparation according to any one of claims 1 to 7 for the prevention and treatment of gastric and esophageal reflux diseases of reflux esophagitis and diseases associated with gastric hyperproliferation including gastritis, duodenitis, gastric ulcer, duodenal ulcer and peptic ulcer.

9. A process for preparing a pharmaceutical formulation comprising esomeprazole, or a pharmaceutically acceptable salt thereof, comprising:

(a) mixing esomeprazole, or a pharmaceutically acceptable salt thereof, with a diluent;

(b) adding a disintegrant, a binder, and a lubricant to the mixture of step (a) and then mixing;

(c) obtaining mini-tablets (MUST) or tablets by dry granulation and then tabletting of the mixture of step (b);

(d) endothelialising the tabletted mini-tablets or tablets obtained in step (c) using a fluid bed dryer (FBG) and a coating machine; and is

(e) Using a mixture comprising methacrylic acid copolymer S and methacrylic acid copolymer L in step

(f) The endothelial coated mini-tablet or tablet obtained in (1) forms a controlled release coating layer.