KR102579095B1 - Pharmaceutical formulation comprising Esomeprazole or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation comprising a core layer containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an endothelial coating layer formed on the core layer, and an enteric coating layer formed on the endothelial coating layer. It offers size advantages and improved stability.

Description

Pharmaceutical formulation comprising Esomeprazole or pharmaceutically acceptable salt thereof}

The present invention relates to a pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present invention relates to a pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, which has excellent stability and dissolution characteristics and is convenient for taking due to its small formulation size.

Esomeprazole is a representative proton pump inhibitor used to treat dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. It is a proton pump inhibitor (PPI).

It is well known in the art that esomeprazole is easily decomposed or transformed in acidic and neutral media, and more specifically, it is known that the decomposition half-life of esomeprazole in an aqueous solution with a pH value of 3 or less is less than 10 minutes. Therefore, in the case of oral dosage forms containing esomeprazole, exposure to acidic gastric juice must be prevented, and the pH must be almost neutral and must be allowed to be rapidly absorbed in the corresponding gastrointestinal tract after pH 5.5. To this end, the development of formulations using methods such as forming an enteric coating layer has been actively conducted.

Specifically, oral esomeprazole formulations to date have focused on simply preventing exposure to gastric acid in the stomach and developing an enteric coating for absorption in the intestine. In addition, based on research on pH-dependent release characteristics, release begins from a specific time after the desired delay time has elapsed after oral administration, release occurs for a desired time, and release is completed after a specific time has elapsed. Development of the formulation has been carried out, but the use of an excessive amount of coating for acid resistance not only requires a lot of manufacturing process time, but also causes problems such as tablets bursting during use, so the expensive packaging material Alu-Alu is used. In this situation, there is an urgent need to study a formulation with pH-dependent drug release characteristics containing esomeprazole with improved stability, and a manufacturing method and packaging method with improved convenience of use.

Republic of Korea Patent Publication No. 10-2001-7005682

The object of the present invention is to provide a pharmaceutical formulation that exhibits excellent pH-dependent drug release properties.

Another object of the present invention is to provide a pharmaceutical formulation with excellent stability that allows inexpensive packaging such as HDPE rather than Alu-Alu packaging.

Another object of the present invention is to provide a pharmaceutical formulation that can improve medication convenience by providing a small-sized formulation.

Another object of the present invention is to provide a pharmaceutical product that has excellent pH-dependent drug release characteristics, does not require Alu-Alu packaging, has improved stability to the extent that HDPE packaging is possible, can be manufactured in small sizes, improves medication convenience, and shows bioequivalence. It provides a dosage form.

In order to achieve the above object, as a result of research efforts by the present inventors, the pharmaceutical formulation of the present invention was completed. Hereinafter, the pharmaceutical formulation of the present invention will be examined in detail.

The present invention includes (1) a core layer containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, (2) an endothelial coating layer formed on the core layer, and (3) an enteric coating layer formed on the endothelial coating layer. And, the enteric coating layer includes methacrylic acid-ethyl acrylate copolymer and sodium bicarbonate, and the content of the methacrylic acid-ethyl acrylate copolymer is 55 to 65% by weight based on the total weight of the enteric coating layer, A pharmaceutical formulation is provided in which the content of sodium bicarbonate is 1.5 to 2.5% by weight based on the total weight of the enteric coating layer.

According to an embodiment of the present invention, for 100 parts by weight of the core layer of the pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, 2 to 10 parts by weight of the endothelial coating layer and 10 to 10 parts by weight of the enteric coating layer. It may be 20 parts by weight.

According to an embodiment of the present invention, the “pharmaceutically acceptable salt” may be a metal salt such as sodium, potassium, calcium, magnesium, zinc, lithium, or an ammonium salt, but is not limited thereto. Preferably, it may be a magnesium salt.

Additionally, according to an embodiment of the present invention, esomeprazole or a pharmaceutically acceptable salt thereof may be a hydrate or solvate thereof. The hydrate includes hydrates such as monohydrate, dihydrate, and trihydrate, and may preferably be trihydrate.

According to an embodiment of the present invention, the content of esomeprazole or a pharmaceutically acceptable salt thereof may be 12 to 24% by weight, preferably 15 to 20% by weight, based on the total weight of the core layer. It is not limited.

According to an embodiment of the present invention, the core layer may include one or more additives selected from the group consisting of excipients, binders, disintegrants, lubricants, stabilizers, and surfactants.

According to one embodiment of the present invention, the excipient may be one or more selected from the group consisting of mannitol, L-arginine, microcrystalline cellulose, lactose, cellulose, low-substituted hydroxypropyl cellulose, starch, and sorbitol. , but is not limited thereto, and mannitol may be preferably used. The excipient may be 50 to 75% by weight relative to the total weight of the core layer, preferably 55 to 70% by weight, but is not limited thereto.

According to one embodiment of the present invention, the binder is a group consisting of hydroxypropyl methylcellulose (HPMC), polyvinylphylloridone (povidone), pregelatinized starch, and low-substituted hydroxypropylcellulose (HPC-L). One or more types selected from may be used, but are not limited thereto, and hydroxypropyl methylcellulose (HPMC) may be preferably used. The binder may be 1 to 5% by weight, preferably 1.5 to 4% by weight, based on the total weight of the core layer, but is not limited thereto.

According to one embodiment of the present invention, the disintegrant may be one or more selected from the group consisting of crospovidone, croscarmellose sodium, corn starch, and low-substituted hydroxypropyl cellulose (HPC-L). It is not limited to this, and preferably low-substituted hydroxypropyl cellulose or crospovidone can be used. The disintegrant may be 5 to 15% by weight, preferably 7 to 12% by weight, based on the total weight of the core layer, but is not limited thereto.

According to one embodiment of the present invention, the lubricant may be one or more selected from the group consisting of sodium stearyl fumarate, magnesium stearate, talc, polyethylene glycol, calcium behenate, calcium stearate, and hydrogenated castor oil. It is not limited to this, and preferably sodium stearyl fumarate can be used. The content of the lubricant may be 1 to 5% by weight, preferably 2 to 4% by weight, based on the total weight of the core layer, but is not limited thereto.

According to one embodiment of the present invention, the stabilizer may be one or more selected from the group consisting of antioxidants, acidifiers, or alkalizing agents, but is not limited thereto, and meglumine may be preferably used among the alkalizing agents. there is. The content of the stabilizer may be 1 to 3% by weight, preferably 1.5 to 2.5% by weight, based on the total weight of the core layer, but is not limited thereto.

According to one embodiment of the present invention, the surfactant may be one or more from the group consisting of polysorbate, sodium lauryl sulfate, sodium docusate, and sorbitan, but is not limited thereto, and is preferably lauryl. Sodium sulfate may be used. The content of the surfactant may be 0.5 to 2% by weight, preferably 0.7 to 1.5% by weight, based on the total weight of the core layer, but is not limited thereto.

According to one embodiment of the present invention, the endothelial coating layer of the pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof may be one or more selected from the group consisting of coating agents, skin adjuvants, colorants, and stabilizers. However, it is not limited to this.

According to one embodiment of the present invention, the coating agent consists of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), starch, and gelatin. One or more selected from the group may be used. Preferably, hydroxypropylmethylcellulose (HPMC) can be used, but is not limited thereto.

According to one embodiment of the present invention, the stabilizer may be magnesium oxide.

According to one embodiment of the present invention, the methacrylic acid-ethyl acrylate copolymer of the present invention may be included in 55 to 65% by weight, preferably 58 to 63% by weight, based on the total weight of the enteric coating layer. , more preferably 60 to 62% by weight. If the methacrylic acid-ethylacrylate copolymer exceeds 65% by weight relative to the total weight of the enteric coating layer, the film of the coating layer is not flexible, making it impossible to prepare a formulation suitable for acid resistance. In addition, if the methacrylic acid-ethyl acrylate copolymer is less than 55% by weight, coated tablets with release characteristics after 30 minutes in a pH 5.5 eluate can be manufactured, but the coating amount must be increased, so the process time cannot be shortened, which reduces productivity. This falls.

According to one embodiment of the present invention, sodium bicarbonate contained in the enteric coating layer has the effect of preventing tablets from sticking during low-temperature coating of the enteric coating layer and preventing moisture from penetrating through the film layer after completion of the coating layer. It plays a role in improving the stability of the formulation. The sodium bicarbonate may contain 1.5 to 2.5% by weight, preferably 1.6 to 2.0% by weight, based on the total weight of the enteric coating layer. If the amount of sodium bicarbonate is less than 1.5% by weight relative to the total weight of the enteric coating layer, problems in the manufacturing process may arise in which a homogeneous coating layer cannot be manufactured due to insufficient dissolution of the methacrylic acid-ethyl acrylate copolymer, and 2.5 If the weight % is exceeded, the pH of the coating solution may increase, causing methacrylic acid-ethyl acrylate to be released faster than the target time, causing decomposition of esomeprazole and lowering the absorption rate in the body.

According to one embodiment of the present invention, the enteric coating layer of the pharmaceutical formulation containing esomeprazole or a pharmaceutically acceptable salt thereof may further include a plasticizer.

According to an embodiment of the present invention, the plasticizer may be triethyl citrate. The triethyl citrate may be 5 to 15% by weight, preferably 5 to 10% by weight, based on the total weight of the enteric coating layer. However, it is not limited to this.

According to one embodiment of the present invention, the pharmaceutical formulation provides a manufacturing method comprising the following steps:

(1) preparing a core layer containing esomeprazole or a pharmaceutically acceptable salt thereof;

(2) forming an endothelial coating layer on the core layer; and

(3) Forming an enteric coating layer on the endothelial coating layer.

The core layer is (a) 60 to 80% by weight of esomeprazole or a pharmaceutically acceptable salt thereof forms a first composition with 85 to 95% by weight of the disintegrant,

(b) 20 to 40% by weight of esomeprazole or a pharmaceutically acceptable salt thereof may be formed of the binder and the second composition.

Preferably, the first composition and the second composition are mixed to form granules, and 5 to 15% by weight of the disintegrant and a lubricant are mixed with the granules to form a core layer.

When the core layer is prepared by mixing the first composition and the second composition, the release rate of esomeprazole or a pharmaceutically acceptable salt thereof increases, thereby improving the absorption rate.

According to one embodiment of the present invention, the core layer may disintegrate within 10 minutes in a disintegration test before coating.

According to one embodiment of the present invention, in the pharmaceutical formulation, esomeprazole or a pharmaceutically acceptable salt thereof can be dissolved in a pH 5.5 dissolution test solution (50 rpm) after 30 minutes.

According to one embodiment of the present invention, the pharmaceutical formulation is capable of maintaining its shape and color. According to an embodiment of the present invention, the pharmaceutical formulation is stored in an open container at 40° C. and 75% relative humidity. It may maintain its properties when exposed and stored for one month.

According to an embodiment of the present invention, the pharmaceutical formulation may be stored in a high density polyethylene (HDPE) bottle. Therefore, there is no need to store it in Alu-Alu packaging, thereby securing economic efficiency.

According to an embodiment of the present invention, the pharmaceutical formulation may have a diameter of 5 to 10 mm and a thickness of 3 to 5 mm, preferably a diameter of 6 to 9.5 mm and a thickness of 4 to 5 mm. It may be 4.5 mm. For example, this refers to the circular dosage form in Figure 1. Therefore, unlike commercially available Nexium tablets, the convenience of taking medication can be improved by providing a small dosage form.

The pharmaceutical formulation of the present invention has excellent pH-dependent drug release characteristics, has improved stability to the extent that Alu-Alu packaging is not required and HDPE packaging is possible, and can be manufactured in small sizes, improving medication convenience and showing bioequivalence.

Figure 1 is a photograph comparing the sizes of tablets manufactured in an example of the present invention and Nexium tablets (commercially available).
Figure 2 is a graph showing the dissolution test results of Example 1 of the present invention and Nexium tablets (commercially available) at pH 5.5.
Figure 3 is a graph showing the dissolution test results of Example 1 of the present invention and Nexium tablets (commercially available) at pH 6.0.
Figure 4 is a graph showing the stability test results of Example 1 of the present invention and Nexium tablets (commercially available) under severe conditions.
Figure 5 is a graph showing the results of a dissolution test for Example 1 and Nexium tablets (commercially available products) under severe conditions.
Figure 6 is a photograph comparing the properties of Example 1 (middle, right) and the generic commercial product (left) under harsh conditions.
Figure 7 is a photograph showing an example of Alu-Alu packaging.

Hereinafter, to aid understanding of the present invention, it will be described in detail through examples and experimental examples. However, the examples and experimental examples according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following examples and experimental examples. The examples and experimental examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

Example 1: Preparation of pharmaceutical formulations of the present invention

The pharmaceutical formulation of Example 1 consists of 250 mg of the core layer, 12.5 mg of the endothelial coating layer, and 32.5 mg of the enteric coating layer. Specific ingredients and contents are shown in Table 1 below.

Specifically, the core layer is a mixture containing 30.0 mg of esomeprazole magnesium trihydrate, 157.60 mg of mannitol, and 25.0 mg of low-substituted hydroxypropylcellulose, 14.5 mg of esomeprazole magnesium trihydrate, 2.40 mg of sodium lauryl sulfate, and hypromellose. The mixture containing 7.0 mg was dissolved in purified water, and a wet body was prepared using a binding solution and then dried. Granules were prepared by mixing 4.0 mg of meglumine, 2.0 mg of crospovidone, and 7.5 mg of sodium stearyl fumarate with the dried granules. The granules were compressed into tablets and molded into 250 mg per tablet to purify the core layer (tablets meeting the standards of tablet hardness of 8 to 12 Kp, disintegration time within 10 minutes, and friability of 0.05% or less were molded).

Afterwards, an endothelial coating layer was formed on the core layer with 12.50 mg of the first coating base, and an enteric coating layer was formed with 32.5 mg of the second coating base.

The specific ingredients and contents of Example 2 are as shown in Table 1, and the manufacturing method was the same as Example 1.

Usage Raw material name Usage (1 tablet) (unit: mg) Example 1 Example 2 chief ingredient Esomeprazole Magnesium Trihydrate 30.00 15.00 chief ingredient Esomeprazole Magnesium Trihydrate 14.50 7.25 excipient Mannitol SD100 157.60 78.80 disintegrant Low-substituted hydroxypropyl cellulose 25.00 12.50 binder Hydroxypropylmethylcellulose (HPMC) 7.00 3.50 Surfactants Sodium lauryl sulfate 2.40 1.20 stabilizer Meglumine 4.00 2.00 disintegrant Crospovidone 2.00 1.00 lubricant Sodium stearyl fumarate 7.50 3.75 Core layer mass 250.00 125.00 Usage Raw material name Usage (1 tablet) Example 1 Example 2 Coating mechanism First coating mechanism 12.50 6.25 Coating mechanism Second coating mechanism 32.50 16.25 Coating layer mass 45.00 22.50 Film coated tablets 295.00 147.50

The composition ratio of the first coating base used as the endothelial coating layer is shown in Table 2 below.

Purpose of mixing Raw material name Composition ratio (% by weight) coating agent Hipmellose 75.163 Skin supplements triacetin 7.995 Colorant (pigment) titanium oxide 7.180 Skin supplements Polyethylene glycol 6000 6.662 stabilizer Magnesium Oxide 3.000 Sum 100

The composition ratio of the second coating base used as the enteric coating layer is shown in Table 2 below.

Purpose of mixing Raw material name Composition ratio (% by weight) coating agent Methacrylic acid-ethylcrylate copolymer 61.160 Skin supplements talc 14.396 coloring agent titanium oxide 12.583 plasticizer Triethyl citrate 7.340 Skin supplements sodium bicarbonate 1.835 Colorant (pigment) red iron oxide 1.140 Skin supplements Light anhydrous silicic acid 0.920 Skin supplements Sodium lauryl sulfate 0.460 Colorant (pigment) yellow iron oxide 0.166 Sum 100.00

Experimental Example 1: Checking the size of the formulation

A comparison of the sizes of the example formulation of the present invention and Nexium tablets (commercially available) is shown in Figure 1. The dosage form of Example 1 had a size that was about 46% smaller than that of 40 mg Nexium tablets, and the dosage form of Example 2 had a size that was about 57% smaller than that of 20 mg Nexium tablets. Therefore, the pharmaceutical formulation of the present invention is smaller than Nexium tablets and can greatly improve medication convenience compared to commercial products.

Experimental Example 2: pH 5.5 / pH 6.0 dissolution test

The dissolution rates of Example 1 and Nexium tablets 40 mg (commercially available) were compared in the pH 5.5 dissolution test solution and the pH 6.0 dissolution test solution under the following conditions.

1) Buffer manufacturing method

- 0.1N hydrochloric acid solution: 8.5 mL of hydrochloric acid mixed with 1 L of purified water

- 0.086M sodium phosphate solution: 12.21 g of disodium hydrogen phosphate dissolved in 1 L of purified water

2) pH 5.5 dissolution test

The tablets were placed in 300 mL of 0.1N hydrochloric acid solution and an acid resistance test was performed for 120 minutes at 100 rpm. 355 mL of 0.086M sodium phosphate solution was added, the solution was taken at 5, 10, 15, 30, and 45 minutes, and 300 μL of 0.25N sodium hydroxide solution was added and the mixed solution was analyzed under the analysis conditions below.

3) pH 6.0 dissolution test

The tablets were placed in 300 mL of 0.1N hydrochloric acid solution and an acid resistance test was performed for 120 minutes at 100 rpm. 400 mL of 0.086M sodium phosphate solution was added, the solution was taken at 5, 10, 15, 30, and 45 minutes, and 250 μL of 0.25N sodium hydroxide solution was added and the mixed solution was analyzed under the analysis conditions below.

4) Analysis conditions (liquid chromatographic method)

- Detector: UV 302 nm

- Column: C18, 4.6 cm

- Flow rate: 1.0 mL/min

- Injection volume: 20 μL

- Mobile phase: Mix 350 mL of acetonitrile and 500 mL of phosphate buffer solution (pH 7.3), then add purified water to make 1,000 mL.

- Phosphate buffer solution (pH 7.3): Add 60 mL of 0.5M disodium hydrogen phosphate to 10.5 mL of 1M sodium hydrogen phosphate, dissolve in 1,000 mL using purified water, and then adjust the pH to 7.3.

The results are shown in Figures 2 and 3, respectively.

As shown in Figure 2, in the case of Nexium tablets, the release of esomeprazole begins at 140 minutes. If esomeprazole is released from this point on, decomposition may occur in acid, which may reduce the drug's efficacy. On the other hand, in Example 1, the release of esomeprazole does not begin until 160 minutes, thereby avoiding the slightly acidic intestine (gastrointestinal tract in the human body) where decomposition may occur. Therefore, the decomposition of esomeprazole can be minimized, making it possible to develop a drug with excellent efficacy.

In addition, as can be seen in Figure 3, Nexium tablets show a release pattern of less than 80% of the maximum, but in Example 1, rapid disintegration occurs in the intestine (gastrointestinal tract in the human body) where drug absorption is required to release esomeprazole. By doing so, the emission pattern approaches 100%. Therefore, it is possible to manufacture pharmaceuticals with excellent efficacy through the formulation of the present invention.

Experimental Example 3: Comparison test of impurities under harsh conditions

Example 1 and 40 mg of Nexium tablets (commercially available) were stored in an open container under harsh conditions of 40° C. and 75% relative humidity for 7 days, and then changes in impurities were measured according to the following conditions.

1) Storage conditions: 40℃, 75% relative humidity, stored in an open container for 7 days.

2) Preparation of test solution: Powder 20 tablets of this drug, take an amount equivalent to about 40 mg of esomeprazole, place it in a 250 mL volumetric flask, mark it with a mobile phase, and stir it using a stirrer for 10 minutes. After this solution was sufficiently cooled, the solution filtered through a 0.45 μm membrane filter was used as the sample solution.

3) Analysis conditions (liquid chromatographic method)

- Detector: UV 280 nm

- Column: C8, 4.6 cm

- Column temperature: constant temperature of about 35 ℃

- Test solution: maintained at 4℃

- Flow rate: 1.0 mL/min

- Injection volume: 40 μL

- Analysis time: 50 minutes

- Mobile phase: mixture of 270 mL of acetonitrile and 730 mL of phosphate buffer solution (pH 7.6)

- Phosphate buffer solution (pH 7.6): Add 1.8 L of purified water to 2.8 g of sodium phosphate decahydrate, adjust the pH to 7.6 with phosphoric acid, and add purified water to make 2,000 mL.

The results are shown in Table 4 and Figure 4 below.

Example 1 Nexium tablets 40 mg Initial impurity generation rate (%) 0.040 0.050 Impurity production rate after 7 days (%) 0.044 0.229

As shown in Table 4 and Figure 4, it was confirmed that the impurities in 40 mg of Nexium tablets increased more than 4 times compared to the initial amount. This is believed to be because some of the enteric-coated pellets on the core layer failed to maintain the enteric film layer, allowing moisture to penetrate, resulting in an increase in impurities among the active ingredients. As a result, the therapeutic effect of the active ingredient may be reduced and may cause some side effects.

On the other hand, in Example 1, it was confirmed that impurities did not increase. Therefore, excellent therapeutic effects without side effects can be expected because the drug remains stable even when stored in harsh conditions or when the expiration date has expired.

Experimental Example 4: Comparison test of dissolution rate under harsh conditions

Example 1 and Nexium tablets 40 mg (commercially available) were stored in an open container under harsh conditions of 40°C and 75% relative humidity for 7 days, and then the active ingredients of Example 1 and Nexium tablets 40 mg (commercially available) were stored in an open container under harsh conditions of 40°C and 75% relative humidity for 7 days. A dissolution test was performed. The results are as shown in Figure 5.

As shown in Figure 5, it was confirmed that the dissolution rate of Nexium tablets decreased compared to the initial stage. This may cause some of the enteric-coated pellets on the core layer to fail to maintain the enteric film layer, allowing moisture to penetrate, causing some of the active ingredients to decompose, reducing the active ingredients and reducing the therapeutic effect.

On the other hand, in Example 1, no change in dissolution rate compared to the initial stage could be confirmed. Considering this, the drug remains stable even when stored in harsh conditions or at the expiration of its expiration date, so excellent therapeutic effects can be expected as in the initial stage.

Experimental Example 5: Comparison test of properties under harsh conditions

The commercially available generic product and Example 1 were stored in an open container under harsh conditions of 40°C and 75% relative humidity for 1 month to check whether there was any change in the properties of the formulation. The results are as shown in Figure 6.

As can be seen in Figure 6, commercial products had a problem with tablets bursting under harsh conditions. Therefore, commercial products have a limitation in that they must be stored in the Alu-Alu packaging shown in FIG. 7.

On the other hand, in Example 1, since the tablets are maintained without bursting even under harsh conditions, there is no need to store them in Alu-Alu packaging, and a cheaper packaging method such as HDPE (high density polyethylene) can be applied.

Experimental Example 6: PK (Pharmacokinetics) Test

A bioequivalence test was performed on 40 mg of Nexium tablets, a commercially available product, as a reference drug in Example 1. The results are shown in Table 5 below.

90% confidence interval (0.80 to 1.25) C _max 0.9792~1.2483 AUC _t 0.8530~1.0285

As shown in Table 5, it was confirmed that Example 1 according to the present invention was excellent in dissolution stability as above and was bioequivalent to commercially available Nexium tablets.

Claims (17)

(1) a core layer containing esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient;
(2) an endothelial coating layer formed on the core layer; and
(3) an enteric coating layer formed on the endothelial coating layer;
The enteric coating layer includes methacrylic acid-ethyl acrylate copolymer and sodium bicarbonate,
The content of the methacrylic acid-ethyl acrylate copolymer is 55 to 65% by weight based on the total weight of the enteric coating layer,
The content of sodium bicarbonate is 1.5 to 2.5% by weight based on the total weight of the enteric coating layer,
The core layer includes one or more additives selected from the group consisting of excipients, binders, disintegrants, lubricants, stabilizers, and surfactants,
The content of esomeprazole or a pharmaceutically acceptable salt thereof is 12 to 24% by weight based on the total weight of the core layer,
The content of the excipient is 50 to 75% by weight relative to the total weight of the core layer,
The content of the binder is 1 to 5% by weight based on the total weight of the core layer,
The content of the disintegrant is 5 to 15% by weight relative to the total weight of the core layer,
The content of the lubricant is 1 to 5% by weight based on the total weight of the core layer,
The content of the stabilizer is 1 to 3% by weight based on the total weight of the core layer,
The content of the surfactant is 0.5 to 2% by weight relative to the total weight of the core layer,
60 to 80% by weight of esomeprazole or a pharmaceutically acceptable salt thereof forms a first composition with 85 to 95% by weight of the disintegrant,
20 to 40% by weight of esomeprazole or a pharmaceutically acceptable salt thereof forms a second composition with the binder,
The endothelial coating layer includes a stabilizer,
The stabilizer is magnesium oxide,
As a pharmaceutical formulation,
In the pharmaceutical formulation, esomeprazole or a pharmaceutically acceptable salt thereof is dissolved in a pH 5.5 dissolution test solution (50 rpm) after 30 minutes,
A pharmaceutical formulation that maintains its properties when stored for 1 month when exposed to an open container at 40°C and 75% relative humidity. delete delete delete According to claim 1,
mixing the first composition and the second composition to form granules,
A core layer is formed by mixing 5 to 15% by weight of the disintegrant and a lubricant with the granules,
Pharmaceutical formulation. According to claim 1,
The endothelial coating layer is hydroxypropylmethylcellulose (HPMC),
Pharmaceutical formulation. delete delete According to claim 1,
The enteric coating layer further includes a plasticizer,
Pharmaceutical formulation. According to clause 9,
The plasticizer is triethyl citrate,
Pharmaceutical formulation. According to claim 10,
The triethyl citrate is 5 to 15% by weight relative to the total weight of the enteric coating layer,
Pharmaceutical formulation. According to claim 1,
(a) 100 parts by weight of core layer;
(b) 2 to 10 parts by weight of an endothelial coating layer; and
(c) 10 to 20 parts by weight of an enteric coating layer;
Pharmaceutical formulation. According to claim 1,
The core layer disintegrates within 10 minutes in a disintegration test before coating,
Pharmaceutical formulation. delete delete According to claim 1,
Can be stored in HDPE (high density polyethylene) bottles,
Pharmaceutical formulation. According to claim 1,
5 to 10 mm in diameter,
having a thickness of 3 to 5 mm,
Pharmaceutical formulation.