WO2024186124A1

WO2024186124A1 - Pharmaceutical formulation comprising esomeprazole or pharmaceutically acceptable salt thereof

Info

Publication number: WO2024186124A1
Application number: PCT/KR2024/002879
Authority: WO
Inventors: Yeo Hye YOON
Original assignee: Joonghun Pharmaceutical Co ltd
Current assignee: Joonghun Pharmaceutical Co ltd
Priority date: 2023-03-06
Filing date: 2024-03-06
Publication date: 2024-09-12
Anticipated expiration: 2025-09-06
Also published as: KR102579095B1

Abstract

The present disclosure relates to a pharmaceutical formulation comprising a core layer comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, an inner coating layer formed on the core layer and an enteric coating layer formed on the inner coating layer, which has benefits of reduced formulation size and improved stability effect.

Description

PHARMACEUTICAL FORMULATION COMPRISING ESOMEPRAZOLE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

The present disclosure relates to a pharmaceutical formulation comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present disclosure relates to a pharmaceutical formulation comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, which has excellent stability and dissolution properties, and has small size that enhances medication compliance.

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

It is well known in the art that esomeprazole is susceptible to degradation or modification in acidic and neutral media, and more specifically that the degradation half-life of esomeprazole in an aqueous solution with a pH value of 3 or less is less than 10 minutes. Therefore, oral formulations containing esomeprazole must avoid exposure to acidic gastric juices, and must be rapidly absorbed in the gastrointestinal tract which has a pH level of nearly neutral and above 5.5. To this end, formulations have been actively developed using methods such as forming an enteric coating layer.

Specifically, oral formulations of esomeprazole to date have focused on simply preventing exposure to stomach acid in the stomach and developing enteric coatings for absorption in the intestine. Furthermore, based on studies of pH-dependent release properties, formulations have been developed to provide an intended delay of certain time between the oral administration and the drug release, an intended duration time of release, and to provide complete releae after a specified time. However, these formulations not only require long manufacturing process time due to the use of excessive amounts of coating for acid resistance, but also require expensive packaging material, Alu-Alu, due to the problem of tablet bursting during use. Therefore, there is an urgent need for formulations containing esomeprazole with pH-dependent drug release properties and improved stability, manufacturing methods thereof, and packaging methods with improved usability.

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

Another objective of the present disclosure is to provide a pharmaceutical formulation that is stable enough to enable inexpensive packaging, such as HDPE, rather than Alu-Alu packaging.

Another object of the present disclosure is to provide a pharmaceutical formulation that can enhance medication compliance by providing a small size formulation.

Another object of the present disclosure is to provide a pharmaceutical formulation having excellent pH-dependent drug release properties and improved stability such that Alu-Alu packaging is not required and HDPE packaging is possible, which can be manufactured in a small size to enhance medication compliance, and which exhibits bioequivalence to a referenced drug.

In order to achieve the above objects, the pharmaceutical formulation of the present invention is completed as a result of research efforts of the present inventors. Hereinafter, the pharmaceutical formulation of the present disclosure will be discussed in detail.

The present disclosure provides a pharmaceutical formulation comprising (1) a core layer comprising esomeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, (2) an inner coating layer formed on the core layer, and (3) an enteric coating layer formed on the inner coating layer, wherein the enteric coating layer contains methacrylic acid-ethyl acrylate copolymer and sodium hydrogen carbonate, and the methacrylic acid-ethyl acrylate copolymer is contained in an amount of 55 to 65 wt% based on the total weight of the enteric coating layer, and the sodium hydrogen carbonate is contained in an amount of 1.5 to 2.5 wt% based on the total weight of the enteric coating layer.

According to an embodiment of the present disclosure, the inner coating layer may be contained in an amount of 2 to 10 parts by weight based on the 100 parts by weight of the core layer, and the enteric coating layer may be contained in an amount of 10 to 20 parts by weight based on the 100 parts by weight of the core layer.

According to embodiments of the present disclosure, the "pharmaceutically acceptable salt" may be, but is not limited to, metal salts such as sodium, potassium, calcium, magnesium, zinc, lithium or the like, or ammonium salt. Preferably, it may be magnesium salt.

Furthermore, according to an embodiment of the present disclosure, the esomeprazole or the pharmaceutically acceptable salt thereof may be a hydrate or a solvate thereof. The hydrate includes a monohydrate, a dihydrate, a trihydrate, or the like, and preferably it may be a trihydrate.

According to an embodiment of the present disclosure, the esomeprazole or the pharmaceutically acceptable salt thereof may be contained in an amount of 12 to 24 wt% based on the total weight of the core layer, preferably 15 to 20 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, the core layer may comprise one or more of additives selected from an excipient, a binder, a disintegrant, a lubricant, a stabilizer and a surfactant.

According to an embodiment of the present disclosure, as the excipient, one or more species selected from, but not limited to, mannitol, L-arginine, microcrystalline cellulose, lactose, cellulose, low-substituted hydroxypropyl cellulose, starch and sorbitol may be used, and preferably mannitol. The excipient may be contained in an amount of 50 to 75 wt% based on total weight of the core layer, preferably 55 to 70 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the binder, one or more species selected from, but not limited to, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (povidone), pregelatinized starch and low-substituted hydroxypropyl cellulose (HPC-L) may be used, and preferably hydroxypropyl methylcellulose (HPMC). The binder may be contained in an amount of 1 to 5 wt% based on the total weight of the core layer, preferably 1.5 to 4 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the disintegrant, one or more species selected from, but not limited to, crospovidone, croscarmellose sodium, corn starch and low- substituted hydroxypropyl cellulose (HPC-L) may be used, and preferably low- substituted hydroxypropyl cellulose (HPC-L) or crospovidone. The disintegrant may be contained in an amount of 5 to 15 wt% based on the total weight of the core layer, preferably 7 to 12 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the lubricant, one or more species selected from, but not limited to, sodium stearyl fumarate, magnesium stearate, talc, polyethylene glycol, calcium behenate, calcium stearate and hydrogenated castor oil may be used, and preferably sodium stearyl fumarate. The lubricant may be contained in an amount of 1 to 5 wt% based on the total weight of the core layer, preferably 2 to 4 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the stabilizer, one or more species selected from, but not limited to, an antioxidant, an acidifier and an alkalizer may be used, and preferably meglumine as an alkalizer. The stabilizer may be contained in an amount of 1 to 3 wt% based on the total weight of the core layer, preferably 1.5 to 2.5 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the surfactant, one or more species selected from, but not limited to, polysorbate, sodium lauryl sulfate, docusate sodium and sorbitan may be used, and preferably sodium lauryl sulfate. The surfactant may be contained in an amount of 0.5 to 2 wt% based on the total weight of the core layer, preferably 0.7 to 1.5 wt% based on the total weight of the core layer, but is not limited to.

According to an embodiment of the present disclosure, as the inner coating layer of the pharmaceutical formulation comprising the esomeprazole or the pharmaceutically acceptable salt thereof, one or more species selected from, but not limited to, a coating agent, an epidermal supplement, a colorant and a stabilizer may be used.

According to an embodiment of the present disclosure, as the coating agent, one or more species selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), starch and gelatin may be used. Preferably, hydroxypropyl methylcellulose (HPMC) may be used, but is not limited to.

According to an embodiment of the present disclosure, the stabilizer may be magnesium oxide.

According to an embodiment of the present disclosure, the methacrylic acid-ethyl acrylate copolymer of the present disclosure may be contained in an amount of 55 to 65 wt% based on the total weight of the enteric coating layer, preferably 58 to 63 wt% based on the total weight of the enteric coating layer, and more preferably 60 to 62 wt% based on the total weight of the enteric coating layer. If the methacrylic acid-ethyl acrylate copolymer is contained in an amount of more than 65 wt% based on the total weight of the enteric coating layer, the film of the coating layer will not be flexible enough and the formulation will not be suitable for acid resistance. In addition, when the methacrylic acid-ethyl acrylate copolymer is contained in an amount of less than 55 wt%, it is possible to manufacture coated tablets with properties of releasing after 30 minutes in a dissolution solution at pH 5.5, but the process time cannot be shortened due to the need to increased coating amount, resulting in low productivity.

According to an embodiment of the present disclosure, the sodium hydrogen carbonate contained in the enteric coating layer prevents the tablet from sticking during the coating process of the enteric coating layer at low temperature and prevents the penetration of moisture through the film layer after the completion of the coating layer, thereby improving stability of the formulation. The sodium hydrogen carbonate may be contained in an amount of 1.5 to 2.5 wt% based on the total weight of the enteric coating layer, preferably 1.6 to 2.0 wt% based on the total weight of the enteric coating layer. If the sodium hydrogen carbonate is contained in an amount of less than 1.5 wt% based on the total weight of the enteric coating layer, the methacrylic acid-ethyl acrylate copolymer may not dissolve enough to produce homogeneous coating layer which may cause problems during manufacturing process, and if more than 2.5 wt% based on the total weight of the enteric coating layer, the pH of the coating solution will rise which may lead to the problem of the earlier release of methacrylic acid-ethyl acrylate compared to the intended time, which may cause esomeprazole to degrade and lower the body absorption rate.

According to an embodiment of the present disclosure, the enteric coating layer of the pharmaceutical formulation comprising the esomeprazole or the pharmaceutically acceptable salt thereof may further comprise plasticizer.

According to an embodiment of the present disclosure, the plasticizer may be triethyl citrate. The triethyl citrate may be contained in an amount of 5 to 15 wt% based on the total weight of the enteric coating layer, preferably 5 to 10 wt% based on the total weight of the enteric coating layer. However, it is not limited thereto.

According to an embodiment of the present disclosure, a method of manufacturing the pharmaceutical formulation is provided as comprising the following steps:

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

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

(3) forming an enteric coating layer on the inner coating layer.

A core layer may be formed from (a) Composition 1 that is formed from 60 to 80 wt% of the esomeprazole or the pharmaceutically acceptable salt thereof with 85 to 95 wt% of the disintegrant, and (b) Composition 2 that is formed from 20 to 40 wt% of the esomeprazole or the pharmaceutically acceptable salt thereof with the binder.

Preferably, the Composition 1 and the Composition 2 are mixed to form granules, and the granules are mixed with 5 to 16 wt% of the disintegrant, and the lubricant to form a core layer.

When the Composition 1 and the Composition 2 are mixed to prepare a core layer, the release rate of the esomeprazole or the pharmaceutically acceptable salt thereof is increased, resulting in improved absorption.

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

According to an embodiment of the present disclosure, the esomeprazole or the pharmaceutically acceptable salt thereof may be dissolved after 30 minutes in dissolution test solution at pH 5.5 (50 rpm).

According to an embodiment of the present disclosure, the pharmaceutical formulation may retain its appearance of shape and color, and according to an embodiment of the present disclosure, the pharmaceutical formulation may retain its appearance when stored in for 1 month by exposure to an open container at 40°C and 75% relative humidity.

According to an embodiment of the present disclosure, the pharmaceutical formulation may be stored in high density polyethylene (HDPE) bottle. Therefore, it does not need to be stored in Alu-Alu packaging, which makes it economical.

According to an embodiment of the present disclosure, the pharmaceutical formulation may be 5 to 10 mm in diameter, preferably 6 to 9.5 mm in diameter, and 3 to 5 mm thick, preferably 4 to 4.5 mm thick. The circular formulation in FIG. 1 is an example. Therefore, it may improve medication compliance by providing a smaller formulation, unlike Nexium tablets which is commercially available.

The pharmaceutical formulation of the present disclosure has excellent pH-dependent drug release properties and improved stability so that Alu-Alu packaging is not required and HDPE packaging is possible, and it can be manufactured in small size to enhance medication compliance, while exhibiting bioequivalence to a referenced drug.

FIG. 1 shows the size comparison of tablets of Example to Nexium tablet (commercially available).

FIG. 2 shows the results of dissolution test of Example 1 and Nexium tablet (commercially available) at pH 5.5.

FIG. 3 shows the results of dissolution test of Example 1 and Nexium tablet (commercially available) at pH 6.0.

FIG. 4 shows the results of the stability test of Example 1 and Nexium tablet (commercially available) under a stress condition.

FIG. 5 shows the results of dissolution test of Example 1 and Nexium tablet (commercially available) under a stress condition.

FIG. 6 shows the comparison of appearance of Example 1 (center, right) and the generic commercially available products (left) under a stress condition.

Hereinafter, detailed descriptions through embodiments and experimental examples are provided to aid understanding of the present disclosure. However, the embodiments and experimental examples according to the present disclosure may be transformed into many other forms, and the scope of the present disclosure should not be construed as being limited to the following embodiments and experimental examples. The embodiments and experimental examples of the present disclosure are provided to more fully explain the disclosure to a person of ordinary skill in the art.

Example 1: Manufacture of the pharmaceutical formulation of the present disclosure

The pharmaceutical formulation of Example 1 comprises 250 mg of a core layer, 12.5 mg of an inner coating layer and 32.5 mg of an enteric coating layer. The specific ingredients and content are shown in Table 1 below. Specifically, the core layer was prepared by dissolving a mixture comprising esomeprazole magnesium trihydrate 30.0 mg, mannitol 157.60 mg and low-substituted hydroxypropylcellulose 25.0 mg and a mixture comprising esomeprazole magnesium trihydrate 14.5 mg, sodium lauryl sulfate 2.40 mg and hypromellose 7.0 mg in purified water, and then using the binder solution to prepare a wet bulk, which was then dried. The dried granules were mixed with 4.0 mg of meglumine, 2.0 mg of crospovidone and 7.5 mg of sodium stearylfumarate to prepare granules. These granules were tableted and molded into 250 mg per tablet to prepare the core layer (tablets were molded to have tablet hardness of 8 to 12 Kp, disintegration time of 10 minutes or less, and friability of 0.05% or less).

The core layer was then coated with 12.50 mg of Coating Agent 1 to form an inner coating layer and 32.5 mg of Coating Agent 2 to form an enteric coating layer.

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

[Table 1]

The Coating Agent 1 used as the inner coating layer has the composition ratio as follows in Table 2.

[Table 2]

The Coating Agent 2 used as the enteric coating layer has the composition ratio as follows in Table 3.

[Table 3]

Experimental Example 1: Verification of size of the formulation

FIG. 1 shows the size comparison of the Example formulations of the present disclosure and Nexium tablets (commercially available). The formulation of Example 1 is about 46% smaller than Nexium 40 mg tablets, and the formulation of Example 2 is about 57% smaller than Nexium 20 mg tablets. Thus, the pharmaceutical formulations of the present disclosure are smaller than Nexium tablets, thereby significantly improving medication compliance compared to commercially available products.

Experimental Example 2: Dissolution tests at pH 5.5 / pH 6.0

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

1) Buffer Preparation

- 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 sodium dihydrogen phosphate dissolved in 1 L of purified water

2) pH 5.5 dissolution test

Acid resistance test was performed with the tablets placed in 300 mL of 0.1N hydrochloric acid solution at 100 rpm for 120 minutes. Aliquots were taken at 5, 10, 15, 30, and 45 minutes after the addition of 355 mL of 0.086 M sodium phosphate solution, and they were mixed with 300 μL of 0.25N sodium hydroxide solution and analyzed under the following assay condition.

3) pH 6.0 dissolution test

Acid resistance test was performed with the tablets placed in 300 mL of 0.1N hydrochloric acid solution at 100 rpm for 120 minutes. Aliquots were taken at 5, 10, 15, 30 and 45 minutes after the addition of 400 mL of 0.086 M sodium phosphate solution, and they were mixed with 250 μL of 0.25N sodium hydroxide solution and analyzed under the following assay condition.

4) Assay condition (Liquid Chromatography Method)

- Detector: UV 302 nm

- Column: C18, 4.6 cm X 150 mm, 5 μm

- Flow rate: 1.0 mL/min

- Injection amount: 20 μL

- Mobile phase: Liquid made up to 1,000 mL by mixing 350 mL of acetonitrile with 500 mL of phosphate buffer (pH 7.3) and adding purified water

- Phosphate buffer (pH 7.3): 60 mL of 0.5 M sodium hydrogen phosphate in 10.5 mL of 1 M sodium hydrogen phosphate, which was dissolved in 1,000 mL of purified water and then adjusted to pH 7.3.

Results thereof are shown in FIGS. 2 and 3.

As shown in Figure 2, the release of esomeprazole from Nexium tablets started at 140 minutes, at which time esomeprazole may be subject to acidic degradation, which may result in reduced efficacy. On the other hand, in Example 1, the release of esomeprazole does not start until 160 minutes, avoiding the slightly acidic visceral tract (human gastrointestinal tract) where degradation can occur. Thus, the degradation of esomeprazole can be minimized, enabling preparing a drug product with superior efficacy.

Furthermore, as shown in Figure 3, Nexium tablets show a release pattern of less than 80% of the maximum. However, in Example 1, rapid disintegration occurs in the internal section (gastrointestinal tract in the human body) where drug absorption is required to release esomeprazole, resulting in a release pattern approaching 100%. Thus, the formulation of the present disclosure enables the manufacture of pharmaceutical products with excellent pharmaceutical efficacy.

Experimental Example 3: Impurity comparison test under a stress condition

After storing Example 1 and Nexium 40 mg tablets (commercially available) in open containers under a stress condition of temperature 40 °C and 75% relative humidity for 7 days, the changes in impurities were measured under the following conditions.

1) Storage condition: 40°C, 75% relative humidity, stored in open containers for 7 days

2) Preparation of a sample: Twenty of each tablets were powdered, and the amount equivalent to approximately 40 mg of esomeprazole was taken precisely, placed in a 250 mL volumetric flask, labeled with mobile phase, and stirred with a stirrer for 10 minutes. Test solution was prepared by cooling this liquid sufficiently and filtering it through a 0.45 μm membrane filter.

3) Assay condition (Liquid Chromatography Method)

- Detector: UV 280 nm

- Column: C8, 4.6 cm X 125 mm, 5 μm

- Column temperature: Constant temperature of about 35°C.

- Test solution: Maintain at 4 °C

- Flow rate: 1.0 mL/min

- Injection amount: 40 μL

- Analysis time: 50 minutes

- Mobile phase: Liquid prepared by mixing 270 mL of acetonitrile with 730 mL of phosphate buffer (pH 7.6)

- Phosphate buffer (pH 7.6): Prepared by adding 1.8 L of purified water to 2.8 g of sodium phosphate dibasic dodecahydrate, adjusting the pH to 7.6 with phosphoric acid, and adding purified water to make 2,000 mL.

Results thereof are shown in Table 4 and FIG. 4.

[Table 4]

As shown in Table 4 and FIG. 4 above, Nexium 40 mg tablets showed more than 4-fold increase in impurities from the initial level. It is believed that some of the enteric-coated pellets in the core layer failed to maintain the enteric film layer, allowing moisture to penetrate, resulting in an increase in impurities in the active ingredient. This may reduce the therapeutic effectiveness of the active ingredient and may cause some side effects.

In contrast, no increase in impurities was observed in Example 1. Therefore, even when stored in stress conditions or at the end of the expiration date, the drug remains stable, which provides excellent therapeutic effects without side effects.

Experimental Example 4: comparison test of dissolution rate under a stress condition

The dissolution test of the active ingredient over time of Example 1 and Nexium 40 mg tablets (commercially available) was performed after storing Example 1 and Nexium 40 mg tablets in open containers under a stress condition of temperature 40 °C and 75% relative humidity for 7 days. Results thereof are shown in FIG. 5.

As shown in FIG. 5, the dissolution rate of the Nexium tablets was found to decrease from the initial. This may be due to the inability of some of the enteric coated pellets in the core layer to retain the enteric film layer, allowing moisture to penetrate, which may cause some of the active ingredients to degrade, reducing the active ingredients and reducing the therapeutic effect.

In contrast, in Example 1, no change in the dissolution rate from the initial was observed. This suggests that the drug remains stable even when stored in harsh conditions or at the end of the expiration date, and therefore, the same excellent therapeutic effect can be expected as at the beginning.

Experimental Example 5: Appearance comparison test under a stress condition

For a commercially available generic product and Example 1, the change of appearance of formulations was checked after storing them in open containers under a stress condition of temperature 40 °C and 75% relative humidity for 1 month. The result thereof is shown in FIG. 6.

As shown in Figure 6, the commercially available product had a problem that tablets bursted under a stress condition. Therefore, tablets of the commercially available product have the limitation that they must be stored in the Alu-Alu packaging.

In contrast, Example 1 keeps the tablets from bursting under a stress condition, so they do not require Alu-Alu packaging for storage, and cheaper packaging methods such as high density polyethylene (HDPE) can be applied.

Experimental Example 6: Pharmacokinetics (PK) test

A bioequivalence study was performed with Example 1 and Nexium 40 mg tablets, commercially available, as a control. The results are shown in Table 5 below.

[Table 5]

As shown in Table 5 above, Example 1 according to the present disclosure was found to be bioequivalent to the commercially available Nexium tablets (referenced drug), while being superior in dissolution stability and the like.

Claims

A pharmaceutical formulation comprising:

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

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

(3) an enteric coating layer formed on the inner coating layer;

wherein,

the enteric coating layer contains methacrylic acid-ethyl acrylate copolymer and sodium hydrogen carbonate,

and the methacrylic acid-ethyl acrylate copolymer is contained in an amount of 55 to 65 wt% based on the total weight of the enteric coating layer,

and the sodium hydrogen carbonate is contained in an amount of 1.5 to 2.5 wt% based on the total weight of the enteric coating layer.
The pharmaceutical formulation of claim 1,

wherein the core layer comprises one or more of additives selected from an excipient, a binder, a disintegrant, a lubricant, a stabilizer and a surfactant.
The pharmaceutical formulation of claim 2,

wherein the esomeprazole or the pharmaceutically acceptable salt thereof is contained in an amount of 12 to 24 wt% based on the total weight of the core layer;

the excipient is contained in an amount of 50 to 75 wt% based on the total weight of the core layer;

the binder is contained in an amount of 1 to 5 wt% based on the total weight of the core layer;

the disintegrant is contained in an amount of 5 to 15 wt% based on the total weight of the core layer;

the lubricant is contained in an amount of 1 to 5 wt% based on the total weight of the core layer;

the stabilizer is contained in an amount of 1 to 3 wt% based on the total weight of the core layer; and

the surfactant is contained in an amount of 0.5 to 2 wt% based on the total weight of the core layer.
The pharmaceutical formulation of claim 3,

wherein 60 to 80 wt% of the esomeprazole or the pharmaceutically acceptable salt thereof forms Composition 1 with 85 to 95 wt% of the disintegrant,

and 20 to 40 wt% of the esomeprazole or the pharmaceutically acceptable salt thereof forms Composition 2 with the binder.
The pharmaceutical formulation of claim 4,

wherein the Composition 1 and the Composition 2 are mixed to form granules,

and the granules are mixed with 5 to 16 wt% of the disintegrant, and the lubricant to form a core layer.
The pharmaceutical formulation of claim 1,

wherein the inner coating layer is hydroxypropyl methylcellulose (HPMC).
The pharmaceutical formulation of claim 1,

wherein the inner coating layer comprises a stabilizer.
The pharmaceutical formulation of claim 7,

wherein the stabilizer is magnesium oxide.
The pharmaceutical formulation of claim 1,

wherein the enteric coating layer further comprises a plasticizer.
The pharmaceutical formulation of claim 9,

wherein the plasticizer is triethyl citrate.
The pharmaceutical formulation of claim 10,

wherein the triethyl citrate is contained in an amount of 5 to 15 wt% based on the total weight of the enteric coating layer.
The pharmaceutical formulation of claim 1, comprising:

(a) 100 parts by weight of the core layer;

(b) 2 to 10 parts by weight of the inner coating layer; and

(c) 10 to 20 parts by weight of the enteric coating layer.
The pharmaceutical formulation of claim 1,

wherein the core layer disintegrates within 10 minutes in a disintegration test before coating.
The pharmaceutical formulation of claim 1,

wherein the esomeprazole or the pharmaceutically acceptable salt thereof is dissolved after 30 minutes in a dissolution test solution at pH 5.5(50 rpm).
The pharmaceutical formulation of claim 1,

which retains its appearance when stored for 1 month by exposure to an open container at 40°C and 75% relative humidity.
The pharmaceutical formulation of claim 15,

wherein the pharmaceutical formulation is stored in high density polyethylene (HDPE) bottle.
The pharmaceutical formulation of claim 1,

which is 5 to 10 mm in diameter, and 3 to 5 mm thick.