KR20100078462A - Method of priparing s-omeprazole granule and enteric coated granule thereof - Google Patents

Abstract

PURPOSE: A method for manufacturing enteric granule of S-omeprazole is provided to ensure high spheradizing rate, stability, acid resistance, and productivity. CONSTITUTION: A method for manufacturing enteric granule of S-omeprazole comprises: a step of adding S-omeprazole or pharmaceutically acceptable salt in a mixture of soluble excipient and water insoluble excipient with solvent to prepare a core granule; a step of forming a inner surface coating layer; and a step of forming enteric coating layer on the surface of the inner surface coating layer. The ratio of water soluble excipient and water insoluble excipient is 50:50~80:20.

Description

METHOD OF PRIPARING S-OMEPRAZOLE GRANULE AND ENTERIC COATED GRANULE THEREOF}

The present invention relates to granules of esomeprazole having a high sphericity rate, fast dissolution rate in the intestine, excellent acidity, stability and productivity, and a method for producing the enteric granules thereof.

Omeprazole has the property of being degraded in acidic and neutral media, and is accelerated by acidic compounds and stabilized by alkaline compounds. Esmeprazole ((S) -omeprazole) is also an enantiomer of omeprazole, which possesses the above degradation properties, so that in order to prepare a pharmacologically useful pharmaceutical preparation, an enteric coating is applied to prevent direct contact between acidic gastric fluid and pharmacologically active substance. It is common to do

Formulation of such esomeprazole has been studied in various ways. For example, Korean Patent No. 384960 describes the use of an inactive core body using someprazole magnesium salt as a pharmacologically active ingredient, or by using mannitol and microcrystalline cellulose to prepare pellets containing esomeprazole magnesium salt. the method then enteric-coated by the addition of excipients to formulate into tablets, and are disclosed, the preparation prepared by the above method is currently being sold under the trade name Nexium ^® (Nexium ^®).

In addition, efforts are underway to formulate with various salts of eomeprazole.

It is an object of the present invention to provide a method for preparing enteric granules of esomeprazole having high spheronization yield, high dissolution rate in the intestine, excellent acidity, stability and productivity without using a binder. .

Another object of the present invention is to provide an enteric granule of esomeprazole prepared according to the above production method.

Still another object of the present invention is to provide a method for preparing the esomeprazole granules.

 To achieve these and other advantages and in accordance with the purpose of the present invention,

(a) adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight to prepare core granules;

(b) forming an endothelial coating layer on the surface of the core granules; And

(c) forming an enteric coating layer on the surface of the endothelial coating layer,

Provided are methods for preparing enteric granules of esomeprazole.

The present invention also provides an enteric granule of esomeprazole prepared according to the above production method.

The present invention also includes the steps of preparing a granule by adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight, It provides a method for producing esomeprazole granules.

The granules of esomeprazole prepared according to the method of the present invention and their enteric granules have a strength that does not break easily without using a binder, have a high spherical yield, have a high dissolution rate in the intestine, high acid resistance, stability and productivity. It can be used for the treatment and prevention of gastric acid-related diseases such as gastroesophageal reflux, inflammation of the gastrointestinal tract, gastrointestinal ulcers and the like.

In general, in the preparation of granules, binders are used to ensure that the main components and excipients used in the granules bind well with each other to maintain the shape of a sphere. In addition, it is important to maintain the strength so that it does not break or change shape in the coating or the like after the molding of the granules, and for this purpose, it is generally prepared by adding a binder. In this case, as the binder, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), povidone (PVP), carboxymethyl cellulose sodium, and the like are used.

The present inventors have steadily tried to formulate esomeprazole or a pharmaceutically acceptable salt thereof, and the productivity of the esomeprazole or a pharmaceutically acceptable salt thereof greatly depends on the presence or absence of the binder during the scale-up process. I found that That is, when the main components used in the formulation, the someprazole strontium salt and magnesium salts are associated with water, the main components are melted or wetted by water to form a sticky coalescing strongly. The use of conventional binders which are pharmaceutically used in the manufacture of these associations results in the formation of more cohesive associations. Therefore, since the formed coalesce adheres to the wall surface or the bottom of the spheronizer in the spheronization process after extrusion, spherical formation is not easy, and after cleaning the base wall and the bottom of the spheronizer even after one spheronization There is a problem in that productivity is lowered due to difficulty in forming a continuous sphere, such as the following work. In addition, when spheroidized without using a binder, spherical granule formation is not easy, and even when granules are formed, when the granules are floated in the air at a constant air pressure to be coated with a fluidized bed coater, the granules flow in the fluidized bed coater. There is a problem that the granules float in the air and fall to the floor.

Thus, the present inventors have made constant efforts to produce granules having a strength suitable for coating using a fluidized bed coater without the use of a binder. As a result, by appropriately adjusting the blending ratio between the water-soluble excipient and the water-insoluble excipient, a method was developed in which the spherical granules can be industrially produced without the use of a binder.

The method for preparing enteric granules of esomeprazole according to the present invention comprises (a) esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble excipients and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight. Adding a solvent to preparing core granules; (b) forming an endothelial coating layer on the surface of the core granules; And (c) characterized in that it comprises the step of forming an enteric coating layer on the surface of the endothelial coating layer.

Hereinafter, each step of the manufacturing method will be described in more detail.

(a) preparing the core granules

In the present invention, the step of preparing the core granules, the core by adding a solvent to the mixture of water soluble excipient and water insoluble excipient in the ratio of eomeprazole or a pharmaceutically acceptable salt thereof, and 49:51 to 85:15 by weight The process consists of producing granules.

Specifically, the association is prepared by adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight, and the association The spherical core granules may be formed after extrusion molding to form spherical core granules.

Esomeprazole or a pharmaceutically acceptable salt thereof of the present invention is disclosed, for example, in Korean Patent Nos. 641534 and 818753. Pharmaceutically acceptable salts used in the present invention include optically pure, heat stable, non-hygroscopic and high water solubility, for example, strontium salt, magnesium salt, calcium salt, potassium salt, sodium salt, zinc salt Or barium salts and the like can be used, among which strontium salts are particularly preferred.

The amount of esomeprazole or a pharmaceutically acceptable salt thereof is 10 to 60% by weight, preferably 20 to 50% by weight based on the total weight of the core granules.

The water-soluble excipient used in the present invention is preferably selected from the group consisting of D-mannitol, lactose monohydrate, anhydrous lactose, and mixtures thereof, and the water-insoluble excipient is microcrystalline cellulose, dibasic calcium phosphate Group consisting of anhydrides and hydrates, starches, pregelatinized starches, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose, light silicic anhydrides, aluminum magnesium silicate, aluminum magnesium metasilicate, starch glycolate and mixtures thereof It is preferred to be selected from. More preferably, D-mannitol is used as the water-soluble excipient and microcrystalline cellulose is used as the water-insoluble excipient.

The water-soluble excipient and the water-insoluble excipient are preferably used in a mixing ratio of about 49:51 to about 85:15 by weight, more preferably about 50:50 to about 80:20. desirable. If the ratio of the water-soluble excipient is too high, the strength of the granules may be lowered to produce granules unsuitable for coating. If the ratio of the water-soluble excipient is too low, the dissolution rate may occur. desirable.

The mixture of the water-soluble excipient and the water-insoluble excipient may be used in a ratio of 0.1 to 50 parts by weight, preferably 0.3 to 30 parts by weight based on 1 part by weight of esomeprazole or a pharmaceutically acceptable salt thereof.

The combination is prepared by adding a solvent to the above ratio of eomeprazole or a pharmaceutically acceptable salt thereof, and a mixture of a water-soluble excipient and a water-insoluble excipient. As a preferable solvent which can be used for the association, water, ethanol or a mixture thereof can be used.

The present invention is characterized by not using binders commonly used in the formation of core granules of general pharmaceutical formulations in order to improve the productivity of the granules and to increase the stability of esomeprazole or its pharmaceutically acceptable salts.

Subsequently, after further extruding by using an extruder through which a sieve is passed through a sieve by applying a constant pressure to the prepared assembly, a spheronizer commonly used has a particle diameter of 0.3 to 2.0 μm. Core granules in the form of spherical or elongated circular rods can be prepared.

(b) forming an endothelial coating layer

Eomeprazole or a pharmaceutically acceptable salt thereof has the property of being easily degraded by acidic compounds. Therefore, in order to prevent direct contact between the acidic enteric coating layer and the esomeprazole component, an endothelial coating layer is formed on the surface of the core granules prepared in step (a).

The endothelial coating layer is formed of an endothelial coating material selected from the group consisting of hydroxypropylmethyl cellulose, polyvinyl alcohol, povidone, carboxymethyl cellulose sodium and mixtures thereof. The endothelial coating material may be used by itself or diluted with water, ethanol, acetone or a mixture thereof. The endothelial coating material may be used in a ratio of 0.05 to 0.6 parts by weight, preferably 0.1 to 0.4 parts by weight based on 1 part by weight of the core granules.

Coating can be carried out under conventional conditions by spraying in a top spray, bottom spray or tangential spray manner using a commonly used coater, for example a fluidized bed coater. For example, it can be carried out at a spray rate of 1 to 100 ml / min depending on the capacity of the fluidized bed coater using inlet temperature 30 to 80 ℃, outlet temperature 25 to 50 ℃, product temperature 20 to 40 ℃ temperature range After coating, the product temperature may be dried at 20 to 40 ° C. for 0.5 to 2 hours to form an endothelial coating layer.

In the present invention, the endothelial coating layer may be made by further comprising an additive such as talc and titanium oxide in an amount of 1 to 5% by weight based on the core weight, as required, together with the endothelial coating material.

(c) forming an enteric coating layer

The present invention provides a method for forming eosmeprazole or a pharmaceutically acceptable salt thereof, which is easily decomposed by an acidic compound, so as to disintegrate and elute in basic intestinal fluid without disintegrating and eluting in acidic gastrointestinal fluid. An enteric coating layer is formed on the surface of the endothelial coating layer.

The enteric coating layer is an enteric coating selected from the group consisting of hydroxypropylmethylcellulose phthalate (HPMCP), acrylic acid copolymers (eg Eudragit), cellulose acetate phthalate, and mixtures thereof. It is formed of a material. Enteric coatings can be used on their own or diluted with water, ethanol, acetone or mixtures thereof. The enteric coating material may be used in a ratio of 0.2 to 1 parts by weight, preferably 0.2 to 0.8 parts by weight based on 1 part by weight of the core granules on which the endothelial coating layer is formed, and the coating may be performed in the same manner as the endothelial coating layer formation. have.

In the present invention, the enteric coating layer is one or two or more additives such as acetylate monoglycerides, triacetin, polyethylene glycol, propylene glycol, talc, titanium oxide and the like, together with the enteric coating material. It may be further included in an amount of 1 to 10% by weight on a basis.

The present invention also provides an enteric granule of esomeprazole prepared according to the above production method.

The present invention also includes the steps of preparing a granule by adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight. It provides a method for producing esomeprazole granules.

The process for producing the granules is the same as the process for preparing the core granules of step (a) described above.

The granules of esomeprazole prepared according to the preparation method of the present invention and their enteric granules have a strength that does not easily break without using a binder, have a high spherical yield, have a high dissolution rate in the intestine, acid resistance, stability and Excellent productivity can be effectively used for the treatment and prevention of gastric acid-related diseases such as gastroesophageal reflux, gastrointestinal inflammation, gastrointestinal ulcers and the like.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example

<Preparation of core granules containing esomeprazole or a pharmaceutically acceptable salt thereof>

Examples 1 to 4, and Comparative Example 1

In the ratio as shown in Table 1 below, eomeprazole strontium tetrahydrate, microcrystalline cellulose (Avicel PH101, FMC Biopolymer), D-mannitol (Roquette) and an appropriate amount of water were added to prepare an association.

The union was extruded with an extruder (TDG-110PA, Dalton), and then spherical core granules having a particle diameter of 0.3 to 2.0 μm were prepared using a spheronizer (Q-400TG, Dalton).

ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Someprazole Strontium Tetrahydrate
(g) 49.3 49.3 49.3 49.3 49.3 Water soluble excipient / water insoluble excipient (g)
D-mannitol
Microcrystalline cellulose
25
26
30
21
40
11
43
8
46
5

Comparative Examples 2 to 6

As shown in Table 2 below, except that a binder of hydroxypropyl cellulose, povidone and hydroxypropyl methyl cellulose in a proportion was used, the same procedure as in Examples 1 to 4 had a particle diameter of 0.3 to 2.0 μm. Spherical granules were prepared.

ingredient Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Someprazole strontium tetrahydrate (g) 49.3 49.3 49.3 49.3 49.3 Water soluble excipient / water insoluble excipient (g)
D-mannitol
Microcrystalline cellulose
40
11
40
11
40
11
40
11
40
11 Binder (g)
Hydroxypropyl cellulose
Povidone
Hydroxypropylmethylcellulose
0.8
-
-
1.6
-
-
3.2
-
-
-
1.6
-
-
-
1.6

Preparation of Enteric Spherical Granules

Examples 5 and 6

As shown in Table 3 below, in the core granules prepared in Example 3, a coating liquid prepared by dissolving hydroxypropylmethylcellulose (Shin-Etsu) and talc in a mixture of water and ethanol, a fluidized bed coater (NQ-160) The endothelial coating was performed under conditions of an inlet temperature of 45 ° C, an outlet temperature of 30 to 35 ° C, and a coating liquid spray amount of 1 to 1.5 ml / min.

HPMCP (Shin-Etsu), acetylate monoglyceride (Myvacet, Kerry Bio-Science), talc, and titanium oxide dissolved in ethanol and acetone on the surface of the granules on which the endothelial coating layer was formed. Enteric coating was performed under the conditions to prepare enteric spherical granules having a particle diameter of 0.3 to 2.0 mu m.

Example 5 Example 6 Comparative Example 7 Comparative Example 8 Core Granules (g)
Example 3
100.3 Example 3
100.3 Comparative Example 3
101.9 Comparative Example 5
101.9 Endothelial coating (g)
HPMC
Talc
17.3
2.7
17.3
2.7
17.3
2.7
17.3
2.7 Enteric coating (g)
HPMCP
Acetylate monoglycerides
Talc
TiO ₂
21
One
3
0.5
42
2
6
One
42
2
6
One
42
2
6
One Mass ratio of enteric coating layer to core with endothelial coating layer formed 21.2 42.4 41.8 41.8

Test Example 1 Measurement of Spherization Yield According to Use of Binder

In the spheronization process to prepare the granules of Examples 1 to 4 and Comparative Examples 2 to 6, the spherical shape was reduced, except for the amount adhered to the base wall of the spheronizer and the amount passed through the 60 mesh body for the dosage (about 1 kg). Yield obtained by successful conversion is shown as%.

Example 1 Example 2 Example 3 Example 4 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 input
Gross mass (g) 999.9 1014.9 1002.4 1014.6 972.9 987.4 1007.6 1015.6 1046.6 On the wall
Sticking amount (g) 37.4 38.2 25.2 22.2 134.3 162.2 194.2 184.2 224.2 60mesh
Passing amount (g) 0.5 0.7 1.2 1.4 0.6 0.2 0.4 0.4 0.4 Spherical
Success amount (g) 962.0 976.0 976.0 989.0 838.0 825.0 813.0 831.0 822.0 Spherical
yield(%) 96.2% 96.2% 97.4% 97.7% 86.1% 83.6% 80.7% 81.8% 78.5%

As can be seen in Table 4, it can be seen that the granules of Examples 1 to 4 without using the binder have a higher spheronization yield than the granules of Comparative Examples 2 to 6 using the binder.

Test Example 2: Determination of wear and tear of granules according to the ratio of water-soluble excipient and water-insoluble excipient

After the granules prepared in Examples 1 to 4 and Comparative Example 1 were passed through a 60 mesh sieve, the remaining amount was placed in a fluidized bed coater (NQ-160), and constant air was injected to flow the granules. The granules were flowed to adjust the distance of the granules falling into the air (falling width) to about 50 cm and then flowed again for 30 minutes. Thereafter, the granules were collected and passed through a 60 mesh sieve, and then the ratio remaining without breaking was measured.

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Ratio of water soluble excipient / (water soluble excipient + water insoluble excipient) (% by weight) 49.0 58.8 78.4 84.3 90.2 50cm, after 30 minutes drop, 60 mesh (about 300㎛) passage (%) 0.7 1.5 3.2 4.4 12.4 % Not broken 99.3 98.5 96.8 95.6 87.6

As can be seen in Table 5, when the amount of water-soluble excipient relative to the total excipient exceeds 85% by weight, wear and tear increased significantly. On the other hand, in the case of Examples 1 to 4, wherein the water-soluble excipient is about 85% or less with respect to the total excipients, it was confirmed that the spherical granules having excellent abrasion resistance can be prepared without using a binder. Since the water-soluble excipient is more easily broken in Comparative Example 1 than 90%, it can be seen that it is not suitable for fluid bed coating.

Test Example 3 Dissolution Test of Core Granules

For the granules prepared in Examples 1 to 4 and Comparative Examples 2 to 6, 40 mg of esomeprazole was filled into gelatin capsules, and then artificial intestinal fluid (1000 mL, 0.1 mol / L hydrochloric acid 300) was prepared using a sinker. 700 mL of 0.086 mol / L sodium dihydrogen phosphate solution was added to the mL), and 100 turns every 10 minutes for 10 to 60 minutes according to the Dissolution Test Method 2 (paddle method) It was. After exactly 5 mL of the eluate was taken according to the determined time, it was immediately transferred to a test tube containing 1 mL of 0.25 M NaOH and stirred. This was passed through a 0.45㎛ membrane filter and analyzed according to the analysis conditions below to calculate the dissolution rate. The results are shown in FIGS. 1A and 1B.

Figure 1a is a dissolution test results of the core granules prepared in Examples 1 to 4, Figure 1b is a dissolution test results of the core granules prepared in Examples 3 and Comparative Examples 2 to 6.

<Analysis Condition>

Detector: UV absorbance photometer (Hitachi, Japan, Wavelength: 302 nm)

Column: Zorbax Eclipse XDB-C18 (5㎛, 4.6 × 150 mm)

Mobile phase: Acetonitrile: phosphate buffer (pH 7.3): Water mixture (350: 500: 150)

Flow rate: 1.0 mL / min

Injection volume: 10 μl

As shown in Figures 1a and 1b, it can be seen that the granules of Examples 1 to 4 according to the present invention have a faster dissolution rate and a higher dissolution rate than Comparative Examples 2 to 6. From these results it can be seen that the enteric granules according to the present invention has excellent dissolution properties.

Test Example 4: Stability Test

The granules prepared in Example 3 and Comparative Examples 3, 5, and 6 were packaged in HDPE bottles, and then, at 40 ° C. and 75% relative humidity, stability at 2 month intervals for 6 months at the beginning of the test. It was confirmed. The stability comparison was confirmed through the content and the flexible material, and the results are shown in FIGS. 2 to 4.

Figure 2 is the content stability test results of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6, Figure 3 is a total soft material of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6 It is a stability test result, Figure 4 is a soft material stability test results found in 0.45 minutes of the relative retention time (RRT) of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6.

As shown in Figures 2 to 4, the change in the content of the granules of Example 3 without using a binder, compared to the use of HPC, povidone or HPMC, respectively, as a binder It was less than in Examples 3, 5 and 6. In addition, Example 3 was the least amount of increase in the formation of the flexible material over time.

In addition, the flexible material of the relative holding time (RRT) 0.45 minutes of the flexible material shows the most noticeable change, it was confirmed that the amount of the flexible material also the third embodiment. From these results, it can be seen that the granules of Example 3 according to the present invention without using the binder have superior content and stability of the softening material than the granules of the comparative example using the binder.

Test Example 5: Acid resistance test

For enteric-coated granules prepared in Example 6 and Comparative Examples 7, 8, 40 mg of the corresponding amount as esomeprazole was filled into gelatin capsules, and then dissolved in 300 mL of artificial gastric fluid using a sinker. It was tested at 100 revolutions per minute according to Method 2 (paddle method). 2 hours after the start of the elution, the pellet remaining in the elution was filtered through 30 mesh sieve, and only the pellet portion was taken into a 100 mL volumetric flask. Then, 40 mL of phosphate buffer (pH 11.0) and 20 mL of methanol were added and stirred by hand for 5 minutes. Ultrasonic extraction. Phosphate buffer (pH 11.0) was added thereto to exactly 100 mL, and the solution passed through a 0.45 µm membrane filter was analyzed according to the analysis conditions of Test Example 3 to confirm acid resistance. The results are shown in FIG.

5 is an acid resistance test results of the enteric spherical granules prepared in Example 6 and Comparative Examples 7, 8.

As shown in FIG. 5, when the enteric coating material is 0.2 parts by weight or more with respect to 1 part by weight of the core granules on which the endothelial coating layer is formed, the acid resistance of 90% or more is generally required.

Test Example 6: Dissolution Test

For spherical granules of esomeprazole prepared in Example 6 and Comparative Examples 7, 8, the dissolution rate was analyzed in the same manner as in Test Example 3, and the results are shown in FIG.

6 is a dissolution test result of the enteric spherical granules prepared in Example 6 and Comparative Examples 7, 8.

As shown in FIG. 6, the spherical enteric granules of esomeprazole of Example 6 exhibited a rapid dissolution rate at the same level as Nexium tablets commercially available as the esomeprazole formulation, but the enteric granules of Comparative Examples 7 and 8 using a binder. It can be seen that the elution rate is slow compared to Example 6 of the present invention.

Figure 1a is a dissolution test results of the core granules prepared in Examples 1 to 4,

Figure 1b is a dissolution test results of the core granules prepared in Example 3, and Comparative Examples 2 to 6,

2 is a content stability test results of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6,

3 is a test result of the stability of the total cast material of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6,

Figure 4 is a result of the soft material stability test found in 0.45 minutes of the relative retention (RRT) of the spherical granules prepared in Example 3 and Comparative Examples 3, 5, 6,

5 is an acid resistance test results of the enteric spherical granules prepared in Example 6 and Comparative Examples 7, 8,

6 is a dissolution test result of the enteric spherical granules prepared in Example 6 and Comparative Examples 7, 8.

Claims (17)

(a) adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight to prepare core granules; (b) forming an endothelial coating layer on the surface of the core granules; And (c) forming an enteric coating layer on the surface of the endothelial coating layer, Method for preparing enteric granules of esomeprazole. The method of claim 1, The ratio of the water-soluble excipient and water insoluble excipient is 50:50 to 80:20 based on the weight, method for producing enteric granules of esomeprazole. The method of claim 1, The method for producing eomeprazole enteric granules, characterized in that the core granules are prepared in the step (a) without using a binder. The method of claim 3, wherein The binder is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, carboxymethyl cellulose sodium, and mixtures thereof. The method of claim 1, Preparation of enteric granules of esomeprazole, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of strontium salt, magnesium salt, calcium salt, potassium salt, sodium salt, zinc salt, barium salt and mixtures thereof. Way. The method of claim 1, The pharmaceutically acceptable salt is a strontium salt, characterized in that the preparation of enteric granules of esomeprazole. The method of claim 1, The water-soluble excipient is selected from the group consisting of D-mannitol, lactose monohydrate, anhydrous lactose and mixtures thereof, and the water-insoluble excipient is anhydrous and hydrate of microcrystalline cellulose, dibasic calcium phosphate, starch, pregelatinized starch, low substitution The enteric properties of eomeprazole, characterized in that it is selected from the group consisting of hydroxypropyl cellulose, crospovidone, croscarmellose, light silicic anhydride, aluminum magnesium silicate, aluminum magnesium metasilicate, starch sodium glycolate and mixtures thereof. Method for producing granules. The method of claim 1, The mixture of the water-soluble excipient and the water-insoluble excipient, characterized in that used in the ratio of 0.1 to 50 parts by weight based on 1 part by weight of eomeprazole or a pharmaceutically acceptable salt thereof, method for producing enteric granules of eomeprazole. The method of claim 1, The endothelial coating layer is formed of an endothelial coating material selected from the group consisting of hydroxypropyl methyl cellulose, polyvinyl alcohol, povidone, carboxymethyl cellulose sodium, and mixtures thereof. The method of claim 9, The endothelial coating material is used in a proportion of 0.05 to 0.6 parts by weight based on 1 part by weight of the core granules, method for producing enteric granules of esomeprazole. The method of claim 9, The endothelial coating material is used in a proportion of 0.1 to 0.4 parts by weight based on 1 part by weight of the core granules, method for producing enteric granules of esomeprazole. The method of claim 9, The endothelial coating layer is formed by further comprising an additive selected from the group consisting of talc, titanium oxide and mixtures thereof, a method for producing enteric granules of esomeprazole. The method of claim 1, The enteric coating layer is formed of an enteric coating material selected from the group consisting of hydroxypropylmethylcellulose phthalate, acrylic acid copolymer, cellulose acetate phthalate, and mixtures thereof. The method of claim 13, The enteric coating material is 0.2 to 1 parts by weight based on 1 part by weight of the core granules with an endothelial coating layer, characterized in that the preparation method of enteric granules of eomeprazole. The method of claim 13, Enteric coating layer is characterized in that the enteric coating layer is formed by further comprising an additive selected from the group consisting of acetylate monoglycerides, triacetin, polyethylene glycol, propylene glycol, talc, titanium oxide and mixtures thereof Method for producing granules. Esomeprazole enteric granules prepared according to the method of any one of claims 1 to 15. Preparing a granule by adding a solvent to esomeprazole or a pharmaceutically acceptable salt thereof and a mixture of water-soluble and water-insoluble excipients in a ratio of 49:51 to 85:15 by weight to prepare granules of esomeprazole granules. Manufacturing method.

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