KR101845665B1 - Oral solid formulation composition comprising proton pump inhibitor, oral solid formulation comprising the same and manufacturing method thereof - Google Patents

Abstract

The present invention relates to an oral solid formulation composition comprising: a proton pump inhibitor or a pharmaceutically acceptable salt thereof; and a basic additive, wherein a content of the basic additive is 2-13 parts by weight per 100 parts by weight of the proton pump inhibitor or the pharmaceutically acceptable salt thereof, and to an oral solid formulation comprising the same and a method for manufacturing the same. According to the present invention, an oral solid formulation which is excellent in stability against moisture and low pH can be provided, while the production of a soft substance is remarkably reduced.

Description

TECHNICAL FIELD [0001] The present invention relates to an oral solid preparation composition containing a proton pump inhibitor, an oral solid preparation containing the same, and a preparation method thereof,

The present invention relates to an oral solid preparation composition containing a proton pump inhibitor, an oral solid preparation containing the same, and more particularly to a proton pump inhibitor or a pharmaceutically acceptable salt thereof, The present invention relates to an oral solid preparation composition having excellent stability with remarkably reduced production of a flexible substance by including an additive, an oral solid preparation containing the same, and a preparation method thereof.

Proton pump inhibitor (PPI) is an effective inhibitor of gastric acid secretion by the inhibition of H ⁺ , K ⁺ -ATPase, an enzyme involved in the final stage of hydrogen ion production in parietal cells, Related diseases such as gastric ulcer, hemorrhagic ulcer, duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID) -induced ulcer, peptic ulcer, erosive esophagitis, gastroesophageal reflux disease, Helicobacter pylori Infection, Zollinger-Ellison syndrome, indigestion and gastritis.

However, some of the proton pump inhibitors have a property of changing color or rapidly decomposing when exposed to water, and are very unstable under acidic to neutral conditions, and thus there is a considerable restriction on formulation.

In order to solve such a problem, Patent Document 1 (Korean Patent Laid-Open Publication No. 10-2013-0115593) discloses a two-layered tablet containing an NSAID and a proton pump inhibitor, in which a basic additive is added to a layer containing a proton pump inhibitor An agent for creating an environment of a basic condition so as to minimize the generation of a flexible substance by improving the stability of a proton pump inhibitor is disclosed.

According to the prior art, the release of the gastrointestinal tract improves the stability of the drug to a low pH environment, and the production of a soft substance can be suppressed. However, in Patent Document 1, in order to secure the stability of the proton pump inhibitor, 2 to 10 parts by weight of a basic additive is contained based on 1 part by weight of the proton pump inhibitor. Since a large amount of a basic additive is used in this way, . In addition, there is still a problem of storage stability since the property of color change or rapid decomposition does not improve when it is still in contact with moisture.

Therefore, it is necessary to study the method to improve the stability of the proton pump inhibitor and the stability to low pH and to minimize the amount of the basic substance while reducing the content of the basic additive to reduce the size of the oral tablets. It is true.

KR 1020130115593 A

The present invention relates to an oral solid preparation composition having an excellent stability with remarkably reduced production of a soft substance by including a basic additive in a range of 2 to 13 parts by weight based on 100 parts by weight of a proton pump inhibitor or a pharmaceutically acceptable salt thereof, Oral solid preparations.

The present invention also provides a method for producing an oral solid preparation having excellent production efficiency by using a wet granulation method.

In order to solve the above problems, the present invention provides a proton pump inhibitor or a pharmaceutically acceptable salt thereof; And a basic additive, wherein the amount of the basic additive is 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof.

The proton pump inhibitor may be selected from the group consisting of Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Tenatoprazole, , A pharmaceutically acceptable salt thereof, and a precursor thereof, and may preferably include dexlansoprazole.

The basic additive is _{NaOH, NaHCO 3, CaCO 3,} MgCO 3, KH 2 PO 4, K 2 HPO 3, Ca (OH) 2, Mg (OH) 2, Na 2 HPO 4, MgCO 3, NaH 2 PO 4, Na ₃ PO ₄ , calcium trichloro phosphate, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, and pharmaceutically acceptable salts thereof.

The composition may further include at least one selected from the group consisting of a diluent, a water-soluble polymer, and an enteric material.

Specifically, the diluent may include one or more selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol, and glucose, and the water-soluble polymer may include hydroxypropylcellulose, Hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypentylcellulose, and hydroxypropylbutylcellulose, and the enteric substrate may be at least one selected from the group consisting of poly (methylmethacrylate methyl methacrylate) Hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and carboxymethylethylcellulose.

On the other hand, the present invention provides an oral solid preparation comprising the oral solid preparation composition.

The solid preparation may further include at least one selected from the group consisting of mannitol, disintegrant, and glidant.

A core comprising the oral solid preparation composition, a water-soluble coating layer covering the surface of the core, and an enteric coating layer covering the surface of the water-soluble coating layer.

The water-soluble coating layer may include one or more selected from the group consisting of cellulose ether, polyvinylpyrrolidone, and polyvinyl alcohol, wherein the cellulose ether is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose Cellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypentylcellulose, and hydroxypropylbutylcellulose.

The enteric coating layer may include one or more selected from the group consisting of hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate, and derivatives thereof.

In addition, the present invention provides a method for producing the oral solid preparation, which comprises: (1) preparing a mixed powder comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof; (2) preparing a binding liquid containing a basic additive; (3) combining and drying the mixed powder and the coupling liquid; And (4) granulating the dried material obtained in the step (3) to prepare granules.

The amount of the basic additive may be 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof.

The mixed powder may further include at least one selected from the group consisting of a diluent and a water-soluble polymer.

The solvent of the binding solution may be water; And one or more organic solvents which are miscible with water, wherein the organic solvent may be selected from ethanol, isopropanol and acetone. The step of preparing the coupling solution may include the steps of (a) dissolving the basic additive in water, and (b) introducing and mixing the organic solvent into the solution obtained in the step (a). In addition, the step of preparing the binding liquid may further include the step of adding the enteric substrate to the admixture obtained by the step (b) and dispersing the enteric substrate.

In the step (3), drying may be performed at a temperature ranging from 20 to 60 ° C.

The method for preparing a solid preparation for oral use according to the present invention is characterized by further comprising the step of preparing tablets by mixing and granulating at least one selected from the group consisting of mannitol, disintegrant, diluent and glidant in the granules obtained in the step (4) . Coating the tablets thus prepared with a water-soluble coating layer; And coating the surface of the water-soluble coat layer with an enteric coat layer.

The solid preparation composition for oral use according to the present invention can improve the stability of the proton pump inhibitor by incorporating an appropriate amount of a basic additive. Thereby, the granule for oral administration can be minimized, the drug stability to the low pH environment can be improved upon release from the stomach, and the granule for oral administration can be provided with excellent stability without discoloring under the moisture or humidity condition.

In addition, the production method of oral solid preparation according to the present invention can improve the production efficiency by using the wet granulation method.

1 is a schematic view showing a process for producing an oral solid preparation according to an embodiment of the present invention.
Fig. 2 is a photograph showing the colors of the granules prepared according to Examples 1 to 3 and Comparative Examples 1 to 3 in comparison. Fig.
Fig. 3 is a graph showing the dissolution test results of the granules produced according to Example 1. Fig.

The present invention relates to an oral solid preparation composition containing a proton pump inhibitor (PPI), an oral solid preparation containing the same, and a preparation method thereof.

First, with respect to the oral solid preparation composition, the composition comprises a proton pump inhibitor or a pharmaceutically acceptable salt thereof; And a basic additive, wherein the amount of the basic additive is 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof.

The proton pump inhibitor is effective by inhibiting proton pump (H ⁺ / K ⁺ -ATPase) of parietal cell, inhibiting the production of hydrochloric acid and weakening the acidity in digestive organs. In the present invention, the proton pump inhibitor may be selected from the group consisting of Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, (Tenatoprazole), pharmaceutically acceptable salts thereof, and precursors thereof, and preferably dexlaxaprazole may be used.

The dexlaxaprazole is a widely used drug for the treatment of peptic ulcer and the like, and is an optical isomer of lansoprazole, and is a compound represented by the following formula (1).

Formula 1

The dexlaxaprazole has a property of color change or rapid decomposition upon exposure to water, and this property occurs in the same condition even in an acidic or neutral aqueous solution. This may cause a discoloration problem due to moisture or moisture during the manufacturing process or storage process of the oral solid preparation, and may cause a problem of lowering the stability of the drug due to low pH upon release from the stomach.

In the present invention, an appropriate amount of a basic additive is added together with a proton pump inhibitor to improve the stability of the proton pump inhibitor, thereby improving the stability of the proton pump inhibitor. It minimizes the effect under low pH environment and also significantly reduces the amount of the substance produced.

The content of the basic additive is 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof. When the amount of the basic additive is less than 2 parts by weight, the stability of the drug in a low pH environment is deteriorated and the amount of the produced flexible substance is increased. On the other hand, when the amount of the basic additive is more than 13 parts by weight, discoloration occurs under moisture and humidity conditions .

The basic additive is _{NaOH, NaHCO 3, CaCO 3,} MgCO 3, KH 2 PO 4, K 2 HPO 3, Ca (OH) 2, Mg (OH) 2, Na 2 HPO 4, MgCO 3, NaH 2 PO 4, May comprise at least one selected from the group consisting of Na ₃ PO ₄ , calcium trichloro phosphate, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate and pharmaceutically acceptable salts thereof, NaOH. ≪ / RTI >

In the present invention, the oral solid preparation composition may further include at least one selected from the group consisting of a diluent, a water-soluble polymer, and an enteric material.

The diluent represents a material that can maintain a constant volume of granules. As the diluent, any diluent which does not affect the action of the proton pump inhibitor may be used. For example, one or more selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol and glucose may be used, preferably lactose .

The water-soluble polymer is added for delayed release of the drug. As the water-soluble polymer, any water-soluble polymer which does not affect the action of the proton pump inhibitor can be used, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, Hydroxypropylcellulose, hydroxypropylcellulose, and hydroxypropylbutylcellulose, and preferably hydroxypropylmethylcellulose may be used.

The enteric substrate serves to inhibit drug release from above. In the present specification, the term " enteric property " means that disintegration and dissolution do not occur for 2 hours at the stomach condition (near pH 1.2), and disintegration and dissolution at a fast time within 1 hour It means nature. As the enteric base material, any enteric base material which does not affect the action of the active ingredient may be used, and examples thereof include poly (methacrylic acid methyl methacrylate) copolymer (e.g., Eudragit L, Eudragit S, (Germany), hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and carboxymethylethylcellulose, and preferably at least one selected from the group consisting of poly (methylmethacrylate methyl methacrylate) copolymer Coalescence may be used.

On the other hand, the present invention provides an oral solid preparation comprising the oral solid preparation composition. The solid preparation may be any one selected from the group consisting of granules, pellets, tablets and capsules.

The solid preparation may further comprise at least one selected from the group consisting of mannitol, disintegrant, diluent, and glidant. For example, when the formulation of the solid preparation according to the present invention is purified, the granule prepared from the oral solid preparation composition may further contain at least one selected from the group consisting of mannitol, disintegrant, diluent, and glidant.

The above mannitol acts to enhance the flowability of the oral solid preparation composition, and it can provide a solid oral preparation composition having excellent mixing uniformity and fluidity when mannitol is included.

The disintegant serves to facilitate disintegration or disintegration of the solid dosage form after oral administration. The disintegrant may include one or more selected from the group consisting of microcrystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium starch glyconate, sodium carboxymethylcellulose, carboxymethylcellulose calcium and crospovidone have.

The above-mentioned diluent is further included in the solid preparation prepared by using the oral solid preparation composition, and the kind thereof is as described above.

The lubricant improves fluidity of the amorphous dexranosaprazole particles, prevents friction between the particles, and prevents the amorphous dexranosaprazole particles from adhering to the tablet machine. The lubricant may include at least one selected from the group consisting of magnesium stearate, stearic acid, zinc stearate, calcium stearate, talc, sodium stearyl fumarate, talc, silicon dioxide and colloidal silicon dioxide.

The oral solid preparation provided according to the present invention may further comprise a core containing the oral solid preparation composition, a water-soluble coating layer covering the surface of the core, and an enteric coating layer covering the surface of the water-soluble coating layer. Thus, when a solid preparation for oral use is designed as a double coating formulation, acid resistance is secured, drug release from the above can be suppressed, drug release in the intestine can be promoted, and the patient's compliance with dosing can be improved.

The enteric coating layer is a coating layer positioned at the outermost periphery of the oral solid preparation according to the present invention, and plays a role of suppressing the release of the drug from above. Such an enteric coating layer may include one or more selected from the group consisting of hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate, and derivatives thereof.

The water-soluble coating layer is a coating layer existing between the core containing the oral solid preparation composition and the enteric coating layer, thereby allowing the enteric coating layer to be effectively and stably coated. When the enteric coating layer is coated, the pH of the proton pump inhibitor It minimizes the impact on the environment. Such a water-soluble coating layer may include one or more selected from the group consisting of cellulose ether, polyvinyl pyrrolidone, and polyvinyl alcohol. At this time, the cellulose ether may include one or more selected from the group consisting of hydroxyalkylcellulose and hydroxyalkylalkylcellulose, preferably hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethyl Cellulose, hydroxybutylcellulose, hydroxypentylcellulose, and hydroxypropylbutylcellulose.

In addition, the present invention provides a method for producing the oral solid preparation, which comprises: (1) preparing a mixed powder comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof; (2) preparing a binding liquid containing a basic additive; (3) combining and drying the mixed powder and the coupling liquid; And (4) granulating the dried material obtained in the step (3) to prepare granules.

Hereinafter, a method for producing an oral solid preparation according to an embodiment of the present invention will be described with reference to FIG.

(1) Preparation of mixed powder

This step is to prepare a mixed powder comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof. At this time, the mixed powder may further include at least one selected from the group consisting of a diluent and a water-soluble polymer. The types of the proton pump inhibitor, diluent, and water-soluble polymer used in the present invention are as described above.

This step may include sieving the proton pump inhibitor or a pharmaceutically acceptable salt thereof and further additives (for example, a diluent and / or a water-soluble polymer) during the mixed powder production process. It is possible to provide a mixed powder having a uniform mixing state and a desired particle size through the sieving process.

(2) Preparation of bonding liquid

This step is a step for preparing a bonding liquid containing a basic additive. The amount of the basic additive is 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof, and the kind of the basic additive is as described above.

The solid preparation for oral use according to the present invention is prepared by a wet granulation method, and according to a conventional wet granulation method, a combination of an active ingredient and an additive such as a proton pump inhibitor is combined with a binding solution, . In this conventional wet granulation method, a basic additive is incorporated in the mixture in the state that the basic additive is incorporated in the mixture. In this case, a larger amount of a basic additive than the proton pump inhibitor must be added to obtain a solid form having desired stability I could. However, when an excessive amount of the basic additive is included as described above, the size of the tablet to be finally taken becomes large, and the convenience of taking the tablet is deteriorated. As a result of intensive studies to solve such problems, the present inventors have found that, after preparing a binding solution containing a basic additive, the combined powder and the binding solution prepared according to the above step (1) It is possible to produce a binding liquid which can be applied to a wet granulation method only by using a small amount of a basic additive, and thus it is possible to produce an oral solid preparation having excellent stability.

The solvent for preparing the binding solution may be water; And one or more organic solvents that are miscible with water. For example, the organic solvent may be selected from ethanol, isopropanol and acetone, preferably acetone having a boiling point of 60 ° C or lower. This is because the proton pump inhibitor such as dexlanthoxazole exhibits a temperature-sensitive reaction. For example, there is a risk of discoloration when drying granules containing dexlaxaprazole at a high temperature, and an organic solvent Can be preferably used. However, since the basic additive used in the present invention is insoluble in the organic solvent, a binding solution can be prepared through the following steps.

Specifically, the step of preparing the binding liquid may include the steps of (a) dissolving the basic additive in water, and (b) introducing and mixing the organic solvent into the solution obtained in the step (a). The method may further include the step of adding the enteric substrate to the admixture obtained in the step (b) and dispersing the enteric substrate. At this time, the kind of the enteric coating material used is as described above.

(3) Coalition and drying phase

This step is a step of combining the mixed powder obtained in the above (1) and the combined solution obtained in the above (2) and drying. Herein, the term " coalescence " refers to the process of mixing the coupling liquid and the mixed powder to produce wet granules.

 The wet granules formed by the combination of the mixed powder and the binding liquid may be dried through an apple stage. Here, the apple stage represents a process of sieving the wet granules by a sieve and sorting them into particles having a predetermined size or smaller.

The drying process may be carried out in a temperature range of 20 to 60 캜 considering the stability of the front pump inhibitor, preferably at a temperature not exceeding about 50 캜, more preferably not higher than about 40 캜, Most preferably from 20 ° C to 40 ° C, through air drying, fluid bed drying, oven drying or microwave drying.

(4) Granulation step

This step is a step of granulating the dried material obtained in the step (3) to produce granules. The granulation is a process for making the size of the granules constant, and a commonly used granulation machine can be used without limitation. Preferably, when the particle size of the granulated granules is 30 mesh or less, it is preferable to provide an oral tablet having a low degree of malingering through a subsequent tableting process.

The method for preparing a solid preparation for oral use according to the present invention is characterized by further comprising the step of preparing tablets by mixing and granulating at least one selected from the group consisting of mannitol, disintegrant, diluent and glidant in the granules obtained in the step (4) . The hardness of the tablets after the tableting process may be 10 to 25 kp, and the tablets for oral tablets may exhibit a degree of maltosis of 0.5% or less.

The method for preparing a solid preparation for oral use according to the present invention may further comprise the steps of: coating the tablets with a water-soluble coating layer; And coating the surface of the water-soluble coat layer with an enteric coat layer. As a result, a double-coated tablet for oral use is produced, so that the acid resistance of the tablets can be secured and the patient's compliance with dosing can be enhanced.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these embodiments.

Example 1

100 parts by weight of dexlaxaprazole, 108.3 parts by weight of a diluent and 166.7 parts by weight of a water-soluble polymer were mixed to prepare a mixed powder.

Subsequently, a binding solution was prepared by dispersing 5.8 parts by weight of sodium hydroxide (NaOH) as a basic additive in 58.3 parts by weight of purified water, and admixing 50 parts by weight of acetone with 25 parts by weight of the enteric coating material.

Subsequently, the binding solution was added to the mixed powder, and the resulting mixture was combined with apple, and dried at 55 ° C for 2 hours. At this time, the wet powder was selected using the sieve of 14 mesh in the apple process.

Then, the dried material obtained through the drying process was granulated to prepare granules. At this time, granules having a particle size of 30 mesh or less were selected through the granulation process.

Examples 2 to 3 and Comparative Examples 1 to 3

The granules were prepared in the same manner as in Example 1, except that the contents of dexlanthoxazole, diluent, water-soluble polymer, basic additive, enteric-coated base, purified water and acetone were adjusted as shown in Table 1 below. However, the content unit of each component described in Table 1 below is parts by weight.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Dexlanthoxazole 100.0 100.0 100.0 100.0 100 100 diluent 108.3 108.3 108.3 140.0 140 140 Water-soluble polymer 166.7 166.7 166.7 170.0 170 170 Basic additive 5.8 8.3 12.5 1.0 15.0 - Long-lasting mechanism 25.0 25.0 25.0 25.0 25.0 25.0 Purified water 58.3 58.3 58.3 58.0 58.0 58.0 Acetone 50.0 50.0 50.0 50.0 50.0 50.0

* PPI: Dexlansoprazole Amorphous (Amino chemicals)

* Diluent: Lactose (Cellactose 80, MEGGLE Co., Ltd.)

* Water-soluble polymer: Hydroxypropyl methylcellulose (AnyCoat CN101T, Lotte Fine Chemicals Co., Ltd.)

* Basic additives: sodium hydroxide (NaOH, Merck)

* Ingredients of the invention: poly (methyl methacrylate methacrylate) copolymer (Eudragit S100, Ebnix)

* Organic solvent: acetone (Aceton, purified water)

<Evaluation method>

1. Flexible materials (%)

The stability tests of the preparations were carried out on the granules prepared according to Examples 1 to 3 and Comparative Examples 1 to 3. Specifically, the contents of the supersaturated products of dexla- soxaprazole (Imp. B), C (Imp. C) and Dex N-OX sulphoxide and total content of suppositories were measured by liquid chromatography (UPLC) The results are shown in Table 2 below. Here, the Dex N-OX sulphoxide is a derivative of dexlaxaprazole, 2- [3-methyl-1-oxy-4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethanesulfinyl] -1H-benzoimidazole to be.

The HPLC analysis conditions for the above-mentioned flexible substance were as follows.

- Column: X-Bridge Shield RP18 250 mm x 4.6 mm, 5 m

- Injection volume: 20 μl

- Detector: Ultraviolet absorptiometer (wavelength: 285 nm)

- Column temperature: 35 ° C

- mobile phase A: Ammonium Acetate 0.02M, mobile phase B: 100% Acetonitrile

Start: mobile phase A: mobile phase B = 80: 20

25 minutes: mobile phase A: mobile phase B = 25: 75

35 min: mobile phase A: mobile phase B = 25: 75

- Diluent: Methanol / Sodium hydroxide 0.01M (25:75)

2. Dissolution test

The dissolution rate of the granules prepared according to Example 1 was evaluated under the following conditions, and the results are shown in Fig.

- Dissolution method: Dissolution method 2 of Korea Pharmacopoeia (paddle method)

- Type of eluent: Manufacturer - ERWEKA GmbH, Model - DT 1420

- Type of eluent: pH 1.2 (acid stage), pH 7.2 (buffer stage)

- Amount of eluate: 900 mL

- Temperature of eluent: 37 ° C

- Paddle speed: 100 rpm

At this time, the elution test was started with an acid solution having pH 1.2, and after 120 minutes, the solution was changed to a pH 7.2 solution containing 5 mM sodium lauryl sulfate, and the test was conducted for a total of 210 minutes.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Imp.B (%) 0.001 0.001 0.0007 0.012 0.0004 0.01 Imp.C (%) 0.0008 0.001 0.0006 0.007 0.001 0.15 Dex N-OX sulphoxide (%) 0.0002 0.0001 0.0001 0.15 0.0001 0.35 Total Imp. (%) 0.035 0.03 0.028 0.35 0.031 0.54

As shown in Table 1, when the content of the basic additive (NaOH) is 15 parts by weight based on 100 parts by weight of dexlaxaprazole, the content of the basic additive (NaOH) is in the range of 2 to 13 The yield of the suppositories was similar to that of the granules prepared according to Example 1, 2 showing a photograph of the granules produced according to Examples 1 to 3 and Comparative Examples 1 to 3, in the case of granules prepared according to Comparative Example 2, granules prepared according to Examples 1 to 3 It can be seen that it is discolored to yellow compared with water. This indicates that the dexlaxaprazole was discolored in yellow due to the water contained in the binding solution, and that the granules prepared in accordance with Comparative Example 2 were inferior in water stability.

In addition, in the case of the granules prepared according to Examples 1 to 3, it was confirmed that the production rate of the flexible substance was significantly reduced as compared with the granules prepared according to Comparative Examples 1 and 3, which contained the basic additives below the lower limit value. On the other hand, the granules of Comparative Example 3 shown in FIG. 2 exhibit red color, which is a color when an excessive amount of a flexible substance is contained. In the case of granules prepared using a binding liquid containing no basic additive, It can be confirmed by appearance observation that the generation rate becomes very high.

Fig. 3 is a graph showing the dissolution test results of the granules produced according to Example 1. Fig. 3, the elution rate of the granules prepared according to Example 1 was inhibited in the acid state (pH 1.2), and the dissolution rate was rapidly increased in the buffered state (pH 7.2). From the above, it can be seen that, in the case of oral solid preparations prepared according to the present invention, the elution of dexranoseprazole is inhibited from above and promoted in the intestine, thus effectively delivering the body.

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiment, but is to be accorded the widest scope consistent with the appended claims and their equivalents. Should be construed as being included in the scope of the present invention.

Claims (23)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete (1) preparing a mixed powder comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof;
(2) preparing a binding liquid containing a basic additive;
(3) combining and drying the mixed powder and the coupling liquid; And
(4) granulating the dried material obtained in the step (3) to prepare a granule. 16. The method of claim 15,
Wherein the content of the basic additive is 2 to 13 parts by weight based on 100 parts by weight of the proton pump inhibitor or a pharmaceutically acceptable salt thereof. 16. The method of claim 15,
Wherein the mixed powder further comprises at least one selected from the group consisting of a diluent and a water-soluble polymer. 16. The method of claim 15,
The solvent of the binding solution may be water; And one or more organic solvents that are miscible with water, wherein the organic solvent is selected from ethanol, isopropanol, and acetone. 19. The method of claim 18,
Wherein the step of preparing the binding solution comprises the steps of (a) dissolving the basic additive in water, and (b) introducing the organic solvent into the solution obtained in the step (a) &Lt; / RTI &gt; 20. The method of claim 19,
Wherein the step of preparing the binding liquid further comprises the step of adding an enteric substrate to the admixture obtained by the step (b) to disperse the enteric substrate. 16. The method of claim 15,
Wherein the drying in step (3) is performed at a temperature ranging from 20 to 60 ° C. 16. The method of claim 15,
Further comprising the step of preparing a tablet by mixing and granulating at least one selected from the group consisting of mannitol, a disintegrant, a diluent, and a glidant in the granule obtained in the step (4) Way. 23. The method of claim 22,
Coating the tablet with a water soluble coating layer; And coating the surface of the water-soluble coating layer with an enteric coating layer. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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