Novel pharmaceutical composition containing rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and having improved stability

Abstract

The present invention relates to a novel pharmaceutical composition containing rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a method for preparing the same, which has improved stability. The pharmaceutical composition according to the present invention, which contains rabeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, exhibits excellent stability in gastric juice having a low pH, and can minimize side effects.

Description

[Technical Field]

[0001] The present invention relates to a novel pharmaceutical composition containing rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which has improved stability, and a method for preparing the same.

[0002] [Background technology]

[0003] Rabeprazole is a benzimidazole derivative with the structure of Chemical Formula 1, and is a drug that suppresses gastric acid secretion. It is one of the representative proton pump inhibitors (PPIs) that inhibits gastric acid secretion by inhibiting H+ / K+ ATPase on the acid-secreting surface of gastric mucosal parietal cells.

[0004] Currently, rabeprazole is used for a variety of purposes, including the treatment of gastric ulcers, duodenal ulcers, erosive or ulcerative gastroesophageal reflux disease, symptomatic relief of gastroesophageal reflux disease, long-term maintenance therapy of gastroesophageal reflux disease, and combination antibiotic therapy for patients with peptic ulcers infected with Helicobacter pylori.

[0005]

[0006]

[0007] [ka]

[0008] On the other hand, rabeprazole is known to be a compound with low stability, being prone to decomposition or degradation in acidic and neutral media, and such decomposition or degradation of rabeprazole is particularly problematic in acidic environments, and is also known to be affected by moisture, heat, organic solvents, and light.

[0009] In order to produce a dosage form, particularly a tablet-type dosage form, that solves the stability problem of rabeprazole, there have been attempts to use enteric coating or to use sodium bicarbonate or the like to reduce acidity.

[0010] However, the use of a large amount of sodium bicarbonate may reduce the efficacy of rabeprazole and induce side effects. Furthermore, oral administration of a large amount of sodium bicarbonate may cause stomach distension, increasing pain in patients with gastric acid-related diseases, and may worsen gastroesophageal reflux disease by inducing belching and inducing the upward movement of gastric acid. Furthermore, since rabeprazole and sodium bicarbonate do not have good compatibility, the problem of increased related substances occurs when they come into contact with each other.

[0011] Therefore, there remains a pressing need for a dosage form containing rabeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, which has improved stability and minimized side effects.

[0012] Summary of the Invention [Problem to be solved by the invention]

[0013] Under these circumstances, the present invention aims to provide a pharmaceutical composition having improved stability of rabeprazole or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a pharmaceutical dosage form containing the same, and a method for producing the same.

[0014] [Means for solving the problem]

[0015] In order to solve the above problems, the present inventors have endeavored to develop a stabilized dosage form of rabeprazole. As a result, they have discovered that when a pharmaceutical composition containing rabeprazole, a pharmaceutically acceptable salt thereof or a hydrate thereof, and sodium bicarbonate (NaHCO3) additionally contains at least magnesium oxide (MgO) and calcium hydroxide (Ca(OH)2) as alkalizing agents (stabilizers), the stability of rabeprazole is improved to an unpredictable extent, and side effects caused by the use of excessive amounts of sodium bicarbonate are reduced, thereby completing the present invention.

[0016] Accordingly, the present invention provides a pharmaceutical composition comprising rabeprazole, a pharmaceutically acceptable salt thereof or a hydrate thereof, and sodium bicarbonate as active ingredients, and additionally comprising at least magnesium oxide and calcium hydroxide as alkalizing agents, and a pharmaceutical dosage form, particularly a tablet dosage form, comprising said pharmaceutical composition.

[0017] The present invention also provides a pharmaceutical composition containing the stability-improved rabeprazole, its pharmaceutically acceptable salt, or its hydrate as an active ingredient, and a method for preparing a pharmaceutical dosage form containing the same.

[0018] [Effects of the Invention]

[0019] The pharmaceutical composition containing rabeprazole, its pharmaceutically acceptable salt, or its hydrate as an active ingredient according to the present invention and the pharmaceutical dosage form containing the same not only have excellent stability, particularly in the stomach when administered to a living body, but also exhibit excellent stability, such as minimizing the generation of related substances under accelerated and long-term storage conditions during storage before administration to a living body.

[0020] [Brief explanation of the drawings]

[0021] [Figure 1]FIG. 1 shows the results of a gastric stability test using sodium bicarbonate and an alkalizing agent alone under the condition of an initial gastric juice pH of 1.2, as the amount of remaining drug and the pH of the eluate after 30 minutes.

[0022] [Figure 2] FIG. 1 shows the results of a gastric stability test using sodium bicarbonate and two types of alkalizing agents under conditions of initial gastric juice pH 1.2, as the amount of remaining drug and the pH of the eluate after 30 minutes.

[0023] [Figure 3] FIG. 1 shows the results of a comparison of the pharmacokinetics of the dosage form of the present invention with a control drug in an animal model (beagle dogs).

[0024] [Figure 4] FIG. 1 shows stability results (total generation of related substances, %) under accelerated test conditions for manufacturing tablet dosage forms (wet granulation and direct compression processes).

[0025] [Figure 5] FIG. 1 shows stability results (total generation of related substances, %) under intermediate storage conditions according to manufacturing methods (wet granulation and direct compression processes) for tablet dosage forms.

[0026] [Figure 6] FIG. 1 shows the stability results (total amount of related substances generated, %) under long-term storage conditions for tablet dosage forms manufactured using wet granulation and direct compression processes.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Generally, the nomenclature used herein is that which is well known and commonly used in the art.

[0029] In one aspect, the present invention provides a pharmaceutical composition containing rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, sodium bicarbonate, and at least magnesium oxide and calcium hydroxide as alkalizing agents, which significantly improves the stability of rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a pharmaceutical dosage form containing the same.

[0030] In the present invention, rabeprazole is a substance having the structure of chemical formula (1). The pharmaceutically acceptable salt of rabeprazole in the present invention may be any pharmaceutically acceptable salt of rabeprazole known in the art, without limitation. Examples include sodium salt of rabeprazole, hydrochloride, p-toluenesulfonate, fumarate, acetate, succinate, salicylate, oxalate, bromate, phosphate, methanesulfonate, tartrate, maleate, and mandelic acid salt, but are not limited thereto. Sodium rabeprazole, having the structure of chemical formula (2), is preferred.

[0031]

[0032] [ka]

[0033] In the pharmaceutical composition of the present invention, rabeprazole, its pharmaceutically acceptable salt or its hydrate is contained in an amount of 5 mg to 40 mg, preferably 10 mg to 30 mg, more preferably 15 mg to 25 mg based on the weight of rabeprazole;

[0034] Sodium bicarbonate is present in an amount of 500 mg to 1,000 mg, preferably 550 mg to 900 mg, and more preferably 600 mg to 800 mg;

[0035] magnesium oxide is present in an amount of 30 mg to 100 mg, preferably 40 mg to 85 mg, and more preferably 50 mg to 75 mg;

[0036] Calcium hydroxide may be included in an amount of 5 mg to 70 mg, preferably 10 mg to 60 mg, and more preferably 20 mg to 50 mg.

[0037] The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable excipients, and such excipients may be one or more selected from the group consisting of fillers (diluents), disintegrants, binders, lubricants (lubricants), preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.

[0038] Non-limiting examples of fillers (diluents) that may be included in the pharmaceutical compositions of the present invention include mannitol, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, sorbitol, starch, and pregelatinized starch. One or more selected from the group consisting of starch, sucrose, talc, xylitol, maltose maltodextrin, and maltitol may be used, but is not limited thereto.

[0039] Non-limiting examples of disintegrants that can be used in the pharmaceutical composition of the present invention include, but are not limited to, one or more selected from the group consisting of crospovidone, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, and pregelatinized starch.

[0040] Non-limiting examples of binders that can be used in the pharmaceutical composition of the present invention include, but are not limited to, one or more selected from the group consisting of cobovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, acacia mucilage, alginic acid, carbomer, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methyl cellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, and sucrose.

[0041] As non-limiting examples, lubricants (lubricants) contained in the pharmaceutical composition of the present invention may be one or more selected from the group consisting of talc, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, glyceryl behenate, hydrogenated castor oil, stearic acid, glyceryl palmitostearate, glyceryl monostearate, calcium silicate, powdered cellulose, and starch, but are not limited thereto.

[0042] The pharmaceutical dosage form containing the pharmaceutical composition of the present invention is preferably, but not limited to, a capsule, pellet, or tablet, and more preferably, the tablet is a film-coated tablet containing a film coating layer.

[0043] The film coating layer may be formed using one or more coating bases selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum.

[0044] Accordingly, the film coating layer may include one or more film coating bases selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum, but is not limited thereto.

[0045] The polyvinyl alcohol and polyvinyl alcohol / polyethylene copolymer that can be contained in the film coating base may have a weight-average molecular weight of about 2,500 to 1,000,000, preferably about 2,500 to 500,000, and the xanthan gum may have a weight-average molecular weight of about 2,000,000, but is not limited thereto.

[0046] Illustratively, commercially available Opadry II TM Or Opadry AMB™ (Colorcon, USA), ColliCoat IR TM A water-soluble film coating base such as, but not limited to, (BASF, Germany) may be used.

[0047] The content of the water-soluble film coating base may be, but is not limited to, 0.5% to 10% by weight, preferably 0.8% to 7% by weight, and more preferably 1% to 5% by weight, based on the total weight of the dosage form.

[0048] The pharmaceutical composition and pharmaceutical dosage form containing rabeprazole, its pharmaceutically acceptable salt, or its hydrate as an active ingredient according to the present invention, are extremely stable, particularly in the stomach when administered to the body. Preferably, but not limited to, the remaining amount of rabeprazole is 70% or more after 30 minutes in a solution with an initial gastric juice pH of 1.2, and / or the remaining amount of rabeprazole is 95% or more after 30 minutes in a solution with an initial gastric juice pH of 2.0.

[0049] The pharmaceutical dosage form according to the present invention is preferably prepared by a direct compression method (process) because, when tablets are prepared by a wet granulation method (process), rabeprazole is unstable to water and the generation of related substances may increase. Therefore, direct compression is preferred in terms of improving the stability of rabeprazole.

[0050] The pharmaceutical dosage form according to the present invention may, for example, comprise:

[0051] (1) forming granules by mixing sodium bicarbonate with a binder dissolved in a solvent;

[0052] (2) obtaining a mixture (I) by mixing the granules obtained in step (1) with a disintegrant, an excipient, magnesium oxide, and calcium hydroxide;

[0053] (3) mixing the mixture (I) obtained in step (2) with rabeprazole or a pharmaceutically acceptable salt thereof to obtain a mixture (II);

[0054] (4) obtaining a final mixture by mixing the mixture (II) obtained in step (3) with a lubricant; and

[0055] (5) Filling the final mixture into capsules as is, filling it into capsules in pellet form, or producing tablets by directly compressing the final mixture;

[0056] The present invention can be produced by a production method including, but not limited to, the following.

[0057] The dosage and administration interval of the pharmaceutical composition according to the present invention and the pharmaceutical dosage form containing the same may be adjusted depending on the disease state of the subject requiring treatment, and may be preferably administered twice a day or once a day, but is not limited thereto.

[0058] The present invention will be described in more detail with reference to the following examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of illustrating the present invention and that the scope of the present invention is not to be construed as being limited by these examples.

[0059] [Example]

[0060] Example 1. Primary screening of alkalizing agents for rabeprazole stabilization

[0061] To identify suitable alkalinizing agents (stabilizers) that can improve the stability of rabeprazole or its pharmaceutically acceptable salts, the stability of rabeprazole was tested by combining 700 mg of sodium bicarbonate (NaHCO3) with 63 mg of magnesium oxide (MgO), 35 mg of calcium hydroxide (Ca(OH)2), 25 mg of arginine, 65 mg of tribasic sodium phosphate (Na3PO4), 110 mg of dibasic sodium phosphate (Na2HPO4), 75 mg of dibasic potassium phosphate (K2HPO4), and 25 mg of meglumine.

[0062] The amount of each alkalizing agent used was set with reference to the upper limit of daily dosage permitted in the US FDA Inactive Ingredients Database.

[0063] Specifically, assuming a water intake of 100 mL per 100 mL of gastric juice at pH 1.2, 200 mL of eluate was prepared by adding 100 mL of water to 100 mL of pH 1.2 HCl aqueous solution. The eluate was then heated to 37°C, and 700 mg of sodium bicarbonate alone and a combination of each alkalizing agent candidate with sodium bicarbonate were weighed out.

[0064] The weighed sodium bicarbonate and each alkalizing agent combination were each added to an elution vessel together with 20 mg of rabeprazole sodium. Sampling was performed after 5, 10, 15, and 30 minutes and analyzed by HPLC to confirm the amount of remaining drug. The pH of the eluate was also confirmed at 30 minutes to confirm the pH-increasing effect of the alkalizing agent combination.

[0065] As a result, as shown in Table 1 and Figure 1, when sodium bicarbonate, magnesium oxide, and calcium hydroxide were used in combination, the pH increase of the eluate after 30 minutes was relatively greater than when other alkalizing agents were used, demonstrating the advantage in terms of pH increase.

[0066] [Table 1]

[0067] In addition, in relation to the stability of rabeprazole, the remaining amount of rabeprazole over time was examined. As a result, as shown in Table 2 and Figure 1, when sodium bicarbonate and magnesium oxide were used, the remaining amount of rabeprazole was 47.8% after 30 minutes, while when other alkalizing agents were used, the remaining amount of rabeprazole was much lower.

[0068] [Table 2]

[0069] Example 2. Secondary screening for combinations of alkalizing agents for rabeprazole stabilization

[0070] As confirmed in Example 1 above, the combination of sodium bicarbonate (NaHCO3) and magnesium oxide (MgO) was found to improve the stability of rabeprazole to an extent beyond expectations compared to the use of other alkalizing agents.

[0071] However, since there is a need to further improve the stability of rabeprazole, the stability of rabeprazole was confirmed when sodium bicarbonate (NaHCO3) and magnesium oxide (MgO) were used in combination with an additional alkalizing agent. Among these, calcium hydroxide showed the best results, so a case in which calcium hydroxide was used instead of magnesium oxide was used as a comparative example.

[0072] The weighed combinations of sodium bicarbonate and each alkalizing agent were each added to an elution vessel together with 20 mg of rabeprazole sodium. Sampling was performed after 5, 10, 15, and 30 minutes, and the amount of remaining drug was confirmed by HPLC analysis. The pH of the eluate was also confirmed at 30 minutes, confirming the pH-increasing effect of the alkalizing agent combinations.

[0073] The amount of each alkalizing agent used was the same as in Example 1.

[0074] [Table 3]

[0075] In addition, in relation to the stability of rabeprazole, the amount of rabeprazole remaining over time was examined. As a result, as shown in Table 4 and Figure 2, when calcium hydroxide was used together with sodium bicarbonate and magnesium oxide, the amount of rabeprazole remaining after 30 minutes was in the high 20% range, while when other alkalizing agents were used, the amount of rabeprazole remaining was much lower.

[0076] [Table 4]

[0077] Therefore, it was finally confirmed that when calcium hydroxide is used together with sodium bicarbonate and magnesium oxide, the amount of carbon dioxide used can be minimized as intended, thereby preventing side effects and dramatically improving the stability of rabeprazole.

[0078]

[0079] Example 3. Results of gastric stability test under pH 2.0 conditions

[0080] The stabilizing effect of rabeprazole was confirmed in a composition containing sodium bicarbonate as determined in Example 2 and magnesium oxide and calcium hydroxide as alkalinizing agents under dissolution conditions of pH 2.0, which is similar to the normal gastric acidity conditions.

[0081] Specifically, assuming a water intake of 100 mL per 100 mL of gastric juice at pH 2.0, 100 mL of water was added to 100 mL of pH 2.0 aqueous solution to prepare 200 mL of dissolution solution, which was then heated to 37°C. Sodium bicarbonate, magnesium oxide, and calcium hydroxide were weighed in combination and added to a dissolution vessel together with 20 mg of rabeprazole sodium. Samples were taken after 5, 10, 15, and 30 minutes and analyzed by HPLC to confirm the amount of remaining drug. The amounts of each stabilizer used were the same as in Example 1.

[0082] As a result, as shown in Table 5, in the case of a composition containing sodium bicarbonate and magnesium oxide and calcium hydroxide as alkalizing agents, the remaining amount of rabeprazole was close to 99% after 5, 10, 15 and 30 minutes.

[0083] [Table 5]

[0084]

[0085] Example 4. Results of pharmacokinetic tests using animal models of the formulation according to the present invention

[0086] To evaluate the pharmacokinetic properties of rabeprazole according to the present invention, the following pharmacokinetic study was conducted simultaneously in 12 male beagle dogs (10 to 20 months old) using a composition (formulation) containing sodium bicarbonate, magnesium oxide, and calcium hydroxide as alkalinizing agents as determined in Example 2, and a control drug (Pariet tablets, enteric-coated).

[0087] One tablet each of the test drug according to the present invention and the control drug (Pariet tablet, enteric-coated) was orally administered, and blood samples were collected before administration and 15, 30, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 12 hours after administration. Two-mL blood samples were collected from the jugular vein and immediately centrifuged to separate plasma, which was then stored in a freezer until analysis. LC-MS / MS was used to analyze rabeprazole in plasma, with rabeprazole-d4 sodium salt as the internal standard.

[0088] A faster T for the test drug compared with the control drug (Pariet tablets, enteric-coated) in an animal (beagle) model max As a result of checking whether it was possible to secure a high AUC and a similar level of AUC, as shown in Table 6 and Figure 3, it was found that the AUC and C were higher than those of the control drug. max Ensuring results and T max This confirmed that the combination of selected stabilizers quickly neutralized gastric acid in the animal's body, protecting rabeprazole from rapid decomposition in acidic solutions, and demonstrating faster efficacy than the control drug (enteric-coated tablet) which is released from the small intestine.

[0089] [Table 6]

[0090]

[0091] Example 5. Tablet manufacturing example and stability evaluation by manufacturing method

[0092] 5.1 Preparation of post-mixed (direct compression) tablets of rabeprazole sodium after sodium bicarbonate granulation

[0093] According to the final formulation established in the above example, film-coated tablets containing rabeprazole sodium were prepared using direct compression as follows.

[0094] in particular,

[0095] (1) Sodium bicarbonate (700 mg) was mixed with copovidone dissolved in ethanol to form granules, and then

[0096] (2) Mixing the granules obtained in step (1) with crospovidone, D-mannitol, magnesium oxide (63 mg), and calcium hydroxide (35 mg) to obtain a mixture (I);

[0097] (3) Mixing the mixture (I) obtained in step (2) with rabeprazole sodium salt (20 mg) to obtain a mixture (II),

[0098] (4) Adding magnesium stearate to the mixture (II) obtained in step (3) and mixing to obtain a final mixture, followed by tableting;

[0099] (5) Tablets were prepared by coating with Opadry II dissolved in purified water (165 mg).

[0100] 5.2 Manufacture of wet granulated tablets of sodium bicarbonate and rabeprazole sodium

[0101] According to the final formulation established in the above example, film-coated tablets containing rabeprazole sodium were prepared using a wet granulation method as follows.

[0102] in particular,

[0103] (1) Sodium bicarbonate (700 mg) was mixed with copovidone dissolved in ethanol to form granules, and then

[0104] (2) Rabeprazole sodium salt (20 mg), mannitol, magnesium oxide (63 mg), and calcium hydroxide (35 mg) were mixed with copovidone dissolved in ethanol to form granules, and then

[0105] (3) obtaining a mixture by mixing the granules obtained in steps (1) and (2) with crospovidone;

[0106] (4) Add magnesium stearate to the mixture obtained in step (3) and mix to obtain a final mixture, which is then tableted.

[0107] (5) Tablets were prepared by coating with Opadry II dissolved in purified water (165 mg).

[0108] 5.3 Stability due to manufacturing method

[0109] In the tablet manufacturing processes of Examples 5.1 and 5.2, the stability of film-coated tablets manufactured by each process was evaluated to confirm the effects of the addition of solvents and water involved in the wet granulation manufacturing process and the resulting drying process on drug stability. Each tablet was filled into a high-density polyethylene (HDPE) bottle, sealed with an appropriate amount of silica gel, and stored in a stability chamber according to each storage condition, and the change in related substances (% impurities) over storage time was evaluated.

[0110] The analysis conditions were as follows:

[0111] *HPLC analysis conditions

[0112] Detector: ultraviolet absorption photometer (measurement wavelength: 290 nm)

[0113] Column: 150 mm long x 4.6 mm inner diameter (5 μm particle size) packed with octadecyl silica (C18) or a similar column

[0114] Column temperature: 30℃

[0115] Mobile phase: 0.05 mol / L phosphate buffer solution (pH 7.0) containing methanol A Mixture of

[0116] A: Add 0.05 mol / L sodium monohydrogen phosphate TS to 0.05 mol / L potassium dihydrogen phosphate TS and adjust to pH 7.0 (volume ratio approximately 2:1).

[0117] Flow rate: Adjust so that the maintenance time of rabeprazole sodium is approximately 5 minutes.

[0118] Injection volume: 10μL

[0119] Analysis time: 50 minutes

[0120] First, as a result of the accelerated test (40°C ± 2°C / relative humidity 75% ± 5%), as shown in Figure 4, the total impurity content of tablets manufactured by the direct compression process was approximately 2.23% after 6 months, while the total impurity content of tablets manufactured by the wet granulation process was 6.36%, confirming that the amount of impurities generated by tablets manufactured by direct compression was significantly reduced and stability was improved.

[0121] In addition, as a result of the stability evaluation under intermediate storage conditions (30°C±2°C / relative humidity 65%±5%), as shown in Figure 5, the total impurity content of tablets manufactured by the direct compression process was approximately 0.84% ​​after 6 months, while the total impurity content of tablets manufactured by the wet granulation process was 1.35%, confirming that the amount of impurities generated was significantly reduced in the case of tablets manufactured by direct compression.

[0122] In addition, as a result of evaluating the stability under long-term storage conditions (25°C±2°C / relative humidity 60%±5%), as shown in Figure 6, the total impurity content of tablets manufactured by the direct compression process was approximately 0.60% after 6 months, while the total impurity content of tablets manufactured by the wet granulation process was 0.68%, confirming that the amount of impurities generated was improved in the case of tablets manufactured by direct compression.

[0123] Although the present invention has been described above with reference to preferred embodiments, it will be apparent to those skilled in the art that the present invention can be embodied in various modified forms without departing from the essential characteristics thereof.

[0124] Therefore, the above examples should be considered as illustrative rather than restrictive. The scope of the present invention is defined by the appended claims, not the above description, and all variations within the scope of the claims should be construed as being within the scope of the present invention.

Claims

1. A pharmaceutical composition comprising rabeprazole or a pharmaceutically acceptable salt thereof; sodium bicarbonate; and at least magnesium oxide and calcium hydroxide as alkalizing agents.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of rabeprazole is rabeprazole sodium salt.

3. 5 to 40 mg of rabeprazole or a pharmaceutically acceptable salt thereof; 500-1,000 mg sodium bicarbonate; 30 to 100 mg of magnesium oxide; and 5-70 mg calcium hydroxide; 2. The pharmaceutical composition according to claim 1, comprising:

4. 2. The pharmaceutical composition according to claim 1, further comprising one or more excipients selected from the group consisting of diluents, disintegrants, binders and lubricants.

5. 10. The pharmaceutical composition of claim 1, which is administered once a day.

6. 2. The pharmaceutical composition according to claim 1, wherein the amount of rabeprazole remaining after 30 minutes in a solution of pH 1.2 is 70% or more.

7. 7. The pharmaceutical composition according to claim 6, wherein the amount of rabeprazole remaining after 30 minutes in a solution of pH 2.0 is 95% or more.

8. A pharmaceutical dosage form comprising a pharmaceutical composition according to any one of claims 1 to 7.

9. 9. Pharmaceutical dosage form according to claim 8, characterized in that it is a capsule, pellet or tablet.

10. 10. Pharmaceutical dosage form according to claim 9, characterized in that it is a tablet or a film-coated tablet.

11. 11. The pharmaceutical dosage form according to claim 10, wherein the tablet or film-coated tablet is manufactured by direct compression.

12. (1) forming granules by mixing sodium bicarbonate with a binder dissolved in a solvent; (2) mixing the granules obtained in step (1) with a disintegrant, an excipient, magnesium oxide, and calcium hydroxide to obtain a mixture (I); (3) mixing the mixture (I) obtained in the step (2) with rabeprazole or a pharmaceutically acceptable salt thereof to obtain a mixture (II); (4) Mixing the mixture (II) obtained in step (3) with a lubricant to obtain a final mixture; and (5) Filling the final blend into capsules as is, filling into capsules in pellet form, or directly compressing the final blend to produce tablets; 1. A method for producing a pharmaceutical dosage form containing rabeprazole or a salt thereof, comprising:

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