Novel pharmaceutical composition with improved stability comprising rabeprazole, pharmaceutically acceptable salt or hydrate thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to a novel pharmaceutical composition comprising rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, having improved stability, and a method for manufacturing the pharmaceutical composition. Background Art

[0002] Rabeprazole is a benzimidazole derivative having the structure of Chemical Formula 1 and is a drug that inhibits gastric acid secretion. Rabeprazole is a representative proton pump inhibitor (PPI) that inhibits gastric acid secretion by inhibiting the H+ / K+ ATPase on the acid-secreting surface of the parietal cells of the gastric mucosa.

[0003] Currently, rabeprazole is widely used for the treatment of gastric ulcers, duodenal ulcers, or erosive or ulcerative gastroesophageal reflux disease to relieve the symptoms of gastroesophageal reflux disease, as a long-term maintenance therapy for gastroesophageal reflux disease, and as a combination therapy with antibiotics for patients with peptic ulcers due to Helicobacter pylori infection.

[0004] [Chemical Formula 1]

[0005]

[0006] Meanwhile, rabeprazole is known to be a compound having low stability and is liable to decompose or deteriorate in acidic and neutral media. This decomposition or deterioration of rabeprazole is particularly problematic in an acidic environment and is also known to be affected by water, heat, organic solvents, and light.

[0007] In order to manufacture a preparation that solves the stability problem of rabeprazole, particularly a tablet preparation, many attempts have been made, such as using enteric coating or using sodium bicarbonate to reduce acidity.

[0008] However, in the case where a large amount of sodium bicarbonate is used, the efficacy of rabeprazole may be reduced and side effects may be caused. In addition, in the case where a large amount of sodium bicarbonate is orally administered, the pain of patients suffering from gastric acid-related diseases may be aggravated due to flatulence and hiccups may be induced, which may cause the upward movement of gastric acid, thereby worsening gastroesophageal reflux disease. In addition, when rabeprazole having poor mixing stability and sodium bicarbonate come into contact with each other, problems such as an increase in related substances occur.

[0009] Therefore, there is an urgent need for a preparation that contains rabeprazole or a pharmaceutically acceptable salt thereof as an active ingredient, having improved stability and minimized side effects. Summary of the Invention

[0010] Technical Problem

[0011] Accordingly, an object of the present invention is to provide a pharmaceutical composition having improved stability of rabeprazole, its pharmaceutically acceptable salt or its hydrate, a pharmaceutical preparation comprising the pharmaceutical composition, and a method for manufacturing the same.

[0012] Technical solution

[0013] To solve the above problems, the inventors of the present invention have made great efforts to develop a stable preparation of rabeprazole, and thus have determined that when a pharmaceutical composition comprising rabeprazole, its pharmaceutically acceptable salt or its hydrate and sodium bicarbonate (NaHCO3) further comprises at least magnesium oxide (MgO) and calcium hydroxide (Ca(OH)2) as an alkalinizer (stabilizer), not only can the stability of rabeprazole be improved to an unpredictable extent, but also the side effects caused by the use of excessive sodium bicarbonate can be reduced, thereby completing the present invention.

[0014] Accordingly, the present invention provides a pharmaceutical composition comprising rabeprazole, its pharmaceutically acceptable salt or its hydrate as an active ingredient, and sodium bicarbonate, and further comprising at least magnesium oxide and calcium hydroxide as an alkalinizer, and provides a pharmaceutical preparation comprising the pharmaceutical composition, particularly a tablet preparation.

[0015] In addition, the present invention provides a pharmaceutical composition having improved stability comprising rabeprazole, its pharmaceutically acceptable salt or its hydrate as an active ingredient, and a method for manufacturing a pharmaceutical preparation comprising the pharmaceutical composition.

[0016] Advantageous effects

[0017] According to the present invention, a pharmaceutical composition comprising rabeprazole, its pharmaceutically acceptable salt or its hydrate as an active ingredient and a pharmaceutical preparation comprising the pharmaceutical composition are not only very superior in terms of stability, particularly gastric stability, when administered in vivo, but also exhibit excellent stability such that the generation of related substances is minimized under accelerated and long-term storage conditions when stored before in vivo administration. Description of the drawings

[0018] Figure 1 Shows the results of in-gastric stability tests using sodium bicarbonate and a single alkalinizer under the condition of an initial gastric pH of 1.2, representing the residual amount of the drug and the pH of the dissolution solution after 30 minutes;

[0019] Figure 2 Shows the results of in-gastric stability tests using sodium bicarbonate and two alkalinizers under the condition of an initial gastric pH of 1.2, representing the residual amount of the drug and the pH of the dissolution solution after 30 minutes;

[0020] Figure 3 Shows the results of the pharmacokinetic comparison of the preparation according to the present invention and the control drug in an animal model (beagle);

[0021] Figure 4 Shows the results of the stability (total amount of related substances generated, %) under accelerated test conditions depending on the process of manufacturing the tablet preparation (wet granulation and direct compression);

[0022] Figure 5 Shows the results of the stability (total amount of related substances generated, %) under intermediate storage conditions depending on the process of manufacturing the tablet preparation (wet granulation and direct compression); and

[0023] Figure 6 Shows the results of the stability (total amount of related substances generated, %) under long-term storage conditions depending on the process of manufacturing the tablet preparation (wet granulation and direct compression). Detailed Description

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein is well-known and typical in the art.

[0025] Aspects of the present invention relate to a pharmaceutical composition having significantly improved stability of rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a pharmaceutical preparation comprising the pharmaceutical composition, the pharmaceutical composition comprising rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof, sodium bicarbonate, and at least comprising magnesium oxide and calcium hydroxide as alkalizing agents.

[0026] In the present invention, rabeprazole is a material having the structure of Chemical Formula 1, and any pharmaceutically acceptable salt of rabeprazole known in the art can be used without limitation, and examples thereof include but are not limited to rabeprazole sodium, hydrochloride, p-toluenesulfonate, fumarate, citrate, succinate, salicylate, oxalate, bromate, phosphate, mesylate, tartrate, maleate, and mandelate, and rabeprazole sodium having the structure of the following Chemical Formula 2 is preferred.

[0027] [Chemical Formula 2]

[0028]

[0029] In the pharmaceutical composition according to the present invention, based on the weight of rabeprazole, the amount of rabeprazole, a pharmaceutically acceptable salt thereof, or a hydrate thereof contained may be 5 to 40 mg, preferably 10 to 30 mg, more preferably 15 to 25 mg,

[0030] The amount of sodium bicarbonate contained may be 500 to 1,000 mg, preferably 550 to 900 mg, more preferably 600 to 800 mg,

[0031] The amount of magnesium oxide contained may be 30 to 100 mg, preferably 40 to 85 mg, more preferably 50 to 75 mg, and

[0032] The amount of calcium hydroxide contained may be 5 to 70 mg, preferably 10 to 60 mg, more preferably 20 to 50 mg.

[0033] The pharmaceutical composition according to the present invention may further comprise at least one pharmaceutically acceptable excipient, and the excipient may include at least one selected from the group consisting of: fillers (diluents), disintegrants, binders, lubricants, preservatives, antioxidants, buffers, chelating agents, solubilizers and sweeteners.

[0034] As a non-limiting example, the filler (diluent) contained in the pharmaceutical composition according to the present invention may include, but is not limited to, at least one selected from the group consisting of: mannitol, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, microcrystalline cellulose, microcrystalline siliconized cellulose, powdered cellulose, glucose binder, glucose, fructose, lactitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin and maltitol.

[0035] As a non-limiting example, the disintegrant contained in the pharmaceutical composition according to the present invention may include, but is not limited to, at least one selected from the group consisting of: crospovidone, alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, sodium carboxymethylcellulose crosslinked, sodium docusate, guar gum, hydroxypropyl cellulose, methyl cellulose, polacrilin potassium, poloxamer, polyvinylpyrrolidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch and pregelatinized starch.

[0036] As a non-limiting example, the binder contained in the pharmaceutical composition according to the present invention may include, but is not limited to, at least one selected from the group consisting of: copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gum arabic mucilage, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methyl cellulose, polydextrose, polyethylene oxide, polyvinylpyrrolidone, sodium alginate, starch paste, pregelatinized starch, and sucrose.

[0037] As a non-limiting example, the lubricant contained in the pharmaceutical composition according to the present invention may include, but is not limited to, at least one selected from the group consisting of: talc, sodium stearyl fumarate, magnesium stearate, colloidal silica, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, glyceryl behenate, hydrogenated castor oil, stearic acid, glyceryl palmitostearate, glycerol monostearate, calcium silicate, powdered cellulose, and starch.

[0038] The pharmaceutical preparation comprising the pharmaceutical composition according to the present invention is preferably, but not limited to, a capsule, pellet, or tablet, and more preferably the tablet is a film-coated tablet comprising a film coating layer.

[0039] The film coating layer may be formed using at least one coating matrix selected from the group consisting of: polyvinyl alcohol, copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide, and xanthan gum.

[0040] Accordingly, the film coating layer may include at least one film coating matrix selected from the group consisting of: polyvinyl alcohol, copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide, and xanthan gum, but the present invention is not limited thereto.

[0041] The polyvinyl alcohol and the copolymer of polyvinyl alcohol and polyethylene that may be included in the film coating matrix 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 the present invention is not limited thereto.

[0042] For example, a water-soluble film coating matrix such as commercially available Opadry II TM or Opadry AMB TM (Colorcon, USA), Kollicoat IR TM (BASF, Germany), etc. may be used, but the present invention is not limited thereto.

[0043] Based on the total weight of the preparation, the content of the water-soluble film coating matrix can be, but is not limited to, 0.5 to 10 wt%, preferably 0.8 to 7 wt%, more preferably 1 to 5 wt%.

[0044] The pharmaceutical composition comprising rabeprazole, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient according to the present invention and a pharmaceutical preparation comprising the pharmaceutical composition are very superior in terms of stability, especially gastric stability, when administered in vivo, and are preferably characterized in that the residual amount of rabeprazole is 70% or more after 30 minutes in a solution having an initial gastric pH of 1.2 and / or the residual amount of rabeprazole is 95% or more after 30 minutes in a solution having an initial gastric pH of 2.0, but the present invention is not limited thereto.

[0045] The pharmaceutical preparation according to the present invention is preferably manufactured by a direct compression method (process). This is because rabeprazole is unstable in water when manufacturing tablets using a wet granulation method (process), which can increase the formation of related substances. Therefore, in terms of improving the stability of rabeprazole, it is preferably to carry out the direct compression method.

[0046] For example, the pharmaceutical preparation according to the present invention can be manufactured by a manufacturing method including the following:

[0047] (1) Forming granules by mixing sodium bicarbonate with a binder dissolved in a solvent;

[0048] (2) Obtaining a mixture (I) by mixing the granules obtained in step (1) with a disintegrant, an excipient, magnesium oxide and calcium hydroxide;

[0049] (3) Obtaining a mixture (II) by mixing the mixture (I) obtained in step (2) with rabeprazole or a pharmaceutically acceptable salt thereof;

[0050] (4) Obtaining a final mixture by mixing the mixture (II) obtained in step (3) with a lubricant; and

[0051] (5) Filling the final mixture into capsules as it is, granulating the final mixture and filling the pellets into capsules, or manufacturing tablets by directly compressing the final mixture,

[0052] However, the present invention is not limited thereto.

[0053] The pharmaceutical composition according to the present invention and the pharmaceutical preparation comprising the pharmaceutical composition can be administered according to the dosage and interval of administration that can be adjusted depending on the disease state of the subject to be treated, and it is preferably administered twice a day or once a day, but the present invention is not limited thereto.

[0054] A better understanding of the present invention can be obtained through the following examples. These examples are only stated for illustrative purposes of the present invention and should not be construed as limiting the scope of the present invention, as will be apparent to those skilled in the art.

[0055] [Examples]

[0056] Example 1. Preliminary screening of alkalizing agents for stabilizing rabeprazole

[0057] To test suitable alkalizing 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 each of 63 mg of magnesium oxide (MgO), 35 mg of calcium hydroxide (Ca(OH)2), 25 mg of arginine, 65 mg of trisodium phosphate (Na3PO4), 110 mg of disodium hydrogen phosphate (Na2HPO4), 75 mg of dipotassium hydrogen phosphate (K2HPO4), and 25 mg of N-methyl-D-glucamine.

[0058] The amount of each alkalizing agent used was set with reference to the upper limit of daily intake approved by the Inactive Ingredients Database of the US FDA.

[0059] Specifically, assuming 100 ml of water is ingested per 100 ml of gastric juice at pH 1.2, 200 ml of the dissolution solution prepared by adding 100 ml of water to 100 ml of an HCl aqueous solution at pH 1.2 was warmed to 37 °C, followed by weighing out 700 mg of sodium bicarbonate alone and in combination with the alkalizing agent candidates.

[0060] The combinations of the weighed sodium bicarbonate with each alkalizing agent, together with 20 mg of sodium rabeprazole, were placed in a dissolution reactor, and samples were collected after 5, 10, 15, and 30 minutes and analyzed by HPLC to confirm the residual amount of the drug. The pH of the dissolution solution at 30 minutes was also measured to confirm the pH increase effect of the combination with the alkalizing agent.

[0061] Based on Table 1 below and Figure 1 the results shown, when sodium bicarbonate was used in combination with magnesium oxide or calcium hydroxide, the pH of the dissolution solution increased after 30 minutes compared to when other alkalizing agents were used, confirming the advantage in terms of pH increase.

[0062] [Table 1]

[0063] Results of in-gastric stability test (pH change) depending on the combination with the stabilizer

[0064] Combination with stabilizer pH after 30 min Example 1-1 <![CDATA[NaHCO3+MgO]]> 6.9 Example 1-2 <![CDATA[NaHCO3+Ca(OH)2]]> 6.48 Example 1-3 <![CDATA[NaHCO3 + arginine]]> 6.35 Example 1-4 <![CDATA[NaHCO3+Na3PO4]]> 6.42 Example 1-5 <![CDATA[NaHCO3+Na2HPO4]]> 6.4 Example 1-6 <![CDATA[NaHCO3+K2HPO4]]> 6.35 Example 1-7 <![CDATA[NaHCO3 + meglumine]]> 6.3

[0065] In addition, regarding the stability of rabeprazole, based on the results of confirming the residual amount of rabeprazole over time, as shown in Table 2 below and Figure 1 as shown, when using sodium bicarbonate and magnesium oxide, the residual amount of rabeprazole is 47.8% after 30 minutes, while when using other alkalizing agents, its residual amount is much lower.

[0066] [Table 2]

[0067] Results of intragastric stability test (residual amount of rabeprazole) depending on the combination with stabilizers

[0068]

[0069] *100 (%) - Residual amount reduced at 30 minutes (%)

[0070] Example 2. Secondary screening of combinations of alkalizing agents for stabilizing rabeprazole

[0071] As confirmed in Example 1, the combination of sodium bicarbonate (NaHCO3) and magnesium oxide (MgO) can improve the stability of rabeprazole to an unpredictable extent compared to when using other alkalizing agents.

[0072] However, since the stability of rabeprazole needs to be further improved, when an additional alkalizing agent is used in combination with sodium bicarbonate (NaHCO3) and magnesium oxide (MgO), the stability of rabeprazole was verified, and among them, calcium hydroxide showed the best results, so the case where calcium hydroxide was used instead of magnesium oxide was used as a comparative example.

[0073] The weighed combination of sodium bicarbonate and the alkalizing agent was placed together with 20 mg of sodium rabeprazole in a dissolution reactor, and samples were collected after 5, 10, 15, and 30 minutes and analyzed by HPLC to confirm the residual amount of the drug. The pH of the dissolution solution at 30 minutes was also measured to confirm the pH-increasing effect of the combination with the alkalizing agent.

[0074] The amount of each alkalizing agent used was the same as in Example 1.

[0075] [Table 3]

[0076] Results of intragastric stability test (pH change) depending on 3 types of combinations including stabilizers

[0077] Combination with stabilizer pH after 30 min Example 2-1 <![CDATA[NaHCO3+MgO+Ca(OH)2]]> 7.3 Example 2-2 <![CDATA[NaHCO3+MgO+Na3PO4]]> 7.12 Example 2-3 <![CDATA[NaHCO3+MgO+Na2HPO4]]> 7.09 Comparative Example 2-1 <![CDATA[NaHCO3+Ca(OH)2+Na3PO4]]> 6.59 Comparative Example 2-2 <![CDATA[NaHCO3+Ca(OH)2+Na2HPO4]]> 6.59

[0078] In addition, regarding the stability of rabeprazole, based on the results of confirming the residual amount of rabeprazole over time, as shown in Table 4 below and Figure 2As shown, when calcium hydroxide is used together with sodium bicarbonate and magnesium oxide, the decomposition of rabeprazole is within the high 20% range after 30 minutes, while when other alkalizing agents are used, the residual amount is much lower.

[0079] [Table 4]

[0080] Results of in - vivo stability tests (residual amount of rabeprazole) depending on the combination of 3 types including stabilizers

[0081]

[0082]

[0083] Therefore, it was confirmed that when calcium hydroxide is used together with sodium bicarbonate and magnesium oxide, side effects etc. are prevented by minimizing the amount of carbonic acid used as expected, and furthermore, the stability of rabeprazole is extremely improved.

[0084] Example 3. Results of in - vivo stability tests at pH 2.0

[0085] Under the conditions of a dissolution solution at pH 2.0 similar to typical in - vivo acidity conditions, the stabilizing effect of the composition containing sodium bicarbonate, magnesium oxide, and calcium hydroxide as alkalizing agents determined in Example 2 on rabeprazole was evaluated.

[0086] Specifically, assuming the intake of 100 ml of water per 100 ml of gastric juice at pH 2.0, 200 ml of the dissolution solution prepared by adding 100 ml of water to 100 ml of an aqueous solution at pH 2.0 was warmed to 37 °C, and then sodium bicarbonate, magnesium oxide, and calcium hydroxide were combined and weighed, and the resulting combination together with 20 mg of rabeprazole sodium was placed in a dissolution reactor. Samples were collected after 5, 10, 15, and 30 minutes and analyzed by HPLC to confirm the residual amount of the drug. Therefore, the amount of each stabilizer used was the same as in Example 1.

[0087] Based on the results shown in Table 5 below, in the composition containing sodium bicarbonate, magnesium oxide, and calcium hydroxide as alkalizing agents, the residual amount of rabeprazole was close to 99% after all 5, 10, 15, and 30 minutes.

[0088] [Table 5]

[0089] Results of in - vivo stability tests (residual amount of rabeprazole) depending on the combination with stabilizers

[0090]

[0091] Example 4. Results of pharmacokinetic tests in an animal model according to the formulation of the present invention

[0092] To evaluate the pharmacokinetic characteristics of rabeprazole according to the present invention, the following pharmacokinetic tests were conducted in parallel in 12 male beagle dogs (10 to 20 months old) using the composition (formulation) containing sodium bicarbonate and magnesium oxide and calcium hydroxide as alkalizing agents determined in Example 2 and a control drug (Pariet tablets, enteric-coated).

[0093] Tablets of the test drug according to the present invention and the control drug (Pariet tablets, enteric-coated) were orally administered, and blood samples were collected before administration and at 15, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, and 12 hours after administration. Each 2 ml of blood collected from the jugular vein was immediately centrifuged to separate plasma, which was then stored in a refrigerator until analysis. LC-MS / MS was used to analyze rabeprazole in plasma, and rabeprazole-d4 sodium was used as an internal standard.

[0094] Based on the results of confirming whether a rapid onset T can be obtained for the test drug compared to the control drug (Pariet tablets, enteric-coated) in an animal (beagle dog) model 最大 and similar AUC levels, as shown in Table 6 below and Figure 3 as shown, due to the high AUC and C 最大 results and short T 最大 , rapid absorption was thus confirmed. This indicates that the selected combination of stabilizers rapidly neutralizes gastric acid in the animal body, prevents the rapid decomposition of rabeprazole in acidic solutions, and exhibits a rapid onset of efficacy compared to the control drug (enteric-coated tablets) released in the small intestine.

[0095] [Table 6]

[0096] Pharmacokinetic characteristics of the test drug with the final formulation

[0097] Parameter Test drug (G1) Control drug (G2) <![CDATA[AUC 最后 (ng·hr / ml)]]> 1450.6 1207.3 <![CDATA[C 最大 (ng / ml)]]> 2265 1470 <![CDATA[T 最大 (hr)]]> 0.5 1

[0098] Example 5. Tablet manufacturing examples and evaluation of stability depending on the manufacturing method

[0099] 5.1 Tablets were manufactured by post-mixing (direct compression) of sodium rabeprazole after granulating sodium bicarbonate

[0100] According to the final formulation determined in the above examples, film-coated tablets containing sodium rabeprazole were manufactured using the following direct compression method.

[0101] Specifically, the method includes:

[0102] (1) Granules were formed by mixing sodium bicarbonate (700 mg) with copovidone dissolved in ethanol,

[0103] (2) A mixture (I) is obtained by mixing the particles obtained in step (1) with crospovidone, D-mannitol, magnesium oxide (63 mg) and calcium hydroxide (35 mg).

[0104] (3) A mixture (II) is obtained by mixing the mixture (I) obtained in step (2) with rabeprazole sodium (20 mg).

[0105] (4) The final mixture is obtained by mixing the mixture (II) obtained in step (3) with magnesium stearate, followed by tabletting, and

[0106] (5) The tablets are manufactured by coating with Opadry II dissolved in pure water (165 mg).

[0107] 5.2 Tablets are manufactured by wet granulation of sodium bicarbonate and rabeprazole sodium.

[0108] According to the final formulation determined in the above examples, film-coated tablets containing rabeprazole sodium are manufactured using the following wet granulation method.

[0109] Specifically, the method includes:

[0110] (1) Particles are formed by mixing sodium bicarbonate (700 mg) with copovidone dissolved in ethanol.

[0111] (2) Particles are formed by mixing rabeprazole sodium (20 mg), mannitol, magnesium oxide (63 mg) and calcium hydroxide (35 mg) with copovidone dissolved in ethanol.

[0112] (3) A mixture is obtained by mixing the particles obtained in steps (1) and (2) with crospovidone.

[0113] (4) The final mixture is obtained by mixing the mixture obtained in step (3) with magnesium stearate, followed by tabletting, and

[0114] (5) The tablets are manufactured by coating with Opadry II dissolved in pure water (165 mg).

[0115] 5.3 Stability depending on the manufacturing method

[0116] In the process of manufacturing tablets according to Examples 5.1 and 5.2, the stability of the film-coated tablets manufactured by each process was evaluated to confirm the effect of the addition of solvents and water involved in the manufacture of wet granules and the subsequent drying process on drug stability. Each tablet was placed in a high-density polyethylene (HDPE) bottle, sealed with an appropriate amount of silica gel, and then stored in a stability chamber under separate storage conditions. The change in related substances (% of impurities) depending on the storage time was evaluated.

[0117] The analysis conditions are as follows.

[0118] *HPLC analysis conditions

[0119] Detector: UV spectrophotometer (measurement wavelength: 290 nm)

[0120] Column: Length 150 mm × inner diameter 4.6 mm (particle size 5 μm) or similar column, packed with octadecylsilica (C18)

[0121] Column temperature: 30 °C

[0122] Mobile phase: Methanol 0.05 mol / L phosphate buffer solution (pH 7.0) A mixed solution

[0123] A: pH 7.0 adjusted by adding 0.05 mol / L potassium dihydrogen phosphate test solution to 0.05 mol / L disodium hydrogen phosphate test solution (volume ratio approximately 2:1)

[0124] Flow rate: Flow rate adjusted to give a retention time of approximately 5 minutes for rabeprazole sodium.

[0125] Injection volume: 10 μl

[0126] Analysis time: 50 minutes

[0127] As Figure 4 seen, the results of the accelerated test (40 °C ± 2 °C / relative humidity 75% ± 5%) showed that after 6 months, the tablets manufactured by the direct compression process had a total impurity content of approximately 2.23%, while the tablets manufactured by the wet granulation process had a total impurity content of 6.36%, confirming that the generation of impurities in the tablets manufactured by direct compression was significantly reduced, resulting in improved stability.

[0128] In addition, as Figure 5As seen, the results of the stability evaluation under intermediate storage conditions (30°C ± 2°C / relative humidity 65% ± 5%) showed that after 6 months, the total impurity content of the tablets manufactured by the direct compression process was approximately 0.84%, while that of the tablets manufactured by the wet granulation process was 1.35%, confirming that the generation of impurities in the tablets manufactured by direct compression was significantly reduced.

[0129] In addition, as Figure 6 seen, the results of the stability evaluation under long-term storage conditions (25°C ± 2°C / relative humidity 60% ± 5%) showed that after 6 months, the total impurity content of the tablets manufactured by the direct compression process was approximately 0.60%, while that of the tablets manufactured by the wet granulation process was 0.68%, confirming that the generation of impurities in the tablets manufactured by direct compression was reduced.

[0130] So far, the preferred embodiments of the present invention have been mainly described. Those of ordinary skill in the art to which the present invention pertains should understand that the present invention can be implemented in a modified form without departing from its essential features.

[0131] Therefore, the above embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated by the claims, rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims

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

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

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

4. The pharmaceutical composition according to claim 1, comprising at least one excipient selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered once a day.

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

2.

7. The pharmaceutical composition according to claim 6, wherein, The residual amount of rabeprazole is 95% or more after 30 minutes in a solution at pH 2.

0.

8. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical preparation according to claim 8, wherein the pharmaceutical preparation is a capsule, a pill, or a tablet.

10. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a tablet or a film-coated tablet.

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

12. A method for manufacturing a pharmaceutical preparation comprising rabeprazole or a salt thereof, comprising: (1) forming granules by mixing sodium bicarbonate with a binder dissolved in a solvent; (2) obtaining a mixture (I) by mixing the granules obtained in step (1) with a disintegrant, an excipient, magnesium oxide, and calcium hydroxide; (3) obtaining a mixture (II) by mixing the mixture (I) obtained in step (2) with rabeprazole or a pharmaceutically acceptable salt thereof; (4) obtaining a final mixture by mixing the mixture (II) obtained in step (3) with a lubricant; and (5) filling the final mixture as it is into a capsule, granulating the final mixture and filling the pellets into a capsule, or manufacturing a tablet by directly compressing the final mixture.

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