KR20210047234A - Stable pharmaceutical composition comprising proton pump inhibitor and sodium bicarbonate, and method for preparing the same - Google Patents

Abstract

The present invention relates to: a stable pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizer, and a calcium silicate; and a method for manufacturing the same. Therefore, the present invention has an effect of improving bioavailability by allowing the PPI, which is stable in an acidic and/or watery environment and an active component, to be immediately released in the stomach.

Description

A stable pharmaceutical composition containing a proton pump inhibitor and sodium hydrogen carbonate, and a manufacturing method thereof TECHNICAL FIELD [STABLE PHARMACEUTICAL COMPOSITION COMPRISING PROTON PUMP INHIBITOR AND SODIUM BICARBONATE, AND METHOD FOR PREPARING THE SAME}

The present invention relates to a stable pharmaceutical composition comprising a proton pump inhibitor (PPI) and sodium hydrogen carbonate and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical composition with improved bioavailability and a method for preparing the same by allowing the proton pump inhibitor (PPI), which is an active ingredient, to be immediately released in the stomach, which is stable in an acidic and/or moisture environment.

Proton pump inhibitor (PPI) is a drug that inhibits the production of acid by inhibiting the ^{proton pump (H +} /K ^{+ -ATPase) of parietal cells and weakens the strength of acid in the digestive tract.} It shows the efficacy in esophageal reflux disease, pharyngeal reflux disease, or peptic ulcer disease. In particular, benzimidazole-based compounds or salts thereof are used as treatments for peptic ulcers that have a proton pump inhibitory effect. The inner parietal cell passes through the basal cell membrane and enters the parietal cell. The proton pump inhibitor (PPI), which has passed through the cell membrane of parietal cells, enters and accumulates in the cell in the form of a prodrug, and is converted into sulfenamide, an active substance, by acid. This activator binds to the proton pump present in the cell membrane and inactivates the proton pump, thereby inhibiting acid secretion. Examples of such proton pump inhibitors (PPI) include omeprazole, lansoprazole, rabeprazole, pantoprazole, and the like.

However, since the benzimidazole-based compound type proton pump inhibitor (PPI) is a prodrug, it is easily decomposed by gastric acid when passing through the stomach. As described above, since the benzimidazole-based compound is very unstable at acidic pH, many attempts have been made to prevent rapid decomposition in acidic gastric juice when administered orally and to allow the active ingredient to reach the small intestine.

International Patent Publication WO 2004075881 discloses a formulation containing an antioxidant to stabilize rabeprazole, which is unstable in acid. However, in the case of including antioxidants in the finished product, it is difficult to develop practically commercially because it is necessary to prove the aspect of reduction and preservation of antioxidants during storage period. European Patent Document EP 2032126A2 discloses a formulation containing calcium hydroxide as an alkalizing agent as a stabilizer for rabeprazole and protecting the active ingredient by forming an intermediate layer between enteric coatings. 10499775 discloses a capsule in which rabeprazole, a proton pump inhibitor, is stabilized with an alkalizing agent and filled with enteric-coated pellets. At this time, since the polymers used for enteric coating are mainly acidic compounds, they are decomposed by direct or indirect contact with rabeprazole, and their content decreases with time, so there is a problem in storage. On the other hand, since the enteric-coated tablet does not cause immediate absorption in the stomach and is designed to be dissolved and absorbed in the intestine, it is not suitable for the treatment of diseases that require an immediate therapeutic effect after administration, such as gastric acid-related diseases.

Therefore, the development of technology that can improve the stability in acid and moisture of the proton pump inhibitor (PPI) of benzimidazole-based compounds such as rabeprazole, and at the same time improve the bioavailability due to immediate release from the stomach, has been developed. It is a situation that is desperately needed.

It is an object of the present invention to provide a novel pharmaceutical composition comprising a proton pump inhibitor having improved instability in acid and/or moisture.

Another object of the present invention is to provide a novel pharmaceutical composition with improved instability in acid and/or water and immediately released in the stomach, thereby improving bioavailability.

Another object of the present invention is to provide a method for preparing a novel pharmaceutical composition comprising a proton pump inhibitor having improved instability in acid and/or moisture.

The present invention relates to a pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizer, and a calcium silicate.

Proton pump inhibitors of the present invention include omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, tenatoprazole, and drugs thereof. It is preferably selected from the group consisting of scientifically acceptable salts, precursors, and mixtures thereof.

The proton pump inhibitor is preferably rabeprazole, more specifically, rabeprazole sodium salt.

The rabeprazole sodium salt of the present invention is preferably about 5 mg to about 40 mg, more specifically about 10 mg to about 25 mg, based on the unit formulation.

The gastric acid neutralizing agent according to the present invention is sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium oxide, magnesium hydroxide, magnesium carbonate, and magnesium. It is preferable to be selected from the group consisting of carbonate hydroxide (Magnesium Carbonate Hydroxide), calcium carbonate (Calcium Carbonate), calcium hydroxide (Calcium hydroxide), pharmaceutically acceptable salts thereof, and mixtures thereof.

The gastric acid neutralizing agent is preferably sodium bicarbonate.

The sodium hydrogen carbonate may be included in an amount of 20 to 60 parts by weight based on 1 part by weight of rabeprazole.

The calcium silicate of the present invention may be included in an amount of 0.1% to 20% by weight of the total weight of the composition, more preferably 1% to 10% by weight of the total weight of the composition.

Calcium silicate according to the present invention may be included in an amount of 0.5% to 7% by weight based on 1 part by weight of the proton pump inhibitor.

In the present invention, in a pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizer, and calcium silicate, the proton pump inhibitor is 5 mg based on the rabeprazole sodium salt. To 40mg, the gastric acid neutralizing agent based on sodium hydrogen carbonate 500mg to 1200mg, the calcium silicate relates to a pharmaceutical composition comprising 10mg to 60mg.

In the pharmaceutical composition of the present invention, the time to reach the maximum blood concentration (Tmax) of the proton pump inhibitor when administered orally may be within 1 hour.

The present invention comprises the steps of (a) wet granulation by mixing a gastric acid neutralizing agent, calcium silicate, and a pharmaceutically acceptable carrier; (b) drying the mixture; (c) adding and mixing a proton pump inhibitor and a pharmaceutically acceptable carrier to the dried product; And, (d) obtaining an oral dosage form prepared from the obtained mixture. More specifically (a) wet granulation by mixing sodium hydrogen carbonate, calcium silicate, and a pharmaceutically acceptable carrier; (b) drying the mixture; (c) adding and mixing rabeprazole sodium salt and a pharmaceutically acceptable carrier to the dried product; And, (d) obtaining an oral dosage form prepared from the obtained mixture, and the addition of the rabeprazole sodium salt may be added in the wet granulation step. Meanwhile, the drying step may be prepared by including the step of making the loss on dry (LOD) less than 1.5%, and the oral dosage form may further include storing with a desiccant or a deoxidant.

The present invention relates to a stable pharmaceutical composition comprising a proton pump inhibitor (PPI), sodium hydrogen carbonate, and a method for preparing the same. The pharmaceutical composition of the present invention is stable in an acidic and/or moist environment, so that the active ingredient, a proton pump inhibitor (PPI), is immediately released in the stomach, thereby improving bioavailability.

1 shows the analysis results of rabeprazole content according to pH.
Figure 2 shows the results of measuring the pH of the artificial gastric juice according to the dose of sodium hydrogen carbonate.
3 shows the results of measuring changes in the blood concentration of rabeprazole for the test drug and the reference drug.

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by those of ordinary skill in the related fields of the present invention. In addition, although preferred methods or samples are described in the present specification, those similar or equivalent are included in the scope of the present invention. The contents of all publications referred to herein by reference are incorporated herein by reference in their entirety.

The present invention provides a pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizing agent, and calcium silicate.

Proton pump inhibitors, especially rabeprazole, are very unstable at acidic pH, so they can be administered in combination with a gastric acid neutralizer or administered in combination form to suppress rapid decomposition in acidic gastric juice when administered orally and to exhibit a stable drug effect. . However, it was found by the present invention that when the gastric acid neutralizing agent and rabeprazole are administered together, the formulation compatibility is poor and the stability of rabeprazole is inhibited. The instability problem of rabeprazole can be solved by a pharmaceutical composition comprising a proton pump inhibitor, a gastric acid neutralizer, and a calcium silicate according to the present invention.

According to the present invention, in order to stabilize rabeprazole, which is the most unstable in acid among proton pump inhibitors, rabeprazole is stable even within the stomach residence time without enteric coating, as opposed to the prior art that could not show immediate effect in the stomach due to the inevitable enteric coating. By providing the composition, it is possible to provide a pharmaceutical composition that is rapidly dissolved in the stomach and can be absorbed into the body.

At this time, the proton pump inhibitors are omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, tenatoprazole, and its pharmacology. It may be any one or more selected from the group consisting of acceptable salts, precursors, and mixtures thereof, preferably rabeprazole, but is not limited thereto.

The pharmaceutically acceptable salts of the proton pump inhibitor are alkali salts, magnesium, sodium, calcium, potassium, manganese, iron, copper, zinc, aluminum, lithium, basic amino acids, ammonia, primary amines, secondary amines and tertiary amines. It may be any one or more selected from the group consisting of primary amines, preferably rabeprazole sodium salt, but is not limited thereto.

In the pharmaceutical composition of the present invention, the active ingredient, a proton pump inhibitor or a pharmaceutically acceptable salt thereof, may be used in a therapeutically effective amount. For example, rabeprazole may be administered once to several times a day in an amount of about 5 mg to about 40 mg, more preferably about 10 mg to about 25 m, based on a unit formulation (i.e., unit dosage form). .

The gastric acid neutralizer of the pharmaceutical composition according to the present invention maintains the environment in the stomach at a minimum pH of 8 or more to stabilize rabeprazole during the disintegration time of rabeprazole. Rabeprazole is known to exhibit pH dependent solution stability, and a gastric acid neutralizer to maintain a pH above 8 in the stomach achieves this.

The gastric acid neutralizing agent according to the pharmaceutical composition of the present invention is preferably sodium hydrogen carbonate, but is not limited thereto, and a pharmaceutically suitable weak base or strong base (and their Mixture). The gastric acid neutralizing agent is preferably a sufficient amount to substantially achieve the above function. Examples of such gastric acid neutralizing agents include sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium oxide, magnesium hydroxide, magnesium carbonate, and magnesium carbonate. Hydroxide (Magnesium Carbonate Hydroxide), calcium carbonate (Calcium Carbonate), calcium hydroxide (Calcium hydroxide), pharmaceutically acceptable salts thereof, and mixtures thereof. In the pharmaceutical composition of the present invention, the pH of sodium hydrogen carbonate, which is a gastric acid neutralizer, increases as the amount increases. The amount of sodium hydrogen carbonate that maintains a pH of 8 or more to ensure the stability of rabeprazole is based on 1 part by weight of rabeprazole. It may be in an amount of 20 to 60 parts by weight.

On the other hand, it is a known fact that proton pump inhibitors are unstable not only in acid but also in moisture. Therefore, even if sodium hydrogencarbonate, a gastric acid neutralizer, raises the pH of the stomach to relieve the acid instability of rabeprazole, rabeprazole is decomposed in the process of tableting by wet granulation of sodium hydrogen carbonate and rabeprazole, resulting in poor stability. . Even if sodium bicarbonate and rabeprazole are prepared as separate compartmentalized two-layer tablets or three-layer tablets by conventional formulation, rabeprazole is unstable and related substances are generated. This is presumed that rabeprazole is unstable because hydrogen ions move in the solid phase even if the wet granulation solvent and the main component rabeprazole are in direct contact in a single tablet, or in the case of a separate compartment, that is, a multi-layered tablet, even if it is not in direct contact. The pharmaceutical composition according to the present invention eliminates the water instability of rabeprazole and achieves stability even when rabeprazole is in direct contact with the binding liquid by containing calcium silicate.

Calcium silicate/calcium silicate is represented by the formula Ca2SiO4 or 2CaO.SiO2., and refers to a group of compounds prepared by reacting calcium oxide and silica in various ratios. Calcium silicate is broadly 3CaO.SiO2, Ca3SiO5; 2CaO.SiO2, Ca2SiO4; Compounds represented by 3CaO.2SiO2, Ca3Si2O7 and CaO.SiO2, CaSiO3 may be included. It exists in a solid state of a white powder having a low bulk density in a standard state, and is stable at room temperature and pressure. Calcium silicate is easily synthesized by a known method, or Cell (Mico-cel), Calsil, Florite R (Florite R), Marimet 45 (Marimet 45), Macrocal RT (Microcal ET), A number of commercially available formulations are available such as Silene EF, SilmosT, Solex, and Starlex L.

The content of calcium silicate in the composition may be appropriately selected depending on the type of proton pump inhibitor, which is a pharmaceutical active ingredient, and dosage form. In one embodiment, the calcium silicate may be present in 0.1% to 20% by weight of the total amount of the composition, but is not limited thereto. For example, the pharmaceutical composition according to the present invention comprises calcium silicate in an amount of 0.5% to 15% by weight, preferably 1% to 10% by weight of the total amount of the composition. Meanwhile, calcium silicate may be present in an amount of 0.5% to 3% by weight based on 1 part by weight of the proton pump inhibitor, but is not limited thereto.

In addition, the pharmaceutical composition of the present invention may further contain additives such as conventional stabilizers, excipients, binders, disintegrants, lubricants, etc., which are used pharmaceutically, if necessary.

Stabilizers are alkalizing agents that may be additionally added in addition to sodium hydrogen carbonate, which is a gastric acid neutralizing agent, and include magnesium oxide, sodium hydroxide, sodium carbonate, and the like, but are not limited thereto.

Disintegant refers to a substance added to facilitate disintegration or disintegration of a solid dosage form after administration in vivo. The excipients may be starch, lactose, sucrose, mannitol, sorbitol, glucose, microcrystalline cellulose, calcium monohydrogenate, crospovidone, low-substituted hydroxypropyl cellulose, etc., alone or in combination, but are not limited thereto.

Binder refers to a material used to provide adhesion to a powdery material to facilitate compression and improve fluidity. The binder may include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; It can be starch, gelatin, povidone, or gum arabic.

Disintegant refers to a substance added to facilitate disintegration or disintegration of a solid dosage form after administration in vivo. The disintegrant is starch; Starch derivatives such as sodium starch glycolate; Carboxymethylcellulose derivatives such as calcium carboxymethylcellulose and crosslinked carboxymethylcellulose; It may be microcrystalline cellulose, crospovidone, hydroxypropylcellulose, and the like.

Glidants or lubricants refer to substances that function to prevent adhesion of powder to the pressing equipment and improve the flow of granules. The lubricant may be stearic acid and a pharmaceutically acceptable alkali metal salt or amine salt thereof, colloidal silicon dioxide, silicates, talc, and the like. In addition to this, pigments, antioxidants, etc. can be added and used as necessary.

The pharmaceutical composition of the present invention may be a tablet, and may have a formulation of a single tablet, a separate compartment formulation, for example, a double-layer tablet, a three-layer tablet, a nucleated tablet, or a pellet-containing capsule formulation. It can be prepared according to a tablet manufacturing method generally known in the pharmaceutical field. In one embodiment, the pharmaceutical composition of the present invention has a single dosage form.

The composition of the present invention is prepared by granulating a proton pump inhibitor, a gastric acid neutralizing agent, a calcium silicate, and a pharmaceutically acceptable carrier together by a wet granulation method.

As used herein, the term "granulation" refers to a processing technique that increases the total particle size of a formulation by permanent agglomeration of small particles. The term “wet granulation” or “wet granulation method” refers to a granulation process performed by wetting with a solvent or a binder solution so that small particles can adhere to each other. In the case of wet granulation, the cohesive power and compression properties of the powder are improved compared to the granules produced by the dry granulation method, the distribution of the finely divided low-dose drug is uniform, and the intact shape is maintained even after drying to prevent the separation of components. It has the advantage of being. The proton pump inhibitor, particularly rabeprazole, is very unstable not only in acid but also in moisture, so it was not possible to apply the wet granulation method in the past, but the pharmaceutical composition according to the present invention can be wet granulated by calcium silicate.

In one embodiment, sodium hydrogen carbonate, calcium silicate and a pharmaceutically acceptable carrier are mixed, wet granulated, dried, and then rabeprazole sodium salt and a pharmaceutically acceptable carrier are added and mixed. When drying, calcium silicate contained in the granules can extremely drop the moisture content in the granules, so it is possible to make the loss on dry (LOD) less than 1.5%. Meanwhile, the sodium salt of rabeprazole, which is the main component, may be added by post-mixing after wet granulation, but may be added in the wet granulation step. That is, sodium hydrogen carbonate, calcium silicate, rabeprazole sodium salt, and a pharmaceutically acceptable carrier are wet-granulated, dried, and then mixed with an additional lubricant, and then tableted to obtain a final tablet.

The pharmaceutical composition of the present invention is stabilized by using calcium silicate in sodium rabeprazole, which is extremely unstable in acid and moisture, so that decomposition of the active ingredient is suppressed even under acidic conditions, thereby exhibiting excellent effects, and maintaining the storage stability of the formulation for a long time It shows an action effect.

Hereinafter, one or more specific examples will be described in more detail through the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

Examples 1 to 3: Preparation of a single tablet of rabeprazole sodium salt and sodium hydrogen carbonate containing calcium silicate

According to the compositions shown in Examples 1 to 3 of Table 1, tablets containing rabeprazole sodium salt and sodium hydrogen carbonate were prepared by the following method.

1. Manufacture of granules (wet granulation)

Sodium hydrogen carbonate, stabilizer magnesium oxide, mannitol, calcium silicate, and low-substituted hydroxypropyl cellulose were uniformly mixed, and then pulverized to a uniform size using a 25 to 35 mesh sieve and sieved. To the pulverized and sieved mixture, hydroxypropylmethylcellulose is added to purified water, which is a solvent, and mixed until granules are formed.

2. Dry

Put the granules in a dryer (Speed Dryer), set the air supply temperature to 60℃ or higher, and the drying time to 30 minutes or longer, and dry them until the loss on dry (LOD) becomes 0.3% to 1.5%, and then 20 It was sieved and sieved to a uniform size using a mesh sieve.

3. Manufacture of post mixture (simple mixing)

To the sized granules, the sodium salt of rabeprazole, which is the main component, and a pharmaceutically acceptable carrier were mixed afterward.

4. Tableting and coating

The obtained mixture was compressed to prepare a single tablet having an appropriate level of hardness (kp) of the solid formulation. The obtained tablets were put in a pan coater and then first coated with Opadry 03K19229, and then second coated with Opadry 88A620055 (AMBII) to obtain coated tablets. The content in Table 1 represents the content per tablet.

Example 4: Preparation of single tablet of rabeprazole sodium salt and sodium hydrogen carbonate containing calcium silicate

According to the composition shown in Example 4 of Table 1 below, a tablet containing rabeprazole sodium salt and sodium hydrogen carbonate was prepared by the following method. The preparation method of Examples 1 to 3 is the same as in Examples 1 to 3, except that rabeprazole sodium salt is added to the mixing step before the granulation is prepared.

Example 5: Preparation of single tablet of rabeprazole sodium salt and sodium hydrogen carbonate containing calcium silicate

Tablets containing rabeprazole sodium salt and sodium hydrogen carbonate were prepared by the following method. Except for adding the rabeprazole sodium salt to the binding solution, the preparation method of Examples 1 to 3 is the same.

Comparative Examples 1 to 2: Preparation of a single tablet of rabeprazole sodium salt and sodium bicarbonate containing no calcium silicate or magnesium alumino silicate

According to the components and contents of Comparative Examples 1 to 2 of Table 2 below, a single matrix tablet containing no calcium silicate or containing magnesium aluminum silicate was prepared.

1. Manufacture of granules (wet granulation)

After uniformly mixing sodium hydrogen carbonate, stabilizer magnesium oxide, mannitol, magnesium aluminosilicate (Comparative Example 1), and low-substituted hydroxypropyl cellulose, uniform size using a 25 to 35 mesh sieve And sieved. Binder and stabilizer are added to the pulverized and sieved mixture and mixed until granules are formed.

2. Dry

The granules were put in a speed dryer, and the air supply temperature was set to 60° C. or higher, and the drying time was set to 30 minutes or longer, and dried, and then sieved and sieved to a uniform size using a 20 mesh sieve.

3. Manufacture of post mixture (simple mixing)

To the sized granules, the sodium salt of rabeprazole, which is the main component, and a pharmaceutically acceptable carrier were mixed afterward.

4. Tableting and coating

The obtained mixture was compressed to prepare a single tablet having an appropriate level of hardness (kp) of the solid formulation. The obtained tablets were put in a pan coater and then coated first with Opadry 03K19229, followed by secondary coating with Opadry 88A620055 (AMBII). The content in Table 2 represents the content per tablet.

Comparative Example 3: Preparation of two-layer tablets of rabeprazole sodium salt and sodium hydrogen carbonate that do not contain calcium silicate or contain magnesium aluminosilicate

According to the components and contents of Comparative Example 3 in Table 3 below, a single matrix tablet containing no calcium silicate or containing magnesium aluminum silicate was prepared.

1. Preparation of granules containing sodium hydrogen carbonate

After homogeneously mixing sodium hydrogen carbonate with mannitol and magnesium aluminosilicate, it was combined with a binding solution and dried, and then granules were prepared using a 25-35 mesh sieve. Subsequently, magnesium stearate was added and mixed to prepare sodium hydrogen carbonate granules.

2. Preparation of granules containing rabeprazole

After mixing the rabeprazole sodium salt with a stabilizer and a pharmaceutically acceptable excipient, it was combined as a binding solution, dried, and then 25-35 mesh sieve granules were prepared. Then, magnesium stearate and sodium stearyl fumarate were added and mixed to prepare rabeprazole sodium salt granules.

3. Preparation of two-layer tablet

The sodium hydrogen carbonate granule mixture and the rabeprazole granule mixture prepared in the above 1 and 2, respectively, were tableted using a two-layer tableting machine to prepare a two-layer tablet.

4. Coating

After the primary coating with Opadry 03K19229, the secondary coating was performed with Opadry 88A620055 (AMBⅡ). The content in Table 3 represents the content per tablet.

Test Example 1: Stability test of rabeprazole according to pH

After adding 20 mg of rabeprazole solution to 100 ml of the buffer solution, the content according to the pH was analyzed, and the analysis method is as follows.

<Analysis method>

A) Detector: UV-visible absorbance photometer (measurement wavelength: 280 nm)

B) Column: Inertsil C8-3 (4.6 × 150 mm, 5 μm) or equivalent column

C) Injection volume: 20 µl

D) Flow rate: 1.5 mL/min

E) Column temperature: constant temperature around 40℃

F) Sample temperature: a constant temperature around 10 ℃

G) Analysis time: 6 minutes

H) Mobile phase: A mixture of pH 7.6 buffer and acetonitrile (65:35)

As for the pH 7.6 buffer, take 0.725 g of sodium hydrogen phosphate monohydrate (NaH2PO4·H2O) and 4.472 g of disodium hydrogen phosphate anhydride (Na2HPO4), put it in a 1 L volumetric flask, dissolve with purified water, and take 250 mL of the marked solution and take 1 L volume. This solution is put in a flask, labeled with purified water, and then adjusted to pH 7.6 with phosphoric acid.

The analysis results are shown in Table 4 and FIG. 1 below.

Rabeprazole (%) pH1.2 pH4.0 pH6.0 pH6.8 pH7.5 pH8.0 pH8.5 pH9.0 0 100 100 100 100 100 100 100 100 5 7 16 59 78 90 95 97 96 10 0 0 5 47 79 89 94 96 15 0 0 One 31 72 88 93 96 30 0 0 0 17 63 82 91 93 45 0 0 0 8 52 75 86 89 60 0 0 0 5 47 71 84 88 120 0 0 0 2 36 64 79 85

As shown in Table 4, in order for rabeprazole to be stable, it needs to be at least pH 8 or higher.

Test Example 2: Test to confirm the pH of artificial gastric juice according to the sodium hydrogen carbonate dose

In order to set the sodium bicarbonate content, drug release conditions and gastric juice conditions were set as follows. Specifically, 1) the amount of gastric juice on an empty stomach is generally 30 mL, 2) the amount of gastric juice secretion is about 83 mL/hr, and 3) when taking the drug, it is taken with water, and the amount of water at this time is 240 mL.

On an empty stomach (Condition 1: 30 mL of gastric juice + 240 mL of purified water), 30 minutes of exposure to tablets (Condition 2: 72 mL of gastric juice + 240 mL of purified water), 60 minutes of exposure to tablets (Condition 3: 113 mL of gastric juice + 240 mL of purified water). The pH was measured while changing, and the measurement results are shown in Table 5 and FIG. 2 below.

Sodium hydrogen carbonate
(mg) 0 100 200 300 400 500 600 700 800 900 1000 1200 Condition 1 pH 10.0 10.1 9.8 9.6 9.5 9.4 9.4 9.3 9.2 9.2 9.1 9.1 Condition 2 3.1 6.5 7.1 7.4 7.7 8.0 8.1 8.2 8.2 8.3 8.3 8.4 Condition 3 2.1 2.3 2.6 4.8 6.0 6.4 6.6 6.8 6.9 7.1 7.2 7.3

As shown in Table 5, in condition 1, a high pH was maintained even in the absence of sodium hydrogen carbonate, but in conditions 2 and 3, it was confirmed that the pH tends to increase as the amount of sodium hydrogen carbonate increased.

Since the disintegration time of the tablet is within 30 minutes, it was confirmed that the amount of sodium hydrogen carbonate maintained above pH 8.0 to ensure the stability of rabeprazole was at least 500 mg.

Test Example 3: Stability test of the formulation with or without calcium silicate

After filling the tablets of Examples 1 to 5 and each of the tablets of Comparative Examples 1 to 3 in a high-density polyethylene (HDPE) bottle and sealing with an appropriate amount of silica gel or a deoxidant, After storage in the chamber, the change (% by weight) of related substances according to the storage time was evaluated, and the evaluation results are respectively shown in Table 6 below.

Analysis conditions are as follows.

* Liquid chromatograph analysis conditions

Detector: Ultraviolet absorption photometer (measurement wavelength 290nm)

Column: A stainless tube having an inner diameter of about 4.6 mm and a length of about 25 cm is filled with 5 μm of octadecylsilylated silica gel.

Column temperature: about 30℃

Mobile phase: methanol pH 7.0 0.05moL/L phosphate buffer (3:2)

Flow rate: Adjust the flow rate so that the retention time of sodium rabeprazole is about 5 minutes.

Injection volume: 10 µl

Referring to Table 6, in Examples 1 to 5 containing calcium silicate as a stabilizer, magnesium aluminosilicate having a porosity similar to that of calcium silicate was added as compared to Comparative Example 1 that does not contain a separate stabilizer. Thus, it can be seen that the content of related substances during storage for 12 weeks is significantly lower than that of Comparative Example 2 obtained by wet granulation. In particular, in Examples 1 to 5, rabeprazole sodium salt, which is unstable in moisture in the manufacturing process, is added directly to the binding solution (Example 5), or mixed in the premixing step so as to directly contact the binding solution (Example 4), It was found that even when mixed in the post-mixing step (Examples 1 to 3), the amount of related substances generated was very small. In the case of wet granulation by including calcium silicate in the granule, the loss on dry (LOD) of the granules can be kept extremely low to less than 1% during drying, thereby improving the stability of the final tablet extremely. Because there is.

In addition, even if only about 1% of the total weight of the tablet was added to calcium silicate (Example 3), a separate stabilizer was not included (Comparative Example 2) or a tablet containing magnesium aluminosilicate (Comparative Example 1), and sodium hydrogen carbonate and Compared to the two-layer tablet physically separated from rabeprazole (Comparative Example 3), it was found that the amount of related substances generated when stored for 4 weeks or longer and the stability of the active ingredient, rabeprazole sodium salt, could be improved. .

On the other hand, in the tablets of Examples 1 to 3, the calcium silicate was wet-granulated with sodium hydrogen carbonate, and then the rabeprazole sodium salt was mixed and tableted.Example 4B in which the rabeprazole sodium salt was included in the granular part. It can be seen that, compared to Example 5, which was granulated by adding rabeprazole sodium salt to the binding solution, the content of related substances was lowered at 12 weeks or longer, resulting in higher stability.

On the other hand, it can be seen that Example 1, in which the content of calcium silicate in the tablet is 60 mg, has less generation of related substances when stored for 12 weeks or longer, compared to Example 3, in which the content of calcium silicate in the tablet is 10 mg. It can be seen that the active ingredient rabeprazole sodium salt is stable in proportion to the content of.

Test Example 3: Blood concentration of rabeprazole

Changes in the blood concentration of rabeprazole in the blood over time by performing a pharmacokinetic test (PK test) of ^{a tablet and a reference drug (commercially available Parisat tablet TM} ) prepared according to the manufacturing method of the test drug (Example 1) And AUC values are shown in Table 7 and FIG. 3 below.

Nine healthy beagle dogs were divided into 2 groups of 3 each, and the first group was administered with a control drug, and the second group was administered a tablet of the test drug (Example 1). The method of administration is to open the mouth with the beagle dog naturally located in the breeding box, put the tablet of the control drug and the test drug into the inside of the tongue, close the mouth, gently stroke the throat to swallow, and then check if swallowed. 10 ml of water was fed using a syringe. Feed was fasted for more than 16 hours before administration, and feed was fed after starting the tablet administration of the control drug and the test drug. Blood was collected at 0, 0.5, 0.75, 1, 1.5, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours after administration, and labe using ULPC-MS/MS (Waters ACQUITY UPLCTM system). The plasma concentration of prazol was quantified. After quantification, the AUC and Cmax of rabeprazole at the time of administration of the control drug and the test drug were statistically processed.

Mean† PK parameters Reference drug Test drug` AUC(last) 1407.42 1274.10 AUC(inf) 1414.91 1275.57 Cmax 1258.18 1331.70 Tmax 2.94 1.00 CL(inf)/F 23.13 29.05 Vz(terminal)/F 38.00 14.35 t1_2 0.70 0.37 AUC_Extrp.% 1.61 0.18

According to Table 7 above, it was confirmed that the test drug was immediately eluted and absorbed after administration, and the highest blood concentration was 1331.70mg/L, which was higher than 1258.18mg/L of the control drug, which is an enteric formulation.

In addition, the time to reach the highest concentration of rabeprazole in the blood (Tmax) after administration of the reference drug was 2.94 hours, whereas the test drug was 1 hour, which was about 1 hour faster than the reference drug. In addition, according to FIG. 3, it can be seen that the test drug exhibits a higher blood concentration up to 2 hours compared to the reference drug and thus has excellent bioavailability.

Claims (19)

Proton pump inhibitor (Proton pump inhibitor, PPI) or a pharmaceutically acceptable salt thereof, a stable pharmaceutical composition comprising a gastric acid neutralizing agent and calcium silicate.
The method of claim 1,
The proton pump inhibitors are omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, tenatoprazole, and its pharmaceutical Stable pharmaceutical composition selected from the group consisting of acceptable salts, precursors, and mixtures thereof.
The method of claim 2,
The proton pump inhibitor is a stable pharmaceutical composition of rabeprazole.
The method of claim 3,
The rabeprazole is a stable pharmaceutical composition of rabeprazole sodium salt.
The method of claim 4,
The rabeprazole sodium salt is a stable pharmaceutical composition of about 5 mg to about 40 mg based on a unit formulation.
The method of claim 5,
The rabeprazole sodium salt is a stable pharmaceutical composition of about 10 mg to about 25 mg based on a unit formulation.
The method of claim 1,
The gastric acid neutralizing agent is sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium carbonate hydroxide Side (Magnesium Carbonate Hydroxide), calcium carbonate (Calcium Carbonate), calcium hydroxide (Calcium hydroxide), a stable pharmaceutical composition selected from the group consisting of its pharmaceutically acceptable salts and mixtures thereof.
The method of claim 7,
The stable pharmaceutical composition, wherein the gastric acid neutralizing agent is sodium bicarbonate.
The method of claim 8,
The sodium hydrogen carbonate is contained in an amount of 20 to 60 parts by weight based on 1 part by weight of rabeprazole, a stable pharmaceutical composition.
The method of claim 1,
The calcium silicate is contained in an amount of 0.1% to 20% by weight of the total weight of the composition, a stable pharmaceutical composition.
The method of claim 10,
The calcium silicate is contained in an amount of 1% to 10% by weight of the total weight of the composition, a stable pharmaceutical composition.
The method of claim 1,
The calcium silicate is contained in an amount of 0.5% by weight to 3% by weight based on 1 part by weight of the proton pump inhibitor, a stable pharmaceutical composition.
In a pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizer, and calcium silicate,
The proton pump inhibitor comprises 5mg to 40mg based on the sodium salt of rabeprazole, the gastric acid neutralizer is 500mg to 1200mg based on sodium hydrogen carbonate, the calcium silicate is a stable pharmaceutical composition comprising 10mg to 60mg.
The method according to any one of claims 1 to 13,
A stable pharmaceutical composition, wherein the time to reach the maximum blood concentration (Tmax) of the proton pump inhibitor when administered orally is within 1 hour.
(a) wet granulation by mixing a gastric acid neutralizing agent, calcium silicate, and a pharmaceutically acceptable carrier;
(b) drying the mixture;
(c) adding and mixing a proton pump inhibitor and a pharmaceutically acceptable carrier to the dried product; And
(d) a method for producing a stable pharmaceutical composition comprising the step of obtaining an oral dosage form prepared from the obtained mixture.
(a) wet granulation by mixing sodium hydrogen carbonate, calcium silicate and a pharmaceutically acceptable carrier;
(b) drying the mixture;
(c) adding and mixing rabeprazole sodium salt and a pharmaceutically acceptable carrier to the dried product; And
(d) a method for producing a stable pharmaceutical composition comprising the step of obtaining an oral dosage form prepared from the obtained mixture.
The method of claim 16,
The addition of the rabeprazole sodium salt can be added in the wet granulation step, a method for producing a stable pharmaceutical composition.
The method according to any one of claims 15 to 16,
The drying step is a step of making the loss on dry (LOD) less than 1.5%, a method for preparing a stable pharmaceutical composition.
The method according to any one of claims 15 to 16,
The oral dosage form further comprises the step of storing a hygroscopic agent or a deoxygenating agent, a method for producing a stable pharmaceutical composition.

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