KR102494141B1 - 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 calcium silicate, and a method for preparing the same. This has the effect of improving bioavailability by allowing the proton pump inhibitor (PPI), which is stable and active in an acidic and/or watery environment, to be immediately released in the stomach.

Description

A stable pharmaceutical composition containing a proton pump inhibitor and sodium bicarbonate and a method for preparing the same

The present invention relates to a stable pharmaceutical composition comprising a proton pump inhibitor (PPI) and sodium bicarbonate and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical composition with improved bioavailability by being stable in an acidic and/or watery environment so that an active ingredient, a proton pump inhibitor (PPI), is immediately released in the stomach, and a method for preparing the same.

A 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 system. It shows its efficacy in esophageal reflux disease, pharyngeal reflux disease or peptic ulcer disease. In particular, benzimidazole-based compounds or salts thereof are used as a peptic ulcer treatment having a proton pump inhibitory action. Most of the currently developed proton pump inhibitors (PPIs) are absorbed in the upper duodenum or small intestine by oral administration and enter the stomach through the bloodstream. Inner parietal cells pass through the basal cell membrane and enter the parietal cells. Proton pump inhibitors (PPI) that pass through the cell membrane of parietal cells enter the cells in the form of prodrugs and accumulate, and are converted to active sulfenamide by acid. This activator inhibits acid secretion by inactivating the proton pump by binding to the proton pump present in the cell membrane. Examples of such proton pump inhibitors (PPIs) include omeprazole, lansoprazole, rabeprazole, pantoprazole, and the like.

However, since these benzimidazole-type compound-type proton pump inhibitors (PPIs) are prodrugs, they are easily decomposed by gastric acid when passing through the stomach. As such, due to the very unstable nature of benzimidazole-based compounds at acidic pH, many attempts have been made to suppress rapid degradation in acidic gastric juice and to allow active ingredients to reach the small intestine when administered orally.

International Patent Publication WO 2004075881 discloses a formulation containing an antioxidant to stabilize acid-labile rabeprazole. However, in the case of including antioxidants in the finished product, it is practically difficult to develop commercially because it is necessary to prove the reduction and preservation of antioxidants during the storage period. European Patent Publication EP 2032126A2 discloses a formulation containing calcium hydroxide, an alkalizing agent, as a stabilizer for rabeprazole and forming an intermediate layer between enteric coatings to protect active ingredients, and Chinese Patent Publication CN 10499775 discloses capsules 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 in the enteric coating are mainly acidic compounds, they are decomposed by direct or indirect contact with rabeprazole, and the content decreases with time, so there is a storage problem. On the other hand, since enteric coated tablets are designed to be dissolved and absorbed in the intestine without immediate absorption in the stomach, they are not suitable for the treatment of diseases requiring immediate therapeutic effect after administration, such as gastric acid-related diseases.

Therefore, the development of technology capable of improving the stability of proton pump inhibitors (PPI) of benzimidazole-based compounds such as rabeprazole in acid and water and at the same time preparing a pharmaceutical composition with improved bioavailability due to immediate release from the stomach. It is desperately needed.

An object of the present invention is to provide a novel pharmaceutical composition comprising a proton pump inhibitor with improved acid and/or water instability.

Another object of the present invention is to provide a novel pharmaceutical composition with improved bioavailability due to improved acid and/or water instability and immediate release in the stomach.

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

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 calcium silicate.

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

Preferably, the proton pump inhibitor is rabeprazole, more specifically rabeprazole sodium salt.

The amount of 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 a unit dosage form.

The gastric acid neutralizer according to the present invention is sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium It is preferably selected from the group consisting of magnesium carbonate hydroxide, calcium carbonate, calcium hydroxide, pharmaceutically acceptable salts thereof, and mixtures thereof.

The gastric acid neutralizer is preferably sodium bicarbonate.

The sodium bicarbonate 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 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.

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 calcium silicate, wherein the proton pump inhibitor is 5 mg based on rabeprazole sodium salt to 40mg, the gastric acid neutralizer relates to a pharmaceutical composition comprising 500mg to 1200mg based on sodium bicarbonate, and 10mg to 60mg of the calcium silicate.

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

The present invention comprises the steps of (a) wet granulation by mixing a gastric acid neutralizer, 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 bicarbonate, 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 include a step of making the LOD (Loss On Dry) 1.5% or less, and the oral dosage form may further include a step of storing the oral dosage form with a moisture absorbent or an oxygen scavenger.

The present invention relates to a stable pharmaceutical composition containing a proton pump inhibitor (PPI) and sodium bicarbonate and a method for preparing the same. The pharmaceutical composition of the present invention is stable in an acidic and/or watery environment and has an effect of improving bioavailability by allowing an active ingredient, a proton pump inhibitor (PPI), to be immediately released in the stomach.

Figure 1 shows the analysis results of rabeprazole content according to pH.
Figure 2 shows the results of measuring the pH of artificial gastric juice according to the amount of sodium bicarbonate.
Figure 3 shows the results of measuring the change in blood concentration of rabeprazole for the test drug and the control drug.

All technical terms used in the present invention are used in the same meaning as commonly understood by a person skilled in the art related to the present invention unless otherwise defined. In addition, although preferred methods or samples are described in this specification, those similar or equivalent thereto are also included in the scope of the present invention. The contents of all publications cited herein by reference are hereby incorporated 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 neutralizer and calcium silicate.

Because proton pump inhibitors, especially rabeprazole, are very unstable at acidic pH, they can be administered in combination with gastric acid neutralizers or administered in combination to suppress rapid degradation in acidic gastric juice when administered orally and to exert drug effects stably. . However, it was found by the present invention that when such a gastric acid neutralizer and rabeprazole are administered together, the stability of rabeprazole is impaired due to poor compatibility. The problem of instability of rabeprazole can be solved by the pharmaceutical composition comprising a proton pump inhibitor, a gastric acid neutralizer and calcium silicate according to the present invention.

According to the present invention, in order to stabilize rabeprazole, which is the most acid-labile among proton pump inhibitors, enteric coating has to be applied to stabilize rabeprazole, which is stable even within the gastric residence time without enteric coating, in contrast to the prior art, which could not show an immediate effect in the stomach. By providing a composition, it is possible to provide a pharmaceutical composition that is rapidly eluted in the stomach and can be absorbed into the body.

At this time, the proton pump inhibitor is omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, tenatoprazole, pharmaceuticals thereof It may be at least one selected from the group consisting of generally acceptable salts, precursors, and mixtures thereof, preferably rabeprazole, but is not limited thereto.

The pharmaceutically acceptable salts of proton pump inhibitors are alkali salts and contain magnesium, sodium, calcium, potassium, manganese, iron, copper, zinc, aluminum, lithium, basic amino acids, ammonia, primary amines, secondary amines and 3 It may be at least one 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 proton pump inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient may be used in a therapeutically effective amount. For example, rabeprazole can 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 mg, based on a unit formulation (i.e., unit dosage form). .

The gastric acid neutralizer of the pharmaceutical composition according to the present invention maintains a minimum pH of 8 or higher in the stomach to stabilize rabeprazole during disintegration time of rabeprazole. Rabeprazole is known to exhibit pH-dependent solution stability, which is achieved by gastric acid neutralizers to maintain a pH of 8 or higher in the stomach.

The gastric acid neutralizer according to the pharmaceutical composition of the present invention is preferably sodium bicarbonate, but is not limited thereto, and is a pharmaceutically suitable weak base or strong base that functions to substantially prevent or inhibit acid decomposition by gastric acid (and their mixture). The gastric acid neutralizer is preferably in an amount sufficient to substantially achieve the above function. Examples of such gastric acid neutralizers are sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium carbonate It includes magnesium carbonate hydroxide, calcium carbonate, calcium hydroxide, pharmaceutically acceptable salts thereof, and mixtures thereof. In the pharmaceutical composition of the present invention, the pH of sodium bicarbonate, which is a gastric acid neutralizer, increases as the amount increases. It may be in an amount of 20 to 60 parts by weight.

Meanwhile, it is known that proton pump inhibitors are unstable to water as well as acid. Therefore, even if sodium bicarbonate, a gastric acid neutralizer, raises the pH in the stomach to eliminate the acid instability of rabeprazole, rabeprazole is decomposed during the wet granulation of sodium bicarbonate and rabeprazole into tablets, resulting in poor stability. . Even if sodium bicarbonate and rabeprazole are separately compartmentalized two-layer or three-layer tablets by conventional formulation, rabeprazole is unstable and related substances are generated. It is presumed that rabeprazole is unstable because the wet granulation solvent and the main component rabeprazole are in direct contact in a single tablet or because hydrogen ions move in the solid phase even if they do not come into direct contact in the case of a separate compartment tablet, that is, in the case of a multi-layer tablet. By including calcium silicate, the pharmaceutical composition according to the present invention solves the water instability of rabeprazole and achieves stability even when rabeprazole is in direct contact with the binding solution.

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

The content of calcium silicate in the composition may be appropriately selected depending on the type of proton pump inhibitor, dosage form, etc., which is a pharmaceutically active ingredient. In one embodiment, calcium silicate may be present in an amount of 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 contains 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, and lubricants used pharmaceutically, if necessary.

The stabilizer is an alkalizing agent that can be added in addition to sodium bicarbonate, which is a neutralizing agent for gastric acid, and includes, but is not limited to, magnesium oxide, sodium hydroxide, and sodium carbonate.

A disintegrant refers to a substance added to disintegrate or facilitate disintegration of a solid dosage form after administration to a living body. Starch, lactose, sucrose, mannitol, sorbitol, glucose, microcrystalline cellulose, calcium monohydrate, crospovidone, low-substituted hydroxypropyl cellulose, etc. may be used alone or in combination, but are not limited thereto.

A binder refers to a material used to facilitate compaction and improve fluidity by imparting adhesiveness to a powdery material. The binder may be cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium; It can be starch, gelatin, povidone, gum arabic, etc.

A disintegrant refers to a substance added to disintegrate or facilitate disintegration of a solid dosage form after administration to a living body. The disintegrant is starch; starch derivatives such as sodium starch glycolate; carboxymethylcellulose derivatives such as calcium carboxymethylcellulose and cross-linked carboxymethylcellulose; It may be microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, and the like.

A glidant or lubricant refers to a substance that functions to prevent adhesion of powder to the compaction equipment and improve the flow of granules. The lubricant may be stearic acid and its pharmaceutically acceptable alkali metal salt or amine salt, colloidal silicon dioxide, silicates, talc, and the like. In addition, pigments, antioxidants, etc. may be added and used as needed.

The pharmaceutical composition of the present invention may be a tablet and may have a single tablet, separate compartment formulation, for example, a two-layer tablet, a three-layer tablet, a press-coated tablet, or a pellet-containing capsule formulation, and may be formulated by dry or wet granulation method or direct compression method. 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 unit dosage form.

The composition of the present invention is prepared by granulating a proton pump inhibitor, a gastric acid neutralizer, 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 aggregation of small particles. The term "wet granulation" or "wet granulation method" refers to a granulation process in which small particles are wetted with a solvent or binder solution so that they adhere to each other. In the case of wet granulation, compared to granules produced by dry granulation, the cohesion and compactability of the powder are improved, the distribution of the finely divided low-dose drug becomes uniform, and the intact form is maintained even after drying, preventing separation of components have the advantage of being Proton pump inhibitors, especially rabeprazole, are very unstable not only in acid but also in water, so conventional wet granulation was not possible, but the pharmaceutical composition according to the present invention can be wet granulated with calcium silicate as described above.

In one embodiment, sodium bicarbonate, calcium silicate and a pharmaceutically acceptable carrier are mixed, wet granulated, dried, and rabeprazole sodium salt and a pharmaceutically acceptable carrier are added and then mixed. During drying, the calcium silicate contained in the granules can extremely drop the water content in the granules, so it is possible to achieve a Loss On Dry (LOD) of 1.5% or less. On the other hand, rabeprazole sodium salt as a main component may be added by post-mixing after wet granulation, but may also be added in the wet granulation step. That is, it is possible to wet-granulate sodium bicarbonate, calcium silicate, rabeprazole sodium salt, and a pharmaceutically acceptable carrier, then dry, add an additional lubricant, etc., mix and tablet to obtain a final tablet.

The pharmaceutical composition of the present invention is stabilized by using calcium silicate for rabeprazole sodium, which is extremely unstable to acids and moisture, so that the decomposition of active ingredients is suppressed even under acidic conditions, showing excellent effects, and the storage stability of the formulation is maintained for a long time. indicates the 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 Single Tablets of Rabeprazole Sodium Salt Containing Calcium Silicate and Sodium Bicarbonate

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

1. Preparation of granules (wet granulation)

After uniformly mixing sodium bicarbonate, magnesium oxide as a stabilizer, mannitol, calcium silicate, and low-substituted hydroxypropyl cellulose, the mixture was pulverized and sieved to a uniform size using a 25 to 35 mesh sieve. To the pulverized and sieved mixture, hydroxypropylmethylcellulose is added to purified water as a solvent and mixed until granules are formed.

2. Drying

Put the granules in a dryer (Speed Dryer), set the supply air temperature to 60 ° C or more and dry time to 30 minutes or more, and dry until the Loss On Dry (LOD) is 0.3% to 1.5%, and then 20 It was sized and sieved to a uniform size using a mesh sieve.

3. Preparation of post-mixture (simple mixing)

Rabeprazole sodium salt, which is the main ingredient, and a pharmaceutically acceptable carrier were mixed with the established granules afterward.

4. Tableting and coating

The obtained mixture was compressed to prepare a single tablet having a hardness (kp) appropriate for a solid dosage form. The obtained tablets were placed in a pan coater, 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 Tablets of Rabeprazole Sodium Salt and Sodium Bicarbonate Containing Calcium Silicate

According to the composition shown in Example 4 of Table 1 below, tablets containing rabeprazole sodium salt and sodium hydrogen carbonate were prepared by the following method. The manufacturing method is the same as in Examples 1 to 3 except that rabeprazole sodium salt is added in the pre-mixing step when preparing granules.

Example 5: Preparation of Single Tablets of Rabeprazole Sodium Salt and Sodium Bicarbonate Containing Calcium Silicate

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

Comparative Examples 1 and 2: Preparation of single tablets containing rabeprazole sodium salt and sodium bicarbonate without calcium silicate or containing magnesium aluminosilicate

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

1. Preparation of granules (wet granulation)

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

2. Drying

The granules were placed in a speed dryer, dried by setting the supply air temperature to 60° C. or more and the drying time to 30 minutes or more, and then sized and sieved to a uniform size using a 20 mesh sieve.

3. Preparation of post-mixture (simple mixing)

Rabeprazole sodium salt, which is the main ingredient, and a pharmaceutically acceptable carrier were mixed with the established granules afterward.

4. Tableting and coating

The obtained mixture was compressed to prepare a single tablet having a hardness (kp) appropriate for a solid dosage form. The obtained tablets were placed in a pan coater, first coated with Opadry 03K19229, and then second coated with Opadry 88A620055 (AMBII). The content in Table 2 represents the content per tablet.

Comparative Example 3: Preparation of two-layer tablet containing rabeprazole sodium salt and sodium bicarbonate without calcium silicate or containing magnesium alumino silicate

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

1. Preparation of granules containing sodium bicarbonate

After uniformly mixing sodium bicarbonate with mannitol and magnesium aluminosilicate, they were combined with a binding solution, dried, and granules were prepared using a 25 to 35 mesh sieve. Next, magnesium stearate was added and mixed to prepare granules of sodium hydrogen carbonate.

2. Preparation of granules containing rabeprazole

A stabilizer and pharmaceutically acceptable excipients were mixed with rabeprazole sodium salt, combined into a binding solution, dried, and then 25 to 35 mesh sieve granules were prepared. Subsequently, magnesium stearate and sodium stearyl fumarate were added and mixed to prepare rabeprazole sodium salt granules.

3. Manufacture of double-layer tablets

The granular mixture of sodium hydrogen carbonate and the granular mixture of rabeprazole prepared in 1 and 2 above were tableted using a double-layer tableting machine to prepare a double-layer tablet.

4. Coating

After the first coating with Opadry 03K19229, the second coating was performed with Opadry 88A620055 (AMBII). The content in Table 3 shows 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 buffer solution, the content was analyzed according to pH, and the analysis method is as follows.

<Analysis method>

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

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

C) Injection amount: 20 μl

D) Flow rate: 1.5 mL/min

E) Column temperature: constant temperature around 40℃

F) Sample temperature: constant temperature around 10℃

g) Analysis time: 6 minutes

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

For the pH 7.6 buffer, 0.725 g of sodium hydrogen phosphate monohydrate (NaH2PO4 H2O) and 4.472 g of disodium hydrogen phosphate anhydrous (Na2HPO4) were put into a 1 L volumetric flask, dissolved in purified water, and 250 mL of the diluted solution was taken to make a 1 L volume. It is a solution that is put in a flask, marked 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 above, in order for rabeprazole to be stable, a minimum pH of 8 or higher is required.

Test Example 2: pH confirmation test of artificial gastric juice according to the amount of sodium bicarbonate

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 secreted is about 83 mL/hr, and 3) the drug is taken with water when taking, and the amount of water at this time is 240 mL.

In the case of fasting (condition 1: gastric juice 30 mL + purified water 240 mL), tablet exposure 30 minutes (condition 2: gastric juice 72 mL + purified water 240 mL), tablet exposure 60 minutes (condition 3: gastric juice 113 mL + purified water 240 mL), sodium bicarbonate dose The pH was measured while changing, and the measurement results are shown in Table 5 and FIG. 2 below.

sodium bicarbonate
(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 bicarbonate, but in conditions 2 and 3, the pH tended to increase as the amount of sodium bicarbonate increased.

Since the disintegration time of the tablet was within 30 minutes, it was confirmed that the amount of sodium bicarbonate maintained at least 500 mg or more was maintained at pH 8.0 or higher to ensure stability of rabeprazole.

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

The tablets of Examples 1 to 5 and each tablet of Comparative Examples 1 to 3 were filled in a High Density Polyethylene (HDPE) bottle, sealed with an appropriate amount of silica gel or an oxygen scavenger, and then stored at 40°C and 75% humidity. After storage in the chamber, the change in related material content (% by weight) according to the storage time was evaluated, and the evaluation results are shown in Table 6 below.

Analysis conditions are as follows.

* Liquid chromatograph analysis conditions

Detector: Ultraviolet absorbance photometer (measurement wavelength 290nm)

Column: A stainless tube with 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 solution (3:2)

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

Injection volume: 10 μl

Referring to Table 6, in Examples 1 to 5 including calcium silicate as a stabilizer, compared to Comparative Example 1 not including a separate stabilizer, magnesium aluminosilicate having a porous property similar to that of calcium silicate was added. It can be seen that the content of related substances generated during 12 weeks of storage is significantly lower than that of Comparative Example 2 in which wet granulation was performed. In particular, in Examples 1 to 5, rabeprazole sodium salt, which is unstable to moisture, was directly added to the binding solution during the manufacturing process (Example 5), or mixed in the pre-mixing step so as to directly contact the binding solution (Example 4), Even when mixed in the post-mixing step (Examples 1 to 3), it was found that the amount of related substances generated was very small. When wet granulation is performed by including calcium silicate in the granulation part, the Loss On Dry (LOD) of the granules can be kept extremely low at 1% or less during drying, which can extremely improve the stability of the final tablet. because there is

In addition, even if calcium silicate is added at only about 1% of the total weight of the tablet (Example 3), a tablet that does not contain a separate stabilizer (Comparative Example 2) or contains magnesium aluminosilicate (Comparative Example 1), sodium bicarbonate and Compared to the two-layer tablet in which rabeprazole was physically separated (Comparative Example 3), it was found that the content of related substances generated was less and the stability of the active ingredient, rabeprazole sodium salt, could be further improved when stored for 4 weeks or longer. .

On the other hand, the tablets of Examples 1 to 3 are compressed into tablets by wet granulating calcium silicate with sodium bicarbonate and then mixing rabeprazole sodium salt. , It can be seen that the content of related substances generated at 12 weeks or more was lower and the stability was higher compared to Example 5 in which rabeprazole sodium salt was added to the binding solution and granulated.

On the other hand, it can be seen that Example 1, in which the content of calcium silicate in the tablet is 60 mg, generated less related substances when stored for 12 weeks or more, 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

Pharmacokinetic test (PK test) was performed on the tablet prepared according to the manufacturing method of the test drug (Example 1) and the control drug (commercially available Pariet tablet ^TM ) to change the blood concentration value of rabeprazole over time 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 the control drug and the second group was administered with the tablets of the test drug (Example 1). The administration method is to open the mouth of the beagle dog in a natural position in the breeding box, put the tablets of the control drug and the test drug on the inside of the tongue, close the mouth, and then gently stroke the throat to swallow and check whether it was swallowed, They were fed with 10 ml of water using a syringe. Food was fasted for more than 16 hours before administration, and feed was provided after the start of tablet administration of the control drug and test drug. Blood was collected at 0, 0.5, 0.75, 1, 1.5, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration, and labe was performed using ULPC-MS/MS (Waters ACQUITY UPLCTM system). The plasma concentration of Prazol was quantified. After quantification, AUC and Cmax of rabeprazole at the time of administration of control drug and 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, it was confirmed that the test drug was immediately dissolved and absorbed after administration, and the highest concentration in blood was 1331.70 mg/L, which was higher than 1258.18 mg/L of the control drug, which was an enteric preparation.

In addition, the control drug took 2.94 hours to reach the highest blood concentration of rabeprazole after administration (Tmax), whereas the test drug took 1 hour, about 1 hour faster than the control drug. In addition, according to FIG. 3, it can be seen that the test drug showed a higher blood concentration up to 2 hours compared to the control drug, indicating excellent bioavailability.

delete

Claims (19)

A stable pharmaceutical composition comprising a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, a gastric acid neutralizer, calcium silicate and a pharmaceutically acceptable carrier,
The proton pump inhibitor is rabeprazole,
The gastric acid neutralizer is sodium bicarbonate,
The sodium bicarbonate is included in an amount of 25 to 60 parts by weight based on 1 part by weight of rabeprazole,
The calcium silicate is included in an amount of 0.5 to 3 parts by weight based on 1 part by weight of rabeprazole,
As the pharmaceutically acceptable carrier,
Magnesium oxide is included in 3 parts by weight based on 1 part by weight of rabeprazole,
Mannitol is included in 0.5 to 4 parts by weight based on 1 part by weight of rabeprazole,
Low-substituted hydroxypropyl cellulose is included in 1.5 parts by weight based on 1 part by weight of rabeprazole,
Crospovidone is contained in 1.5 to 2 parts by weight based on 1 part by weight of rabeprazole, a pharmaceutical composition.
delete delete According to claim 1,
The stable pharmaceutical composition wherein the rabeprazole is rabeprazole sodium salt.
According to claim 4,
The rabeprazole sodium salt is a stable pharmaceutical composition of 5 mg to 40 mg based on unit formulation.
According to claim 5,
The rabeprazole sodium salt is a stable pharmaceutical composition of 10 mg to 25 mg based on a unit formulation.
delete According to claim 1,
A stable pharmaceutical composition that further comprises sodium carbonate in an amount of 5 parts by weight based on 1 part by weight of rabeprazole.
delete According to claim 1,
A stable pharmaceutical composition that further comprises sodium hydroxide in an amount of 0.25 to 0.35 parts by weight based on 1 part by weight of rabeprazole.
delete delete delete According to claim 1,
A stable pharmaceutical composition in which the time to reach the maximum blood concentration (Tmax) of the proton pump inhibitor upon oral administration is within 1 hour.
(a) wet granulation by mixing a gastric acid neutralizer, 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 preparing a stable pharmaceutical composition comprising the step of obtaining an oral dosage form prepared from the obtained mixture,
The proton pump inhibitor is rabeprazole,
The gastric acid neutralizer is sodium bicarbonate,
The total content of the gastric acid neutralizer included in the pharmaceutical composition is 25 to 60 parts by weight based on 1 part by weight of rabeprazole,
The calcium silicate is included in an amount of 0.5 to 3 parts by weight based on 1 part by weight of rabeprazole,
As the pharmaceutically acceptable carrier,
Magnesium oxide is included in 3 parts by weight based on 1 part by weight of rabeprazole,
Mannitol is included in 0.5 to 4 parts by weight based on 1 part by weight of rabeprazole,
Low-substituted hydroxypropyl cellulose is included in 1.5 parts by weight based on 1 part by weight of rabeprazole,
Crospovidone is included in 1.5 to 2 parts by weight based on 1 part by weight of rabeprazole, the manufacturing method.
delete According to claim 15,
The method of producing a stable pharmaceutical composition, wherein the rabeprazole may be added in the wet granulation step.
According to claim 15,
The drying step is a step for producing a stable pharmaceutical composition so that the loss on drying (LOD) is 1.5% or less.
According to claim 15,
The method for producing a stable pharmaceutical composition, further comprising the step of storing the oral dosage form as a moisture absorbent or deoxidizer.

Images