KR20220139698A - Formulation comprising rabeprazole sodium and magnesium oxide having excellent release properties of rabeprazole, and a method for preparing the same - Google Patents

Abstract

The present invention relates to a formulation containing rabeprazole sodium salt and magnesium oxide, and more specifically, to a formulation containing rabeprazole sodium having stability in gastric acid, and magnesium oxide having acid antacid ability to neutralize gastric acid. The present invention can provide: the formulation, which maintains stability so that rabeprazole sodium is eluted from the stomach, and the eluted rabeprazole sodium is absorbed in the stomach without decomposition; and a manufacturing method thereof.

Description

A formulation comprising rabeprazole sodium and magnesium oxide having excellent release properties of rabeprazole, and a method for preparing the same

The present invention relates to a formulation comprising rabeprazole sodium salt and magnesium oxide, and more particularly, to a formulation comprising rabeprazole sodium, which has stability in gastric acid, and magnesium oxide, which has antacid power to neutralize gastric acid. will be.

Antacids neutralize gastric acid and relieve acute gastritis symptoms quickly, but do not suppress gastric acid secretion.

Histamine 2 receptor antagonists are agents that inhibit gastric acid secretion by competing with histamine on the histamine receptors of gastric parietal cells. It is possible to treat gastritis and reflux esophagitis by strongly inhibiting gastric acid secretion and maintaining the pH of gastric acid above 5, and its use is gradually increasing.

Omeprazole, pantoprazole and lansoprazole, which are known as first-generation PPI agents, are known to have a slow pharmacological effect and are known to have small inhibitory effects on acid secretion for 24 hours and acid secretion at night.

On the other hand, rabeprazole and esomeprazole, which are known as second-generation PPI formulations, have advantages such as immediate gastric acid secretion suppression and strong effect and long duration of action, so their use is increasing.

The chemical name of rabeprazole sodium is Monosodium(RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-1H-benzimidazolide (Cas No. 117976-90-6), which is very soluble in water. It is a compound that dissolves well in ethanol and is a representative PPI drug used as a treatment for peptic ulcer treatment and gastroesophageal reflux disease.

Rabeprazole sodium is extremely unstable in acid, so it is decomposed upon contact at pH 4 or less, and it is confirmed that it is unstable even in a neutral aqueous solution of pH 7.

Because of these properties, rabeprazole sodium is commercially available as a tablet by preparing a tablet with rabeprazole sodium excipient in order to solve the stability in gastric acid and then performing a perfect enteric coating.

Although there is Korean Patent Publication No. 10-2006-0134124 for securing the stability of rabeprazole sodium in acid and controlling its dissolution, this is also a single preparation of rabeprazole sodium premised on a perfect enteric coating of rabeprazole sodium.

This perfectly enteric-coated formulation is not absorbed at all in the stomach, but is designed to be dissolved and absorbed in the intestine, so it is difficult to apply the drug to diseases requiring rapid expression of effect.

Laid-open Patent Publication No. 10-2006-0134124

In order to solve this problem, the present inventors have found that rabeprazole sodium is eluted under acidic conditions such as gastric acid from unstable rabeprazole sodium that is decomposed even under acidic or weakly acidic conditions of pH 7 or less, and the stability of the eluted rabeprazole sodium is improved. The present invention was completed by developing a pharmaceutical composition and manufacturing method capable of rapid drug expression of rabeprazole sodium by securing it.

Accordingly, an object of the present invention is to provide a formulation that maintains stability so that rabeprazole sodium is eluted in the stomach, and the dissolved rabeprazole sodium is not decomposed and absorbed in the stomach, and a method for preparing the same.

In order to achieve the above object, the present invention provides a formulation comprising rabeprazole sodium and magnesium oxide. In the formulation, rabeprazole sodium is eluted from gastric acid, and stability can be ensured.

The formulation contains 10 to 50 parts by weight of magnesium oxide, preferably 15 to 40 parts by weight, based on 1 part by weight of rabeprazole sodium. Gastric acid contained below the above range is not well neutralized, and if it exceeds the above range, gastric acid is neutralized too quickly, making it difficult to ensure stability when rabeprazole stays in the stomach.

In one embodiment of the present invention, the formulation may be of a configuration having an inner core and an outer layer. The inner core may include rabeprazole sodium, and the outer layer may include magnesium oxide.

The formulation according to the present invention may further contain 1 to 5 parts by weight, preferably 1.5 to 4 parts by weight, of calcium carboxymethyl cellulose based on 1 part by weight of rabeprazole sodium. When calcium carboxymethyl cellulose is included below the above range, the neutralization rate is slow, and when it exceeds the above range, the neutralization rate is too fast and the stability of rabeprazole sodium may be lowered.

The formulation may further include hypromellose phthalate as a coating agent, and the hypromellose phthalate may be included in an amount of 0.1 to 1 part by weight, preferably 0.2 to 0.9 parts by weight, based on 1 part by weight of rabeprazole sodium. In addition, in an embodiment of the present invention, the coating agent may be included in the inner core.

In one embodiment of the present invention, the formulation may be a formulation containing 10 to 20 mg of rabeprazole sodium and 250 mg to 500 mg of magnesium oxide.

At this time, magnesium oxide can neutralize gastric acid when more than 250 mg per tablet is used. It may be desirable to prepare a tablet that is easy to take and secure.

The formulation according to the present invention may further include a pharmaceutically acceptable carrier, binder, coating agent, lubricant, disintegrant, excipient, solubilizer, dispersing agent, stabilizer, suspending agent, etc., for example, lactose, deck Strawberry, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, alginate, calcium phosphate, calcium silicate, maltodextrin, silicon dioxide, cellulose, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone , methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, stearylfumarate, ethyl methacrylate, etc., but is not limited thereto.

In addition, the formulation may be prepared in the form of tablets, capsules, granules, etc. by a method commonly used for formulation in the art.

According to an embodiment of the present invention, the preparation is prepared by preparing sodium rabeprazole granules or core tablets and coating them with ethyl methacrylate or hypromellose phthalate to enable dissolution in gastric juice, and then tablets or capsules. It can be formulated as an oral preparation.

The formulation according to the present invention can provide a formulation that maintains stability so that rabeprazole sodium is eluted in the stomach, and the dissolved rabeprazole sodium is not decomposed and absorbed in the stomach, and a method for preparing the same.

Figure 1 shows the pH change in rabeprazol sodium and magnesium oxide mixture.
Figure 2 shows the dissolution rate of rabeprazole sodium and magnesium oxide mixture.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

<Example> Preparation of the formulation according to the present invention

1. Preparation of rabeprazole sodium core tablet

As a binder, hydroxypropyl cellulose is dissolved in ethanol to make a binder, and 10 mg or 20 mg of rabeprazole sodium and an excipient such as D-mannitol are mixed with an excipient such as D-mannitol, and then kneaded by adding a binder. In consideration of the interference with magnesium analysis, tablets were made using stearyl fumarate as a lubricant, and the core tablets were coated with hypromellose phthalate.

The amount of hypromellose phthalate to be used is 4 mg to 9 mg per 1 weight of rabeprazole sodium core tablet, but 6 mg is preferable in consideration of the desired release from gastric juice.

2. Manufacture of Magnesium Oxide Granules

To make a binder by dissolving povidone in a mixed solution of ethanol and purified water, 350 mg of magnesium oxide and an excipient such as D-mannitol are mixed, and then a binder is added to form granules, and then sodium stearyl fumarate is added as a lubricant to make magnesium oxide granules. prepared.

3. Combination of rabeprazole sodium and magnesium oxide

Magnesium oxide granules were first added to the tablet machine, core tablets were put, and magnesium oxide granules were added again to prepare tablets. When manufacturing tablets, magnesium oxide tablets were used as a binder such as polyvinylpyrrolidone or calcium carboxymethyl cellulose as a disintegrating aid. was prepared.

<Comparative Example 1>

Tablets were prepared using only rabeprazole sodium without using magnesium oxide, and compared with a combination of rabeprazole sodium and magnesium oxide.

<Experimental Example 1> Analysis method of rabeprazole sodium

Preparation of standard solution: 25 mg of rabeprazole sodium standard is added to a 500 ml flask and labeled with purified water. Take exactly 1 ml of this solution, add 4 ml of the diluted solution, and use it as the standard solution.

- Preparation of sample solution: After starting the dissolution test, take 3 ml of the eluate and filter it with a 0.45um membrane filter. After discarding the initial filtrate, take exactly 1 m and add 4 ml of the diluent to use it as the sample solution.

- Diluent (pH 11): Mix 11 ml of 0.25 mol/L sodium phosphate solution and 22 ml of 0.5 mol/L anhydrous sodium monohydrogen phosphate solution, add to 100 ml volumetric flask, mark with purified water, and pH with 10 mol/L sodium hydroxide solution set to 11.

HPLC test conditions

Detector: UV absorbance spectrometer 290nm

Column: A 4.6mm, 15cm stainless tube filled with 5um of octadecyl silylated silica gel.

- Column temperature: 30℃

- Mobile phase : Methanol : 0.05 mol/L Phosphate buffer =3 : 2

0.05 mol.L phosphate buffer solution (pH 7.0): 4.83 g of dipotassium hydrogen phosphate and 3.02 g of potassium dihydrogen phosphate are dissolved in 1,000 ml of purified water, and the pH is adjusted to 7.0 with potassium hydroxide solution.

<Experimental Example 2> Evaluation of gastric acid neutralization experimental model

Gastric acid secretion is known to be about 80 ml per hour, and in consideration of water intake when taking drugs, 200 ml of artificial gastric juice (pH 1,2) and 200 ml of purified water are added to the dissolution test vessel, heated to 37±0.5° C., and the experimental drug is added, 15 100 rpm until the minute and 200 rpm after that. The test solution was analyzed by taking 3 ml every 5, 10, 15, 20, 25, 30, 45, and 60 minutes.

<Experimental Example 3> Evaluation of stability by pH of rabeprazole sodium

To determine the stability of rabeprazole sodium by pH, 20 mg of rabeprazole sodium was added to each of pH 4.0, 6.8, 9.0 and 400 ml of purified water, and samples were taken at 5, 10, 15, and 30 minutes while rotating at 100 rpm. The residual amount of sodium was analyzed and the results are shown in Table 1.

Stability of Rabeprazole Sodium by pH Test solution time (min) 5 minutes 10 minutes 15 minutes 30 minutes appearance pH 4.0 - - - - yellow pH 6.8 35.55% 30.94% 27.56% 17.51% pale yellow pH 9.0 93.94% 93.93% 93.52% 92.05% colorless Purified water 94.28% 95.52% 90.69% 91.68% colorless

As shown in Table 1, rabeprazole sodium was completely decomposed within 5 minutes at pH 4.0, and it was found that even at pH 6.8, the remaining amount was only 35.55% remaining in 5 minutes, so it was easily decomposed.

It has been shown that rabeprazol sodium is not decomposed in pH 9.0 or purified water. As such, it was confirmed that rabeprazole sodium is easily decomposed even in weakly acidic conditions and is stable in neutral or weakly alkaline conditions such as purified water.

<Experimental Example 4> Evaluation of gastric acid neutralizing ability such as magnesium oxide

To determine the antacid and amount for stabilizing rabeprazole sodium, 350 mg, 300 mg and 250 mg of magnesium oxide, and 350 mg, 400 mg, 450 mg and 500 mg of magnesium hydroxide powder were added to the antacid power measurement model, stirred at 100 rpm for 15 minutes, and then min. The pH was measured at intervals of 5 minutes while stirring at 200 rpm at intervals, and the results are shown in Table 2.

Measurement of antacid power according to antacids and their amounts hour
(minute) magnesium oxide magnesium hydroxide 250mg 300mg 350mg 500mg 350mg 400mg 450mg 500mg 0 1.54 1.59 1.52 1.53 1.64 1.60 1.61 1.52 One 1.65 1.67 1.70 1.81 1.85 1.96 2.01 2.18 2 1.70 1.67 1.90 2.55 1.92 2.08 2.16 2.28 3 1.73 1.69 2.02 4.03 1.92 2.08 2.20 2.35 4 1.73 1.69 2.06 5.36 1.94 2.11 2.27 2.41 5 1.76 1.68 2.10 6.88 1.95 2.12 2.28 2.45 6 1.77 1.68 2.14 7.87 1.96 2.14 2.31 2.52 7 1.78 1.69 2.14 8.81 1.97 2.15 2.34 2.54 8 1.82 1.69 2.16 9.58 1.97 2.16 2.37 2.61 9 1.82 1.69 2.17 9.68 1.98 2.17 2.39 2.85 10 1.85 1.67 2.20 9.72 1.98 2.17 2.41 2.71 11 1.89 1.71 2.20 9.73 1.99 2.17 2.44 2.75 12 1.92 1.85 2.21 9.77 1.99 2.16 2.46 2.81 13 1.93 1.70 2.21 9.79 1.99 2.17 2.48 2.87 14 1.93 1.70 2.21 9.78 1.99 2.17 2.49 2.92 15 1.93 1.71 2.23 9.79 2.00 2.17 2.50 2.97 20 2.04 2.43 8.46 9.77 2.00 2.17 2.56 5.13

As shown in Table 2, when magnesium hydroxide is 500 mg, it can neutralize gastric acid, but when rabeprazole sodium stays in the stomach, it may be difficult to secure stability. In the case of magnesium oxide 350 mg, the stomach acid neutralizing ability is sufficient, so if the dissolution of rabeprazole sodium in the stomach is delayed for more than 20 minutes, the stability of rabeprazole sodium can be secured even in the stomach. It is considered to have neutralizing ability.

<Experimental Example 5> Evaluation of gastric acid neutralization ability according to the amount of calcium carboxymethyl cellulose used in magnesium oxide tablets

After preparing tablets using 0, 30, 35 and 40 mg of calcium carboxymethyl cellulose in magnesium oxide tablets of 350 mg, the pH was measured while stirring at 100 rpm for 15 minutes and stirring at 200 rpm. The values are shown in Table 3.

Neutralization capacity according to the amount of calcium carboxymethyl cellulose in 350 mg tablet of magnesium oxide hours (minutes)
Cal.CMC 5 10 15 20 25 30 45 60 0 1.67 2.15 4.78 7.15 8.57 9.22 9.37 9.42 30mg 2.02 2.28 5.99 8.22 8.85 9.35 9.42 9.41 35mg 2.33 2.54 6.25 8.25 8.99 9.41 9.40 9.43 40mg 2.32 2.66 6.37 8.55 8.95 9.45 9.42 9.42

As shown in Table 3 above, when calcium carboxymethyl cellulose was not used in the magnesium oxide tablet, it was confirmed that the neutralization rate was fast when using 30 mg to 40 mg of calcium carboxymethyl cellulose per 350 mg of magnesium oxide.

<Experimental Example 6>

Stomach acid neutralizing ability in combination of rabeprazole sodium (20mg) and magnesium oxide (350mg)

A mixture of rabeprazol sodium (20mg) and magnesium oxide (350mg) was added to the gastric acid neutralization model, stirred at 100rpm for 15 minutes, and stirred at 200rpm for 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes. , and at 60 and 120 minutes, the pH was measured twice each of 3 tablets in order to check the gastric acid neutralization ability.

pH change in gastric acid neutralization model of rabeprazole sodium and magnesium oxide mixture division 5 minutes 10 minutes 15 minutes 20 minutes 25 minutes 30 minutes 45 minutes 60 minutes 120 minutes outer core individual pH 1.77 2.14 2.87 8.25 9.03 9.27 9.38 9.42 9.42 1.90 2.56 6.72 8.55 9.21 9.26 9.32 9.31 9.41 1.87 2.55 6.23 8.80 9.18 9.29 9.32 9.29 9.41 average pH 1.85 2.42 5.27 8.53 9.14 9.27 9.34 9.34 9.41 inner core + outer core
Secondary individual pH 1.88 2.57 7.14 8.82 8.91 9.18 8.94 9.29 9.30 1.67 1.84 2.12 7.93 8.45 9.12 9.26 9.37 9.37 1.90 2.78 7.39 9.00 9.12 9.18 9.27 9.36 9.37 average pH 1.82 2.40 5.55 8.58 8.83 9.16 9.16 9.34 9.35 without outer core
inner core only individual pH 1.50 1.44 1.44 1.42 1.45 1.43 1.41 1.40 1.42 1.43 1.44 1.45 1.44 1.45 1.42 1.43 1.42 1.44 1.45 1.43 1.45 1.41 1.44 1.41 1.43 1.39 1.41 average pH 1.46 1.44 1.45 1.42 1.45 1.42 1.42 1.40 1.42

As shown in Table 4 and FIG. 1, the gastric acid neutralization ability of the outer core layer of magnesium oxide shows that gastric acid is sufficiently neutralized at pH 8.53 and 8.58 in the 20th minute range, so that when rabeprazol sodium is eluted after 20 minutes, stability is improved. It is considered to be sufficient. In addition, when the magnesium oxide outer core was not added, the pH was uniformly from 1.42 to 1.46.

<Experimental Example 7>

Evaluation of the release rate of rabeprazole in a combination of rabeprazole sodium (20 mg) and magnesium oxide (350 mg)

Rabeprazole sodium 20mg tablet, magnesium oxide 350mg combination, and magnesium oxide-free rabeprazole sodium 20mg were added to the gastric acid neutralization model, stirred at 100rpm for 15 minutes, stirred at 150rpm for 15 minutes, and samples were collected every 5 minutes until 30 minutes and 45 minutes , samples were collected at 60 minutes and 120 minutes, and the dissolution rate of rabeprazole sodium was compared, and the results are shown in Table 5 and FIG. 2 .

Dissolution rate of rabeprazole sodium and magnesium oxide mixture division 5 minutes 10 minutes 15 minutes 20 minutes 25 minutes 30 minutes 45 minutes 60 minutes 120 minutes inner core + outer core
Secondary individual dissolution rate 0.0 0.0 0.0 0.0 0.6 2.4 65.4 97.1 98.5 0.0 0.0 0.0 0.2 0.8 2.0 14.5 93.2 96.4 0.0 0.0 0.0 0.0 1.1 2.3 33.1 98.2 99.3 average dissolution rate 0.0 0.0 0.0 0.1 0.8 2.2 37.7 96.2 98.1 without an outer core
inner core only individual dissolution rate 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Average dissolution rate 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

As shown in Table 5 and FIG. 2, rabeprazole sodium using magnesium oxide starts dissolution from the 20th minute and rapidly elutes after 30 minutes, whereas rabeprazole sodium tablet without magnesium oxide has a perfect enteric coating. It was confirmed that it did not elute in the gastric acid neutralization model.

In view of these results, when magnesium oxide is used as the outer core of rabeprazole sodium, it neutralizes the pH of gastric acid and does not decompose even if rabeprazole sodium is eluted. It can show drug effect expression. In addition, since magnesium oxide also has an antacid effect, it is judged that the therapeutic effect of peptic ulcer patients will be increased if it is formulated and commercialized.

Claims (7)

A formulation comprising rabeprazole sodium and magnesium oxide. The formulation of claim 1, wherein the formulation comprises 15 to 40 parts by weight of magnesium oxide based on 1 part by weight of rabeprazole sodium. The formulation according to claim 1, wherein rabeprazole sodium is contained in the inner core and magnesium oxide is contained in the outer layer. The formulation according to claim 1, wherein the formulation further comprises 1 to 5 parts by weight of calcium carboxymethylcellulose based on 1 part by weight of rabeprazole sodium. The formulation according to claim 3, wherein the inner core further comprises hypromellose phthalate as a coating agent. The formulation according to claim 5, wherein the hypromellose phthalate comprises 0.2 to 0.9 parts by weight based on 1 part by weight of rabeprazole sodium. The formulation according to claim 1, wherein the rabeprazole sodium is 10 to 20 mg, and magnesium oxide is 250 mg to 500 mg.

Images