KR20220126426A - Immediate release oral formulation with enhenced stability comprising Rabeprazole and method for preparing the same - Google Patents

Abstract

The present invention relates to an immediate release oral formulation with enhanced stability comprising rabeprazole as an active component, and a method for manufacturing the same. Specifically, the present invention relates to an immediate release oral formulation and a method for manufacturing the same, wherein, in the case of using calcium hydroxide as a stabilizer and sodium bicarbonate as an antacid to improve the stability of rabeprazole, which is very unstable in acidic conditions, as a formulation, the time to reach the maximum blood concentration (T_max) of rabeprazole is in the range of 0.3 to 0.8 hours, and when administered orally, rabeprazole in an inner core is eluted in the stomach right after the antacid action by the rapid dissolution of sodium bicarbonate in an outer layer.

Description

Immediate release oral formulation with enhanced stability comprising Rabeprazole and method for preparing the same

The present invention relates to an oral immediate-release formulation comprising rabeprazole with improved stability as an active ingredient and a method for preparing the same. Specifically, the present invention uses calcium hydroxide as a stabilizer to improve the stability of rabeprazole, which is very unstable in acidic conditions, and sodium bicarbonate as an antacid. Time to reach maximum plasma concentration of rabeprazole (T _max ) In the range of 0.3 to 0.8 hours, it is an oral immediate-release formulation in which rabeprazole from the inner core is eluted immediately after the antacid action by the rapid dissolution of sodium bicarbonate in the outer layer in the stomach during oral administration and a method for preparing the same.

Rabeprazole is a benzimidazole derivative that inhibits gastric acid secretion. Rabeprazole is a representative proton pump inhibitor (PPI) that inhibits gastric acid secretion by inhibiting H ⁺ /K ⁺ ATPase on the acid-secreting surface of parietal cells of the gastric mucosa. This effect is dose-dependent and induces basal acid secretion and acid secretion inhibition by stimulation, so it is recommended as a first-line agent for the treatment of gastric and duodenal ulcers.

It is well known in the art that rabeprazole is susceptible to degradation or transformation in acidic and neutral media. The decomposition of rabeprazole is accelerated by acidic compounds and is also affected by moisture, heat, organic solvents and light. Therefore, there have been many demands for the preparation of stable rabeprazole tablets. Since rabeprazole tablets sold on the market are very unstable under acidic conditions, the formulation coated with an enteric coating is used to inhibit rapid decomposition in acidic gastric juice and to allow the active ingredients to reach the small intestine when administered orally. . However, this enteric design method has a storage problem because the polymers used for the enteric coating are mainly acidic compounds, so they are decomposed by direct and indirect contact with rabeprazole and the content decreases with time. In addition, it is designed to be dissolved and absorbed in the intestine without immediate absorption in the stomach, so the onset time of the drug is slow, and it is not suitable for gastrointestinal diseases that require immediate therapeutic effect.

As a means for improving the problems related to the stability of rabeprazole, various methods have been developed so far. Conventionally known methods are likely to become the conventions of tablets, and rather, dissolution of the enteric layer by an alkalizing agent may be induced, which may adversely affect the stability of the tablet and increase instability due to gastric juice, so it is not a recommended method. can

On the other hand, when a large amount of sodium bicarbonate is used, there is a risk of reducing the efficacy of rabeprazole and causing side effects. In fact, when a large amount of sodium bicarbonate is orally administered, it can exacerbate pain in patients with gastric acid-related diseases due to gastric distension, and can aggravate gastroesophageal reflux disease by inducing upward movement of gastric acid by inducing belching. In addition, rabeprazole and sodium bicarbonate do not have good mixing stability, which causes a problem in that related substances increase when in contact with each other.

Under this background, the present inventors have developed a formulation capable of securing long-term pharmaceutical stability of rabeprazole tablets, inhibiting the loss of activity due to gastric acid during oral administration, and facilitating drug absorption in the stomach or upper duodenum. wanted to develop.

Korean Patent Publication No. 2001-114225 (2001.12.31)

The present inventors used rabeprazole as an active ingredient, but using calcium hydroxide as a stabilizer for rabeprazole, and sodium bicarbonate as an antacid that can quickly neutralize gastric acid. By stabilizing the unstable rabeprazole sodium tablet using calcium hydroxide, it suppressed the decomposition of rabeprazole under acidic conditions, and it was found that the storage stability of the formulation is maintained for a long period of time even under accelerated storage conditions, thereby improving stability. reached In addition, it was confirmed that rabeprazole can be rapidly absorbed in the stomach by the neutralizing action of sodium bicarbonate in the stomach, thereby realizing immediate release.

Accordingly, an object of the present invention is to provide an oral immediate-release formulation comprising rabeprazole with improved stability as an active ingredient and a method for preparing the same.

Accordingly, in order to achieve the above object, the present invention provides an inner core portion (A) comprising rabeprazole as an active ingredient and calcium hydroxide as a stabilizer; and an outer layer (B) surrounding the inner core and containing sodium hydrogen carbonate as an antacid; provides an oral immediate-release formulation comprising rabeprazole as an active ingredient.

One, the present invention comprises the steps of (i) mixing with Rabeprazole, calcium hydroxide and a pharmaceutically acceptable additive to prepare a mixture; (ii) preparing an inner core part in the form of a tablet by first tableting the mixture; and (iii) secondary tableting with a mixture obtained by mixing with sodium bicarbonate and a pharmaceutically acceptable additive so as to be coated on the inner core part; A method for preparing an immediate release formulation is provided.

The oral immediate-release formulation according to the present invention is stabilized by using calcium hydroxide in rabeprazole sodium tablets, which are very unstable under acidic conditions, thereby inhibiting the decomposition of the active ingredient under acidic conditions, and the storage stability of the formulation is improved even under accelerated storage conditions for a long period of time ( For example, about 6 months) can be maintained to improve stability. In addition, rabeprazole can be rapidly absorbed in the stomach by the neutralizing action of sodium bicarbonate in the stomach, so that immediate release can be realized, and it has a rapid drug effect and excellent bioavailability.

Accordingly, the oral immediate-release formulation according to the present invention not only has excellent physicochemical stability for a long period of time, but is also rapidly absorbed in the stomach and upper duodenum and exhibits a rapid drug effect. have In addition, it is expected that the manufacturing method according to the present invention can be applied to other proton pump inhibitors (PPIs) as well as rabeprazole to be able to manufacture PPI formulations to which various immediate-release designs are applied.

Various studies were carried out to solve the problems that the absorption of rabeprazole sodium is restricted in the stomach due to the physicochemical characteristics that decomposition is accelerated by low pH, heat, moisture, etc. and it is sensitive to stability, and an enteric coating is essential. . Specifically, the present inventors devised to use a stabilizer to ensure long-term stability of rabeprazole tablets, and to use sodium bicarbonate as an antacid to increase intragastric pH so that it can be rapidly absorbed in the stomach. . The present inventors have found that the stability of the rabeprazole tablet is greatly affected by the type of stabilizer, and also confirmed the problem of formulation stability that may appear by simultaneously containing rabeprazole and sodium bicarbonate. In particular, when formulated in the form of a cored tablet containing rabeprazole and calcium hydroxide as an inner core part and sodium hydrogen carbonate as an outer layer part, a coating agent containing ethyl cellulose is used to inhibit contact between the main ingredients by coating the inner core part with rabeprazole and calcium hydroxide as a stabilizer. In this case, the core tablet is physically and chemically stable for a long time (eg, about 6 months under accelerated storage conditions), and the onset time of the drug is faster than that of the conventional rabeprazole tablet (eg, T _max 0.5 hr). ) was found.

Therefore, the present inventors have found that the oral tablet containing rabeprazole and sodium bicarbonate simultaneously has excellent physicochemical stability for a long period of time through a stabilizer and an appropriate coating base, and rapid absorption of rabeprazole in the stomach and upper duodenum and An object of the present invention is to provide an oral immediate-release nucleated tablet that can exhibit medicinal effects.

Hereinafter, the present invention will be described in more detail.

The present invention relates to an inner core part (A) comprising rabeprazole as an active ingredient and calcium hydroxide as a stabilizer; and an outer layer (B) surrounding the inner core and containing sodium hydrogen carbonate as an antacid; provides an oral immediate-release formulation comprising rabeprazole as an active ingredient.

As used herein, the term “rabeprazole” refers to “2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1H-benzimi Dazole sodium salt (common name rabeprazole sodium salt)”, and may be a compound represented by the following formula (1). The rabeprazole may preferably be rabeprazole sodium.

[Formula 1]

The rabeprazole may be commercially available or directly synthesized.

Calcium hydroxide as a stabilizer of the inner core serves to improve the storage stability and acid stability of the formulation, and the increase of related substances is significantly inhibited at room temperature and accelerated storage conditions. The composition ratio of the calcium hydroxide may be in a range that provides excellent stability to the tablet, preferably, 30 to 60% by weight based on the total weight of the inner core portion (A). If it is out of the above range, it is preferable to use it within the above range because the improvement of storage stability and acid stability of the formulation is insignificant.

The content of rabeprazole sodium may be 10 mg to 20 mg as a therapeutically effective content range, but preferably relates to a pharmaceutical formulation containing 10 mg or 20 mg. When the content of rabeprazole exceeds 20 mg, changes in physical properties such as browning may occur under accelerated storage conditions.

In addition, the inner core portion may be coated with a coating agent containing ethyl cellulose. When the outer core of the inner core is coated using a coating solution containing ethyl cellulose, direct contact between the inner core containing rabeprazole and the outer layer containing sodium bicarbonate is separated and/or suppressed to ensure compounding stability plays a role in improving In this case, the coating solution containing ethylulose may be included in the range of 1 to 3% (w/w) based on the total weight of the tablet.

The outer layer surrounds the inner core, and may include sodium bicarbonate as an antacid.

In this case, the content of sodium bicarbonate may be 800 to 1100 mg as a therapeutically effective content range, but preferably relates to a pharmaceutical formulation containing 800 mg. If the content of sodium bicarbonate exceeds 800 mg, physical properties and therapeutic effects may be affected.

The outer layer may further include povidone or copovidone as a binder, and the outer layer may further include corspovidone or sodium starch glycolate as a solubilizing agent.

The content of sodium bicarbonate may be 800 to 1100 mg as a therapeutically effective content range, but preferably relates to a pharmaceutical formulation comprising 800 mg. When the content of sodium bicarbonate exceeds 800 mg, physical properties and therapeutic effects may be affected.

In the immediate release formulation for oral use, the time to reach the maximum plasma concentration of rabeprazole (T _max ) may be in the range of 0.3 to 0.8 hours.

In addition, in the oral immediate-release formulation, rabeprazole may be eluted from the inner core immediately after the antacid action by the rapid dissolution of sodium bicarbonate from the outer layer in the stomach during oral administration.

In addition, the oral immediate-release formulation has a dissolution rate of sodium bicarbonate of 80% or more in 15 minutes in a drug dissolution test at 900 mL of water (Korean Pharmacopoeia, dissolution test method), a rotation speed of 75 rpm, and a medium temperature of 37.5 ° C. The dissolution rate of sodium hydrogen may be 100% or more.

In addition, in the oral immediate-release formulation, the dissolution rate of rabeprazole sodium was 80% in 30 minutes in a drug dissolution test at 1000 mL of a buffer solution (FDA dissolution method DB, Rabeprazole sodium Tablets) of pH 8.0, a rotation speed of 75 rpm, and a medium temperature of 37.5 ° C. may be more than

Therefore, the oral immediate-release formulation according to the present invention has excellent physicochemical stability for a long period of time, and can be provided as an oral immediate-release cored tablet that can exhibit rapid absorption and drug efficacy of rabeprazole in the stomach and upper duodenum. have.

In addition, the present invention comprises the steps of (i) mixing with Rabeprazole, calcium hydroxide and a pharmaceutically acceptable additive to prepare a mixture; (ii) preparing an inner core part in the form of a tablet by first tableting the mixture; and (iii) secondary tableting with a mixture obtained by mixing with sodium bicarbonate and a pharmaceutically acceptable additive so as to be coated on the inner core part; A method for preparing an immediate release formulation is provided.

The step (i) is a step of preparing a mixture by mixing Rabeprazole, calcium hydroxide and a pharmaceutically acceptable additive, wherein the calcium hydroxide is used in an amount of 30 to 60% by weight based on the total weight of the inner core part (A). can

The content of rabeprazole sodium may be 10 mg to 20 mg as a therapeutically effective content range, but preferably 10 mg or 20 mg.

Step (ii) is a step of preparing the inner core part in the form of a tablet by first tableting the mixture. In the present invention, the tablet may be prepared by direct compression (direct compression), but is not limited thereto.

Step (iii) is a step of secondary tableting with a mixture obtained by mixing with sodium bicarbonate and a pharmaceutically acceptable additive to coat the inner core part prepared in step (ii), and after step (ii), the inner core part The step (ii') of coating with a coating solution containing ethylulose may be further included. In this case, the ethylulose may be included in the range of 1 to 3% (w/w) based on the total weight of the tablet. In addition to the above, a lubricant or a glidant may be further included as an additive.

In detail, the lubricant improves the fluidity of the rabeprazole particles, prevents friction between the particles, and prevents the rabeprazole particles from adhering to the tableting machine. The lubricant may include at least one selected from the group consisting of magnesium stearate, stearic acid, zinc stearate, calcium stearate, talc, sodium stearyl fumarate, talc, silicon dioxide and colloidal silicon dioxide, but is not necessarily limited thereto. .

Specifically, the fluidizing agent prevents the tablet constituents from adhering to the surface of the compression machine, and serves to improve the flow rate of tablet granules to facilitate tablet compression. The fluidizing agent is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behanate and polyethylene glycol. It may include, but is not necessarily limited to, more than one species. In the present invention, the tablet may be manufactured by a dry direct hitting method, but is not limited thereto.

Therefore, the oral immediate-release formulation according to the present invention is stabilized by using calcium hydroxide in rabeprazole sodium tablets, which are very unstable under acidic conditions, thereby inhibiting the decomposition of the active ingredient under acidic conditions, and the storage stability of the formulation is improved even under accelerated storage conditions. It exhibits long-lasting effects. In addition, rabeprazole can be rapidly absorbed in the stomach by the neutralizing action of sodium bicarbonate in the stomach, so it can be widely used as an immediate-release nucleated tablet.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example 1. Evaluation of pharmaceutical stability according to the stabilizing agent of inner core tablet

For the evaluation of pharmaceutical stability according to the stabilizing agent of the inner core tablet (or inner core part), the present inventors, as shown in Table 1 below, stabilizing agents of different types from rabeprazole (calcium hydroxide, sodium carbonate, sodium hydroxide, arginine, silico Sodium aluminate, magnesium oxide, precipitated calcium carbonate) 30 to 60% [% (w/w)], D-mannitol, sodium starch glycolate, and low-substituted hydroxypropyl cellulose were mixed, and then magnesium stearate were mixed and tableted (direct compression) to make an inner core tablet. After each tablet obtained was stored at room temperature, accelerated, and severe storage conditions for 2 and 4 weeks, total related substances in the formulation were checked. The results are shown in Table 1 below.

Ingredients [% (w/w)] 1-1 1-2 1-3 1-4 1-5 1-6 1-7 pariet ¹ Rabeprazole Sodium 15 15 15 15 15 15 15 15 stabilizer calcium hydroxide 45 - - - - - - - sodium carbonate - 45 - - - - - - sodium hydroxide - - 45 - - - - - arginine - - - 45 - - - - Sodium silicoaluminate - - - - 45 - - - magnesium oxide - - - - - 45 - - Precipitated Calcium Carbonate - - - - - - 45 - Early related substances 0.03% 0.06% 0.05% 0.03% 0.04% 0.08% 0.07% 0.06% room temperature 2 weeks related substances 0.03% 0.09% 0.05% 0.03% 0.05% 0.08% 0.08% 0.08% 4 weeks related substances 0.04% 0.09% 0.06% 0.06% 0.05% 0.10% 0.08% 0.08% Acceleration 2 weeks related substances 0.23% 0.25% 0.29% 0.28% 0.33% 0.34% 0.43% 0.34% 4 weeks related substances 0.79% 1.51% 0.94% 2.29% 0.84% 0.98% 3.16% 2.38% harsh 2 weeks related substances 1.23% 1.97% 3.81% 2.36% 2.81% 2.49% 3.65% 2.94% 4 weeks related substances 3.04% 4.87% 5.94% 8.85% 6.67% 7.93% 9.90% 6.61% ¹ : Pariet: reference drug (rabeprazole sodium)

From the results in Table 1, it can be seen that when sodium carbonate, sodium hydroxide, arginine, sodium silicoaluminate, magnesium oxide, and precipitated calcium carbonate were used as control drugs and stabilizers, the total amount of related substances of rabeprazole was significantly increased. . In contrast, when calcium hydroxide was used as a stabilizer according to the present invention, it was confirmed that the total amount of related substances generated in rabeprazole was significantly reduced. Therefore, it was found that calcium hydroxide is an optimal material as a stabilizer for rabeprazole.

Example 2. Evaluation of intragastric pH stability of rabeprazole according to sodium bicarbonate dose

To evaluate the intragastric pH stability of rabeprazole according to the sodium bicarbonate dose, the present inventors confirmed the stability of rabeprazole according to the sodium bicarbonate dose in a pH 4.0 buffer solution (intragastric pH 3.5 to 5.0 after meals). In detail, as shown in Table 2, sodium hydrogen carbonate was added and dissolved in each dose in the prepared pH 4.0 buffer solution, and then 20 mg of rabeprazole was administered to check the total amount of related substances generated in rabeprazole over time. The results are shown in Table 2 below.

Buffer Sodium bicarbonate (mg) Total related substances (%) Initial 2hr 4hr pH 4.0
100mL 300 5.34 6.83 7.42 400 2.87 3.91 4.36 500 2.83 3.13 3.58 600 2.33 3.97 4.17 700 2.21 3.86 4.14 800 0.21 1.31 2.09 900 0.32 1.26 2.64 1000 0.37 1.83 2.35 1100 0.19 0.92 1.78

From the results in Table 2, the total amount of related substances generated in rabeprazole was sharply decreased in the range of 800 mg or more of sodium bicarbonate, but in other sodium bicarbonate ranges, the standard value [Japanese Pharmacopoeia rabeprazole] sodium tablet) related substances (impurities), total related substances less than 3.5%]. Therefore, it could be confirmed that it is preferable to include 800 mg or more of sodium bicarbonate through the above results.

Example 3. Evaluation of Intragastric pH Environment Stability of Nucleated Tablets According to Stabilizers

For the evaluation of the intragastric pH environment stability of the nucleated tablet according to the stabilizer, as shown in Table 3 below, different kinds of stabilizers (and other additives that may affect pH) were used in the same manner as in Example 1 An inner core tablet was prepared. The results are shown in Table 3 below.

Sodium Bicarbonate + Stabilizer Rabeprazole sodium content (%) calcium hydroxide sodium carbonate hydroxylated
salt arginine Sodium silicoaluminate Oxidation
magnesium precipitated carbonic acid
calcium Initial 100.16 100.34 100.94 100.28 100.63 100.03 100.07 1hr 100.34 99.81 99.17 100.03 98.16 96.15 93.18 2hr 98.37 96.24 94.34 96.18 95.11 96.03 90.09 4hr 97.97 91.64 93.54 92.79 94.16 92.82 88.64

From the results of Table 3, when calcium hydroxide was used as a stabilizer for the inner core tablet, no significant change in the value of rabeprazole sodium (%) was observed in the gastric pH environment. In contrast, when sodium carbonate, sodium hydroxide, arginine, sodium silicoaluminate, magnesium oxide, and precipitated calcium carbonate are contained as stabilizers, it can be seen that the content of rabeprazole sharply decreases with time. Through this, it was confirmed that when sodium bicarbonate, an antacid, and calcium hydroxide, a stabilizer, were simultaneously contained, the intragastric stability of rabeprazole was very good.

Example 4. 6-month stability evaluation of cored tablets according to the range of stabilizers

For the 6-month stability evaluation of the core-coated tablet according to the range of the stabilizer, as shown in Table 4 below, using calcium hydroxide as a stabilizer, in the same manner as in Example 3, the core-coated tablet was prepared according to the range of calcium hydroxide for the total composition. prepared. The prepared cored tablets were stored for 2 months, 4 months, and 6 months at room temperature and accelerated storage conditions, and then the sodium content of rabeprazole was measured. The results are shown in Table 4 below.

Ingredients [% (w/w)] calcium hydroxide
10 ~ 30 [% (w/w)] calcium hydroxide
30 ~ 60[% (w/w)] calcium hydroxide
60 ~ 80[% (w/w)] Initial 0.16 0.03 0.03 room temperature 2 months 0.88 0.07 0.08 4 months 1.64 0.08 0.08 6 months 1.89 0.26 0.24 Acceleration 2 months 4.84 1.83 1.86 4 months 6.97 2.81 2.73 6 months 8.94 3.41 3.52

From the results of Table 4, when used in the range of 10 to 30 [% (w/w)] of calcium hydroxide and 60 to 80 [% (w/w)] of calcium hydroxide as a stabilizer, 30 to 60 [% (w/w) of calcium hydroxide] )], it was found that the related substances of rabeprazole were relatively increased. Therefore, it is preferable to use 30 to 60 [% (w/w)] of calcium hydroxide as a stabilizer.

Example 5. Comparative study of pharmacokinetics

Pharmacokinetic tests for 30 to 60 [% (w/w)] of nucleated purified calcium hydroxide prepared in Example 3 were performed using beagle dogs. Specifically, 0.083 hours, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours after oral administration of the reference drug (Pariet tablet) and the prepared cored tablet After 24 hours, each blood was collected and analyzed. The results of this analysis are shown in Table 5 below.

parameter AUC _last
(ng hr/mL) C _max (ug/mL) T _max (hr) Comparison drug (pariet®) 1603.1 ± 864.6 1575.4 ± 991.4 1.5 [1 - 2.5] Formulation Example 1
(Calcium hydroxide) 1614.0 ± 793.1 2493.5 ± 1073.2 0.5 [0.3 - 0.8] Formulation Example 2
(Sodium Carbonate) 1438.3 ± 638.2 2119.2 ± 983.4 0.7 [0.3 - 1.1] Formulation Example 7
(precipitated calcium carbonate) 1389.2 ± 831.2 2289.1 ± 892.6 0.6 [0.4 - 0.9]

From the above formulation example, an immediate-release cored tablet of rabeprazole sodium and sodium hydrogen carbonate was prepared. From the results of Table 5, when the pharmacokinetic profile of the existing reference drug was compared, in the case of a tablet containing calcium hydroxide as a stabilizer, the drug efficacy was the same, but the drug effect onset time (T _max ) was confirmed to be about 3 times faster. On the other hand, when sodium carbonate and precipitated calcium carbonate were contained as stabilizers, the onset time (T _max ) was faster than that of the conventional control drug, but the area under the blood concentration curve (AUC _last ) was relatively decreased. Therefore, when all the above results are considered comprehensively, it is confirmed that the cored tablet prepared in the above formulation example is stable physically and chemically for a long period of time, and is an immediate-release formulation that is stably and rapidly absorbed in the stomach when administered orally compared to the existing control drug. could

Therefore, the oral immediate-release formulation according to the present invention contains rabeprazole as an inner core, sodium hydrogen carbonate as an outer layer, and inhibits contact between rabeprazole and sodium bicarbonate through coating of the inner core to ensure formulation stability. In addition to having excellent stability for a long period of time physically and chemically, it has excellent stability by minimizing the generation of related substances for a long period of time (eg, about 6 months) even under accelerated storage conditions. Since rabeprazole is immediately dissolved and absorbed in the stomach through its rapid antacid effect, it has a rapid drug effect and excellent bioavailability, so it can be usefully used as a therapeutic agent for gastroesophageal reflux disease. In addition, it is expected that the manufacturing method according to the present invention can be applied to other proton pump inhibitors (PPIs) as well as rabeprazole to be able to manufacture PPI formulations to which various immediate-release designs are applied.

From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

Claims (12)

an inner core portion (A) containing rabeprazole as an active ingredient and calcium hydroxide as a stabilizer; and
an outer layer (B) surrounding the inner core and containing sodium bicarbonate as an antacid;
An oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that it comprises a.
The method of claim 1,
The oral immediate release formulation comprising rabeprazole as an active ingredient, characterized in that the calcium hydroxide comprises 30 to 60% by weight based on the total weight of the inner core.
The method of claim 1,
The oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that the rabeprazole contains 10 mg to 20 mg.
The method of claim 1,
An oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that it contains 800 to 1100 mg of the sodium hydrogen carbonate.
The method of claim 1,
The oral immediate release formulation comprising rabeprazole as an active ingredient, characterized in that the inner core is coated with a coating agent containing ethyl cellulose.
The method of claim 1,
The outer layer portion is an oral immediate-release formulation comprising rabeprazole, which further includes povidone or copovidone as an active ingredient, as a binder.
The method of claim 1,
The oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that the outer layer may additionally contain corspovidone or sodium starch glycolate as a dissolution aid.
The method of claim 1,
The oral immediate-release formulation is an oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that the time to reach the maximum plasma concentration (T _max ) of rabeprazole is in the range of 0.3 to 0.8 hours.
The method of claim 1,
The oral immediate-release formulation is an oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that rabeprazole from the inner core is eluted immediately after the antacid action by rapid dissolution of sodium bicarbonate from the outer layer in the stomach during oral administration. formulation.
The method of claim 1,
In the drug dissolution test at 900 mL of water (Korean Pharmacopoeia, dissolution test method), rotation speed 75 rpm, and medium temperature 37.5° C., the dissolution rate of sodium bicarbonate in the oral immediate-release formulation is 80% or more in 15 minutes, and sodium bicarbonate in 30 minutes An oral immediate-release formulation comprising rabeprazole as an active ingredient, characterized in that the dissolution rate is 100% or more.
The method of claim 1,
The oral immediate-release formulation is a drug dissolution test at 1000 mL of a buffer solution (FDA dissolution method DB, Rabeprazole sodium Tablets) of pH 8.0, a rotation speed of 75 rpm, and a medium temperature of 37.5 ° C. An immediate release formulation for oral use comprising rabeprazole as an active ingredient.
(i) preparing a mixture by mixing with Rabeprazole, calcium hydroxide and a pharmaceutically acceptable additive;
(ii) preparing an inner core part in the form of a tablet by first tableting the mixture; and
(iii) secondary tableting with a mixture obtained by mixing with sodium bicarbonate and a pharmaceutically acceptable additive so as to be coated on the inner core;
A method for producing an oral immediate-release formulation comprising rabeprazole as an active ingredient, comprising: