KR100761040B1 - Pharmaceutical composition comprising acid-labile benzimidazole compound - Google Patents

Abstract

A pharmaceutical composition is provided to stabilize an acid-labile benzimidazole compound or a pharmaceutically acceptable salt thereof better and be produced at relatively low manufacturing cost. A pharmaceutical composition comprises an effective amount of rabeprazole or a pharmaceutically acceptable salt thereof, at least one metal stearate stabilizing agent selected from the group consisting of zinc stearate, calcium stearate, aluminum stearate and magnesium stearate, and a pharmaceutically acceptable carrier. In the composition, the weight ratio of the rabeprazole, a pharmaceutically acceptable salt thereof and the metal stearate stabilizing agent is 1:5-5:1.

Description

Pharmaceutical composition containing an acid-labile benzimidazole type compound {PHARMACEUTICAL COMPOSITION COMPRISING ACID-LABILE BENZIMIDAZOLE COMPOUND}

The present invention relates to a pharmaceutical composition capable of further stabilizing an acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Benzimidazole-based compounds such as omeprazole, rabeprazole or lansoprazole are known to be effective inhibitors of gastric acid secretion and exhibit potent anti-ulcer action. For this reason, these benzimidazole-based compounds are widely used for the treatment or prevention of gastric peptic ulcer, duodenal peptic ulcer, gastritis or duodenitis.

However, it is well known that such benzimidazole compounds decompose rapidly at acidic and neutral pH. In particular, decomposition of the benzimidazole compound may be accelerated by moisture, an organic solvent, UV irradiation, or the like, and discoloration may occur in a solid state as well as in a liquid state. For example, omeprazole, a benzimidazole-based compound, has a half-life of only about 10 minutes in an aqueous solution of pH 4 or less and only about 18 hours at pH 6.8, while its half-life reaches about 300 days at pH 11. .

As such, as the benzimidazole-based compound exhibits degradability and low stability at acidic or neutral pH, many attempts have been made to improve the stability of such benzimidazole-based compounds.

Korean Patent Publication No. 1991-2641 discloses a nucleus containing an acid labile benzimidazole-based compound, and a water-soluble coating-forming material and a material which forms a suspension as a water-insoluble fine granule therein to cover the nucleus. An internal preparation of an acid labile compound comprising a first layer and a second layer composed of an enteric membrane and covering the first layer is disclosed. In addition, in Korean Patent Publication No. 1991-2641, magnesium oxide, magnesium hydroxide, calcium stearate or magnesium stearate is used as the fine grain material.

According to Korean Patent Publication No. 1991-2641, the acid labile benzimidazole-based compound is stabilized using magnesium oxide, magnesium hydroxide, calcium stearate, or magnesium stearate, and the stabilizing effect is observed over time. It is evaluated by change.

However, in the above Korean Patent Publication No. 1991-2641, when a specific substance such as magnesium oxide is used as the fine substance, decomposition of the acid labile benzimidazole-based compound occurs in the internal preparation depending on the storage time. There is no disclosure that the stability of the acid labile benzimidazole compounds and the oral preparations containing the same is still insufficient, such as the occurrence of a flexible substance and a decrease in the content of the acid labile benzimidazole compound as an active substance. .

In addition, since the fine material for stabilizing the acid labile benzimidazole-based compound forms a first layer covering the nucleus with a suspension with the poorly water-soluble coating-forming material, the Korean Patent Publication No. 1991- To prepare an oral formulation according to US Pat. No. 2641, a suspension must first be obtained using the poorly water-soluble coating-forming material and fine-grained material, and then subjected to a complicated process of coating the nucleus with such a suspension to form a first layer.

Therefore, the manufacturing process of the said oral preparation is difficult, not only the reproducibility or mass productivity of a manufacturing process falls but also a manufacturing cost becomes very high.

Accordingly, the present invention relates to a pharmaceutical composition which can more stabilize the active labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof and can be easily prepared at a relatively low production cost.

The present invention provides a pharmaceutical composition comprising an effective amount of an acid labile benzimidazole compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier comprising a metal stearate stabilizer.

In such pharmaceutical compositions, the metal stearate stabilizer may be any metal stearate, eg, zinc stearate, calcium stearate, aluminum stearate or magnesium stearate, or a mixture of two or more selected from them. Can be. However, preferably, the metal stearate stabilizer may be zinc stearate or calcium stearate.

As will be described in more detail through the following examples, the results of the inventors of the present invention, using the metal stearate stabilizer such as zinc stearate or calcium stearate, the active ingredient, that is, the acid labile benzimidazole-based compound or In the pharmaceutical composition stabilized pharmaceutically acceptable salts, compared to the case of stabilizing such active ingredients using magnesium oxide, the amount of generation of analogues due to decomposition of the active ingredient is reduced and the amount of active ingredient is decreased with storage time. It was also found to shrink.

Therefore, in the above pharmaceutical composition, compared to the conventional pharmaceutical composition in which the active ingredient is stabilized using magnesium oxide, such an active ingredient may be further stabilized, and thus, an acid labile benzimidazole-based compound or a pharmaceutical composition thereof. The stability (storage stability) of pharmaceutical compositions comprising an acceptable salt as an active ingredient can be greatly improved.

In addition, in the pharmaceutical composition, the metal stearate stabilizer is not included in a separate layer covering the active ingredient or the nucleus comprising the same, but is directly mixed with the active ingredient to be used as a pharmaceutical composition or as such a mixture. The constructed nucleus can be used in a form coated with an enteric film or the like. Therefore, since a separate process for incorporating the metal stearate stabilizer into a separate layer covering the active ingredient or nucleus is not necessary, the manufacturing process of the pharmaceutical composition can be simplified and the manufacturing cost thereof can also be lowered.

On the other hand, in the pharmaceutical composition, the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof as the active ingredient is conventionally used for the treatment or prevention of gastric peptic ulcer, duodenal peptic ulcer, gastritis or duodenitis. Any acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof, which has been widely used, may be, for example, omeprazole, rabeprazole or lansoprazole, or a pharmaceutically acceptable salt thereof. However, since the composition of the pharmaceutical composition can more effectively stabilize rabeprazole or a pharmaceutically acceptable salt thereof, the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof may be rabeprazole or its pharmaceutically acceptable salt. It is preferred to be a pharmaceutically acceptable salt.

More specifically, the labeprazole or a pharmaceutically acceptable salt thereof may be an alkali salt of rabeprazole, for example, a sodium salt of rabeprazole.

On the other hand, the pharmaceutical composition may include the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof and the metal stearate stabilizer in a weight ratio of 1: 5 to 5: 1, preferably, 10 to 100 mg of the metal stearate stabilizer, more preferably 20 to 60 mg, while satisfying the weight ratio of the acid labile benzimidazole compound or a pharmaceutically acceptable salt thereof and the metal stearate stabilizer. It may be included in the content.

By satisfying the weight ratio and content range of each of these components, it is possible to more stabilize the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof as the active ingredient in the pharmaceutical composition, the metal stearate stabilizer Too large an amount of the pharmaceutical composition can be prevented from being difficult to prepare in such a form suitable for taking the pharmaceutical composition.

In addition, as the pharmaceutical composition includes the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof as an active ingredient, as already known, the pharmaceutical composition may effectively inhibit gastric acid secretion and exhibit potent anti-ulcer action. have. Thus, the pharmaceutical composition may be used for the treatment or prevention of gastric peptic ulcer, duodenal peptic ulcer, gastritis or duodenitis.

In particular, in the pharmaceutical composition, even when stored for a long time, the degradation of the active ingredient is significantly inhibited and its content decreases little, so that excellent therapeutic or prophylactic efficacy can be maintained.

Meanwhile, the pharmaceutical composition may include one or more pharmaceutically acceptable carriers in addition to the metal stearate stabilizer. In this case, the carrier means any pharmaceutically acceptable inert ingredient included in the pharmaceutical composition.

In addition to the metal stearate stabilizer, suitable carriers which may be included in the pharmaceutical composition include, but are not limited to, 1) binders such as hydroxypropyl cellulose, 2) low-substutited Hydroxypropyl Cellulose; L- Disintegrants such as HPC), 3) lactose, aluminum magnesium silicate, excipients such as microcrystalline cellulose or mannitol, and 4) colorants or preservatives.

However, the type of carrier which may be included in the pharmaceutical composition is not limited to those listed above, and various pharmaceutically acceptable carriers may be included without limitation.

On the other hand, the above-mentioned pharmaceutical composition is mixed with the active ingredient and the metal stearate stabilizer and other pharmaceutically acceptable carrier, and the conventional method, for example, the method of preparing a direct tablet or wet granules, etc. Proceeds can be prepared in the form of tablets or the like suitable for oral administration.

However, as another embodiment, the pharmaceutical composition is a core obtained from the result of the direct tableting method or wet granules manufacturing method, and the core is first coated with a water-soluble polymer or the like, and then secondly with an enteric membrane. As a coating method, it may be prepared in the form of the tablet or the like.

In addition, the pharmaceutical composition may be formulated in the form of a tablet or the like suitable for oral administration and may be administered in a single dose once a day or in accordance with the amount of the active ingredient included in the pharmaceutical composition, if necessary, to vary the number of administrations. .

Hereinafter, the configuration and operation of the present invention through the preferred embodiment of the present invention will be described in more detail. However, the scope of the present invention is not determined according to these embodiments, which are merely presented as examples.

Examples 1-4 and Comparative Examples 1-2: Preparation of Pharmaceutical Compositions Including Rabeprazole Sodium Salt

According to the composition shown in Table 1, Examples 1 to 1 comprising the rabeprazole sodium salt, stabilizers and other pharmaceutically acceptable carriers as an active ingredient, and directly through the tableting method to include the rabeprazole sodium salt 4 and Comparative Examples 1 to 2 were prepared in the form of 140 mg tablets.

TABLE 1

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Active ingredient Rabeprazole Sodium Salt 20 20 20 20 20 20 Binder Hydroxypropyl cellulose 1.4 1.4 1.4 1.4 1.4 1.4 Stabilizer Zinc stearate 10 20 36 60 - - Magnesium oxide - - - - - 60 Disintegrant Crospovidone 40 40 40 40 40 - Low Substituted Hydroxypropyl Cellulose - - - - - 20 Excipient Anhydrous lactose 68.6 58.6 42.6 18.6 78.6 - Aluminum magnesium silicate - - - - - - Mannitol - - - - - 38.6 Sum 140 mg 140 mg 140 mg 140 mg 140 mg 140 mg

For each tablet of Examples 1 to 4 and Comparative Examples 1 to 2, a) flexible material content according to storage time, 1) at a temperature of 40 ° C. and a humidity of 75%, and 2) at a temperature of 60 ° C. Change (wt%) and b) content change (wt%) of the active ingredient were evaluated, and the evaluation results of a) to b) are shown in Tables 2 and 3, respectively.

[Table 2] a) Evaluation of content change of lead substance (% by weight)

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Day 0 0.38 0.36 0.55 0.56 0.65 0.36 Day 7 (40 ℃, 75%) 2.37 2.75 1.85 0.62 10.33 0.57 Day 7 (60 ℃) 5.36 5.24 3.84 1.10 14.32 2.18 Day 14 (40 ℃, 75%) 3.75 3.87 2.38 1.24 11.12 5.55 Day 14 (60 ℃) 5.96 5.96 4.04 2.65 17.24 9.52 Day 21 (40 ℃, 75%) 4.96 5.32 3.01 3.19 24.33 11.25 Day 21 (60 ℃) 7.87 7.33 4.48 4.13 30.24 18.63

B) Evaluation of the change in content of the active ingredient (% by weight)

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Day 0 98.33 99.75 98.63 97.23 98.04 99.24 Day 7 (40 ℃, 75%) 83.21 80.47 84.38 90.28 67.89 85.55 Day 7 (60 ℃) 92.99 92.30 97.99 96.32 78.33 85.91 Day 14 (40 ℃, 75%) 77.44 80.16 80.77 88.77 61.23 63.74 Day 14 (60 ℃) 83.25 89.22 90.74 93.09 67.54 80.33 Day 21 (40 ℃, 75%) 69.45 75.63 76.32 80.63 48.26 55.02 Day 21 (60 ℃) 71.91 87.83 90.91 91.96 55.65 74.03

Referring to Tables 2 and 3 above, the tablets of Examples 1 to 4 containing zinc stearate as stabilizers, compared to the tablets of Comparative Examples 1 and 2, were subjected to decomposition of the active ingredient at least for 14 days. It has been found that the amount of analogues produced is reduced and the decrease in the content of the active ingredient is also reduced.

Accordingly, the tablets of Examples 1 to 4 containing zinc stearate do not contain a separate stabilizer (Comparative Example 1) or Labefra, which is an active ingredient, as compared to tablets containing magnesium oxide as a stabilizer (Comparative Example 2). It has been found that the stability of the sol sodium salt can be further improved.

Examples 5-8 Preparation of Pharmaceutical Compositions Containing Rabeprazole Sodium Salt

According to the composition shown in Table 4, the active ingredient rabeprazole sodium salt, stabilizer (calcium stearate) and other pharmaceutically acceptable carriers are mixed, and through the direct compression method to include the labeprazole sodium salt The pharmaceutical compositions of Examples 5 to 8 were prepared in the form of tablets of 140 mg.

TABLE 4

Example 5 Example 6 Example 7 Example 8 Comparative Example 1 Comparative Example 2 Active ingredient Rabeprazole Sodium Salt 20 20 20 20 20 20 Binder Hydroxypropyl cellulose 1.4 1.4 1.4 1.4 1.4 1.4 Stabilizer Calcium stearate 10 20 36 60 - - Magnesium oxide - - - - - 60 Disintegrant Crospovidone 40 40 40 40 40 - Low Substituted Hydroxypropyl Cellulose - - - - - 20 Excipient Anhydrous lactose 68.6 58.6 42.6 18.6 78.6 - Aluminum magnesium silicate - - - - - - Mannitol - - - - - 38.6 Sum 140 mg 140 mg 140 mg 140 mg 140 mg 140 mg

For each of the tablets of Examples 5 to 8, 1) temperature change of 40 ° C. and humidity of 75%, and 2) change of content (wt%) of the flexible material according to storage time under the temperature condition of 60 ° C. and b) The change in content (% by weight) of the active ingredient was evaluated, and the evaluation results of a) to b) are shown in Tables 5 and 6, respectively. At this time, in order to compare with the evaluation results of Examples 5 to 8, the evaluation results of Comparative Examples 1 and 2 that were already salping bar are shown together in Tables 5 and 6.

[Table 5] a) Evaluation of content change of lead substance (% by weight)

Example 5 Example 6 Example 7 Example 8 Comparative Example 1 Comparative Example 2 Day 0 0.31 0.39 0.45 0.51 0.65 0.36 Day 7 (40 ℃, 75%) 2.31 2.25 1.75 0.61 10.33 0.57 Day 7 (60 ℃) 5.26 4.94 3.54 1.03 14.32 2.18 Day 14 (40 ℃, 75%) 3.53 3.15 2.07 1.16 11.12 5.55 Day 14 (60 ℃) 5.54 5.06 3.88 2.57 17.24 9.52 Day 21 (40 ℃, 75%) 4.75 4.52 2.67 2.04 24.33 11.25 Day 21 (60 ℃) 6.98 6.37 4.21 3.76 30.24 18.63

[Table 6] b) Evaluation of content change of active ingredient (wt%)

Example 5 Example 6 Example 7 Example 8 Comparative Example 1 Comparative Example 2 Day 0 98.02 99.51 98.62 98.23 98.04 99.24 Day 7 (40 ℃, 75%) 85.27 86.47 89.37 91.18 67.89 85.55 Day 7 (60 ℃) 93.99 94.17 96.38 97.23 78.33 85.91 Day 14 (40 ℃, 75%) 79.44 82.61 85.82 88.16 61.23 63.74 Day 14 (60 ℃) 85.25 89.52 92.54 93.79 67.54 80.33 Day 21 (40 ℃, 75%) 72.55 76.33 79.32 83.37 48.26 55.02 Day 21 (60 ℃) 77.01 87.30 91.01 91.67 55.65 74.03

Referring to Tables 5 and 6 above, the tablets of Examples 5 to 8 containing calcium stearate as stabilizers, as compared to the tablets of Comparative Examples 1 and 2, were also used for the decomposition of the active ingredient at least for 14 days. It has been found that the amount of analogues produced is reduced and the decrease in the content of the active ingredient is also reduced.

Therefore, the tablets of Examples 5 to 8 containing calcium stearate also do not contain a separate stabilizer (Comparative Example 1) or Labefra as an active ingredient compared to tablets containing magnesium oxide as a stabilizer (Comparative Example 2). It has been found that the stability of the sol sodium salt can be further improved.

In summary, from the test results for Examples 1 to 8, the pharmaceutical composition of the acid labile benzimidazole compound containing a metal stearate stabilizer, the active ingredient, that is, the acid labile benzimidazole compound or its It has been found that the pharmaceutically acceptable salts can be significantly stabilized to maintain high therapeutic or prophylactic efficacy even with prolonged storage.

As described above, according to the present invention, it is possible to stabilize the acid labile benzimidazole-based compound or a pharmaceutically acceptable salt thereof, which is an active ingredient, and a complicated coating process is not necessary, thereby making it easy to manufacture at a relatively low manufacturing cost. Pharmaceutical compositions can be provided.

Claims (5)

An effective amount of rabeprazole or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising one or more metal stearate stabilizers selected from the group consisting of zinc stearate, calcium stearate, aluminum stearate and magnesium stearate, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of rabeprazole comprises its sodium salt. delete The pharmaceutical composition of claim 1, comprising the labeprazole or a pharmaceutically acceptable salt thereof and a metal stearate stabilizer in a weight ratio of 1: 5 to 5: 1. The pharmaceutical composition of claim 4 comprising the metal stearate stabilizer in an amount of 10 to 100 mg.