KR101148399B1 - Pharmaceutical Composition for Treating Gastric Disease Containing Antiulcerent and Mucosal Protective Agents - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating oral gastrointestinal disorders containing an anti-ulcer agent, ilaprazole, and a mucosal protective agent, bismuth, as an active ingredient.

More specifically, the present invention is an antiulcer agent, ilaprazole, and a mucoprotective agent, such as colloidal bismuth subcitrate, bismuth aluminate, bismuth subcarbonate, bismuth citrate, bismuth gallate, bismuth nitrate, bismuth tartrate, and these Pharmaceutical composition for treating oral gastrointestinal diseases containing bismuth preparations selected from the group consisting of has a particularly excellent efficacy in inhibiting ulcers against ulcers induced by various substances, compared to compositions with other mucoprotective agents. It is a composition that shows the same or better effect even with less active ingredients, which has the advantage of reducing the side effects of continuous administration of the active ingredient or increases the amount of the active ingredient within the acceptable side effects, thereby showing a therapeutic effect in a short time. There are advantages to it.

Ilaprazole, mucoprotectant, bismuth subcitrate, ulcer inhibition rate

Description

Pharmaceutical Composition for Treating Gastric Disease Containing Antiulcerent and Mucosal Protective Agents}

The present invention relates to a pharmaceutical composition for treating oral gastrointestinal diseases, which contains an anti-ulcer agent, ilaprazole, as an active ingredient, and a bismuth agent, which is a mucoprotective agent.

More specifically, the present invention relates to an antiulcer agent, ilaprazole, colloidal bismuth subcitrate, bismuth aluminate, bismuth subcarbonate, bismuth citrate, bismuth gallate, bismuth nitrate, bismuth tartrate and mixtures thereof as active ingredients. Pharmaceutical compositions for the treatment of oral gastrointestinal diseases containing bismuth preparations selected from the group consisting of low quantum ulcers have a particularly excellent efficacy in inhibiting ulcers against ulcers induced by various substances compared to compositions with other mucoprotective agents. The active ingredient of the composition exhibits the same or better effect, which has the advantage of reducing the side effects of the continuous administration of the active ingredient, or can increase the amount of the active ingredient within the acceptable side effects can exhibit a therapeutic effect in a short time there is There is an advantage.

Ilaprazole, an anti-ulcer agent, is a 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative of the following Chemical Formula 1, and has been developed by the present inventors and is used in 26 countries including Korea, Japan, the United States, and 11 European countries. As a novel compound applied or registered as a patent, it acts as a proton pump inhibitor (PPI) as well as omeprazole and lansoprazole, which are already well known.

[Formula 1]

Ilaprazole has been reported to be excellent in treating ulcers and significantly lower side effects than conventional PPI formulations.

As mucosal protective agents, bismuth preparations, scralates, misoprostol, and the like have been used as an adjuvant in treating gastrointestinal diseases, and are prescribed in combination with acid secretion inhibitors in severe ulcers.

On the other hand, while the present inventors are studying the ulcer treatment ability by the combination of ilaprazole and mucoprotective agent, the combination administration of ilaprazole and bismuth agent is significantly superior to the ulcer treatment ability compared with the combination by other combinations, even with a small amount of active ingredients It has been found to exhibit an equivalent or higher ulcer therapeutic ability.

Oral pharmaceutical composition according to the present invention comprises a bismuth preparation as an anti-ulcer agent and mucoprotective agent, to provide an oral pharmaceutical composition showing a particularly excellent effect in the treatment of gastrointestinal diseases.

The above and other objects can be achieved by the present invention described below.

The oral pharmaceutical composition containing the antiulcer agent and mucoprotective agent according to the present invention may include an ilaprazole as an active ingredient and a bismuth preparation as a mucoprotective agent.

The oral pharmaceutical composition may be used simultaneously, individually or sequentially to treat or prevent gastrointestinal diseases.

The bismuth preparation may be selected from the group consisting of colloidal bismuth subcitrate, bismuth aluminate, bismuth subcarbonate, bismuth citrate, bismuth gallate, bismuth nitrate, bismuth tartrate and mixtures thereof.

The bismuth preparation may be included in an amount of 30 to 98 parts by weight based on the total weight of the composition.

The pharmaceutical composition comprises 0.01 to 60% by weight of ilaprazole as an active ingredient based on the total weight of the composition; 30 to 98% by weight of the bismuth preparation; And 1 to 70% by weight of an adjuvant.

The bismuth preparation may be colloidal bismuth subcitrate.

The oral pharmaceutical composition may be in tablet form.

The oral pharmaceutical composition may be in capsule form.

The oral pharmaceutical composition may be in liquid form.

The bismuth preparation according to the present invention is not limited to the following types, but there are colloidal bismuth subcitrate, bismuth aluminate, bismuth subcarbonate, bismuth citrate, bismuth gallate, bismuth nitrate, bismuth tartrate and the like. It can be administered in the above form.

Bismuth preparations according to the present invention comprise from 30 to 98% by weight, based on the total weight of the composition. When included in less than 30% by weight did not show a ulcer treatment effect by the bismuth formulation, when added more than 98% by weight did not show a significant difference compared to the ulcer treatment effect compared to when containing less than.

More preferably, the bismuth preparation according to the present invention contains 40 to 97% by weight based on the total weight of the composition, still more preferably 45 to 96% by weight.

The pharmaceutical composition for treating gastrointestinal diseases according to the present invention is a composition showing an equivalent effect even with a small amount of active ingredients, which has the advantage of reducing the side effects of the continuous administration of the active ingredient, or active within the acceptable side effects By increasing the amount of the component has the advantage that can exhibit a therapeutic effect in a short time.

As an active ingredient, the antiulcer agent ilaprazole according to the invention may be in racemate form, in one form of the enantiomer or in the form of a pharmaceutically acceptable salt thereof. The amount of ilaprazole is not particularly limited, but may be contained in an amount of 0.01 to 60% by weight based on the total weight of the composition, depending on the treatment purpose of the patient.

The antiulcer agent ilaprazole according to the present invention may be prepared in the form of tablets, capsules and liquids according to known production methods, and the amount of the adjuvant is controlled by the amount of the active ingredient and the mucoprotective agent, and the amount thereof is specifically Although not limited, it may be contained in an amount of 1 to 70% by weight based on the total weight of the composition.

The adjuvant according to the invention is selected from the group consisting of excipients, binders, disintegrants, glidants and mixtures thereof.

The excipient may be selected from the group consisting of microcrystalline cellulose (Avicel pH 101,102), lactose, starch, calcium dihydrogen phosphate, hard silicic anhydride, and mixtures thereof, but the present invention is not limited thereto.

The binder is povidone (K-30, K90, crospovidone), starch solution, hydroxypropyl cellulose (HPC-SL, HPC-M, HPC-LF), hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose and Although it may be selected from the group consisting of a mixture thereof, the present invention is not limited thereto.

The disintegrant may be selected from the group consisting of sodium starch glycolate, croscarmellose, calcium carboxymethyl cellulose (Ca-CMC) and mixtures thereof, but the present invention is not limited thereto.

The lubricant may be selected from the group consisting of magnesium stearate, talc and mixtures thereof, but the present invention is not limited thereto.

Hereinafter, the present invention will be described in more detail with reference to the following examples and comparative examples. However, the following Examples and Comparative Examples are only examples, and the scope of the present invention is not limited thereto.

[Example]

Colloidal bismuth subcitrate (CBS) 20 mg / kg (rat) is mixed with 3 mg / kg ilaprazole (rat) Example 1, colloidal bismuth subcitrate (CBS) 20 mg / kg Example 2 was prepared by mixing 1 mg / kg (rat) of ilaprazole in (rat).

[Comparative Example]

Ilaprazole 3mg / kg (rat) was mixed with 150mg / kg of sucralfate (rat) and ilaprazole 3mg / kg (rat) was mixed with 50µg / kg (rat) of misoprostol. Each of Comparative Example 2 was prepared.

Colloidal bismuth subcitrate 20mg / kg (rat) mixed with omeprazole 10mg / kg (rat) and Comparative Example 3, sucralfate 150mg / kg (rat) mixed with omeprazole 10mg / kg (rat) In Example 4, 10 mg / kg (rat) of omeprazole was mixed with 50 µg / kg (rat) of misoprostol to prepare Comparative Example 5, respectively.

Ilaprazole 1mg / kg (rat) was mixed with 150 mg / kg of sucralfate (rat), and ilaprazole 1mg / kg (rat) was mixed with 50µg / kg (rat) of misoprostol. Each of Comparative Example 7 was prepared.

Colloidal bismuth subcitrate 20mg / kg (rat) mixed with omeprazole 3mg / kg (rat), Comparative Example 8, sucralfate 150mg / kg (rat) mixed with omeprazole 3mg / kg (rat) In Example 9, Comparative Example 10 was prepared by mixing omeprazole 3 mg / kg (rat) with 50 µg / kg (rat) of misoprostol.

[Test Example]

The therapeutic ability of the combination of ilaprazole, omeprazole, Examples and Comparative Examples against ethanol-induced ulcer, indomethacin-induced ulcer and stress-induced ulcer was confirmed.

The degree of damage (ulcer index) above is shown by Table 1, the ulcer inhibition rate is represented by the following equation.

  [Ulcer inhibition rate (%) = (ulcer index of control group-ulcer index of treatment group) / ulcer index of control group × 100]

Table 1

score Symptom 2 Weak bleeding 4 Severe bleeding 6 Weak ulcers 8 Severe ulcers 10 Perforated Ulcer

The experimental results were expressed as mean ± SE, and statistical significance test was performed using Student's t- test.

Test 1: Combination effect of ilaprazole and omeprazole with mucosal protective agent on ethanol-induced ulcer

Colloidal bismuth subcitrate (CBS) as ilaprazole and omeprazole and mucoprotectant against gastric ulcer by ethanol (Robert A., Northam JE, Cyroprotection by prostaglandins in rat, Gastroenerology 77: 433-443, 1979) The efficacy of co-administration with, sucralfate and misoprostol was examined.

Ten male 8-week-old male rats were divided into 9 groups and fasted for 24 hours while freely supplying water, followed by ilaprazole (3 mg / kg) and omeprazole (10 mg / kg), Example 1 and Comparative Example 1 To 5 orally. 30 minutes after the test drug administration, ethanol (100%) was orally administered 1 ml per horse, and after 1 hour of ethanol administration, it was lethal to the cervical dislocation and the stomach was extracted, and 10 ml of 4% formalin was injected into the stomach and left for 30 minutes It was. The incision was made along the taiwan section under running water and the degree of ulcer was measured. The results are shown in Table 2 below.

[Table 2]

Administration group Animal count (mari) Ulcer Index Ulcer inhibition rate (%) Control group 10 6.30 ± 0.3 - Ilaprazole 3mg / kg 10 4.40 ± 0.2 ^** 30.16 Example 1 10 2.30 ± 0.3 ^## 63.49 Comparative Example 1 10 3.70 ± 0.3 41.27 Comparative Example 2 10 2.90 ± 0.2 ^## 53.97 Omeprazole 10mg / kg 10 4.70 ± 0.4 ^* 25.40 Comparative Example 3 10 3.90 ± 0.4 38.10 Comparative Example 4 10 4.20 ± 0.3 33.33 Comparative Example 5 10 3.20 ± 0.4 ^# 49.21

*: Significant differences compared to the control (p <0.05)

**: Significant difference compared to control (p <0.01)

#: Significant difference compared to single-dose group (p <0.05)

##: Significant differences were found for the single-administered group (P <0.01)

As can be seen in Table 2, ilaprazole (3 mg / kg) or omeprazole (10 mg / kg) alone group was 30.16% (p <0.01), 25.40% (p <0.05) for ethanol-induced ulcers, respectively, significant compared to the control group Ulcer suppression rate. In addition, as a result of comparing the mucoprotective group with each other, the sucralate combination group (Comparative Examples 1 and 4) was not significant, and the combination of microprostol (Comparative Examples 2 and 5) was not significant. Suppression rate. On the other hand, the colloidal bismuth subcitrate showed a high inhibition rate of 63.49% (p <0.01) when used in combination with ilaprazole (Example 1), and such efficacy was obtained when used in combination with omeprazole (Comparative Example 3). Was not confirmed.

[Test Example 2]: Combination Effect of Ilaprazole and Omeprazole with Mucosal Protective Agents according to Indomethacin-Induced Ulcers

Ilaprazole and omeprazole and colloidal bismuth subcitrate, a mucoprotective agent, for gastric ulceration by indomethacin (Lipmann W: Inhibition of indomethacin-induced gastric ulceration in rats, Prostaglandins 7: 1-10, 1974) The efficacy of the combination with subcitrate (CBS), sucralate (sucralfate) and misoprostol was examined.

Ten male 8-week-old male rats were divided into 9 groups and fasted for 24 hours while freely supplying water, followed by ilaprazole (1 mg / kg), omeprazole (3 mg / kg), Example 2, and Comparative Example 6 To 10 orally. 30 minutes after the test drug administration, indomethacin (30mg / kg / 5ml) was orally administered, and after 5 hours of indomethacin administration, it was lethal to the cervical distal bone, and the stomach was extracted, and 10ml of 4% formalin was injected into the stomach. It was left to stand for 30 minutes. The incision was carried out along the taiwan section under running water and the degree of ulcer was measured. The results are shown in Table 3 below.

[Table 3]

Administration group Animal count (mari) Ulcer Index Ulcer inhibition rate (%) Control group 10 6.00 ± 0.5 - Ilaprazole 1mg / kg 10 2.90 ± 0.3 ^** 51.67 Example 2 10 1.10 ± 0.2 ^## 81.67 Comparative Example 6 10 2.60 ± 0.2 56.67 Comparative Example 7 10 2.30 ± 0.2 61.67 Omeprazole 3mg / kg 10 3.50 ± 0.2 ^** 41.67 Comparative Example 8 10 3.00 ± 0.3 50.00 Comparative Example 9 10 3.40 ± 0.3 43.33 Comparative Example 10 10 2.90 ± 0.4 51.67

**: Significant difference compared to control (p <0.01)

##: Significant differences were found for the single-administered group (p <0.01)

As can be seen in Table 3, the ilaprazole (1 mg / kg) or omeprazole (3 mg / kg) alone group was 51.67% (p <0.01) and 41.67% (p <0.01) for indomethacin-induced ulcers, respectively. Significant ulcer inhibition rate was shown. In addition, as a result of comparing the mucoprotective group with each other, the combination group of sucralate (Comparative Example 6 and Comparative Example 9) and microprostol (Comparative Example 7 and Comparative Example 10) was not significant. Chloridal bismuth subcitrate (Example 2) showed a high inhibition rate of 81.67% (p <0.01), and this effect was not confirmed when combined with omeprazole (Comparative Example 8).

Test 3: Combination effect of ilaprazole and omeprazole with mucosal protective agent on stress-induced ulcer

Colloidal bismuth subcitrate as ilaprazole and omeprazole and mucoprotectant against gastric ulceration by stress (Robert A., Northam JI, Exertion ulcers in the rat, Am J Dig Dis 15: 497-507, 1970): CBS), sucralfate and misoprostol with co-administration were examined.

Ten male 8-week-old male rats were divided into 9 groups and fasted for 24 hours while freely supplying water, followed by ilaprazole (3 mg / kg) and omeprazole (10 mg / kg), Example 1 and Comparative Example 1 To 5 were orally administered. After 30 minutes of administration of the test drug, the rats were placed in a stress cage, put in a water of 20 ° C., and lethal to the cervical dislocation after 6 hours. . The incision was carried out along the taiwan section under running water and the degree of ulcer was measured. The results are shown in Table 4 below.

Table 4

Administration group Animal count (mari) Ulcer Index Ulcer inhibition rate (%) Control group 10 6.60 ± 0.8 - Ilaprazole 3mg / kg 10 3.80 ± 0.3 ^* 42.42 Example 1 10 1.30 ± 0.2 ^## 80.30 Comparative Example 1 10 3.20 ± 0.3 51.52 Comparative Example 2 10 2.70 ± 0.2 ^# 59.02 Omeprazole 10mg / kg 10 4.00 ± 0.2 ^* 39.39 Comparative Example 3 10 3.30 ± 0.4 50.00 Comparative Example 4 10 3.60 ± 0.3 45.45 Comparative Example 5 10 3.30 ± 0.4 50.00

*: Significant differences compared to the control (p <0.05)

#: Significant differences were found for the single-administered group (p <0.05)

##: Significant differences were found for the single-administered group (p <0.01)

As can be seen in Table 4, ilaprazole (3 mg / kg) or omeprazole (10 mg / kg) alone group was 42.42% (p <0.05) and 39.39% (p <0.05) for stress-induced ulcers, respectively. Ulcer inhibition rate was shown. In addition, as a result of comparing the mucoprotective group with each other, the sucralate (Comparative Example 1 and Comparative Example 4) was not significant, and the concomitant group with Misoprostole (Comparative Example 2) was 59.02% p <0.05) showed more significance than ilaprazole alone. In the case of colloidal bismuth subcitrate (Example 1), a high inhibition rate of 80.30% (p <0.01) was observed, and this effect was not confirmed when administered in combination with omeprazole (Comparative Example 3).

The pharmaceutical composition for treating oral gastrointestinal diseases containing the antiulcer agent ilaprazole (Ilaprazole) and mucosal protective agent bismuth as an active ingredient according to the present invention as an active ingredient is a composition showing an equivalent effect or more even with a small amount of the active ingredient, There is an advantage that can reduce the side effects of the continuous administration of the ingredient, or there is an advantage that can increase the amount of active ingredient within the allowable side effects to have a therapeutic effect in a short time.

Although the present invention has been described in detail with reference to specific examples described, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the present invention, and such modifications and modifications are set forth in the appended claims. It is natural to belong.

Claims (9)

In the anti-ulcer composition comprising ilaprazole as an active ingredient, An oral pharmaceutical composition containing an antiulcer agent and a mucoprotective agent containing a bismuth preparation as a mucoprotective agent. The method of claim 1, wherein the bismuth preparation is selected from the group consisting of colloidal bismuth subcitrate, bismuth aluminate, bismuth subcarbonate, bismuth gallate, bismuth nitrate, bismuth tartrate and mixtures thereof. Oral pharmaceutical composition containing an anti-ulcer agent and mucoprotective agent. The oral pharmaceutical composition of claim 1, wherein the bismuth preparation is contained in an amount of 30 to 95% by weight based on the total weight of the composition. delete delete 2. The oral pharmaceutical composition according to claim 1, wherein the bismuth preparation is a colloidal bismuth subcitrate. delete delete delete