KR20180037411A - Pharmaceutical composition for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer disease comprising Lactitol - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating gastroesophageal reflux disease and peptic ulcer, which contains lactitol and a drug for preventing and treating gastroesophageal reflux disease and peptic ulcer, thereby improving prevention and treatment effects while reducing side effects. More specifically, provided is a pharmaceutical composition for preventing and treating esophagitis, gastritis and peptic ulcer, comprising: 1) the drug for treating gastroesophageal reflux disease and peptic ulcer and a pharmaceutically acceptable salt thereof; and 2) one selected from the group consisting of lactitol, lactitol hydrate, and a pharmaceutically acceptable salt of lactitol. The drug for treating gastroesophageal reflux disease and peptic ulcer can be at least one selected from the group consisting of an H_2 inhibitor, a proton pump inhibitor, and a colloidal bismuth compound.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for prevention and treatment of gastroesophageal reflux disease and peptic ulcer disease Lactitol containing lactitol,

The present invention relates to a pharmaceutical composition for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer. The pharmaceutical composition for preventing and treating gastroesophageal reflux disease and peptic ulcer includes lactic acid and a drug for prevention and treatment of gastroesophageal reflux disease and peptic ulcer. And to a pharmaceutical composition for the prevention and treatment of peptic ulcer.

The stomach is a long-term organ that stores the food from the esophagus, breaks it down easily, and controls the sending of food to the duodenum, thereby enabling efficient digestion and absorption by secretion and harmony of the pancreatic enzyme. The stomach secretes stomach acid, which is a strong acid to digest it when food comes in. At this time, the mucous membrane protects the gastric mucosa from being damaged by stomach acid.

Various causes of gastric acid secretion or gastric mucosal protective layer is damaged when the inflammation occurs, and gastric acid reflux to the esophagus will cause inflammation of the esophagus.

This inflammatory lesion is called gastric ulcer when gastritis occurs in the gastric mucosa, esophagitis in the esophagus, ulcer formation in the submucosal tissue and muscle layer through the gastric mucosa. Duodenal ulcers are called duodenal ulcers, and ulcers and duodenal ulcers are collectively called peptic ulcers.

Gastro-gastroesophageal reflux disease (GERD) is a condition that causes uncomfortable symptoms or complications due to stomach contents refluxed into the esophagus. The condition in which double reflux causes morphological changes such as ulcers or erosions in the esophagus is called reflux esophagitis or erosive esophagitis.

This is called Balance Theory because gastroesophageal reflux disease and peptic ulcer are caused by aggravation of attack factors and weakening of protective factors (Gastroenterology pp. 420, 1963). Among the attack factors, there are gastric acid, antiinflammatory agents, bacterial infection, and defense factors include mucus, cell regeneration, and alkaline secretion. Recently, Helicobacter pylori has been identified as an important cause of bacterial infection among the attack factors (Scan J. Gastroenterol 26 (suppl) 6, 1991).

Anti-gastric reflux disease and peptic ulcer treatment include antacid, H ₂ inhibitor and proton pump inhibitor for inhibiting acid secretion, or gastric mucosal protective agent. Recently, Helicobacter pylori The use of antibiotics has been introduced for the purpose of removal. The antacid is characterized by its short duration (New Eng J Med 298: 1041, 1978) and its efficacy by lowering the pH of the stomach to lower the activity of pepsin (New Eng J Med 274: 921, 1966).

However, administration of inorganic substances has been associated with constipation (J Int Med Res 6 (suppl) 11, 1978), diarrhea (Hepatogastroenterol 29: 135, 1982), metabolic alkalosis (Am J Dig Dis 11: 413, 1966) (J Clin Gastroenterol 15 (1): 37, 1992). In the present study, the incidence of acid rebound due to antacids was recently reported to be low (Gastroenterologie 21 (suppl) 117, 1983).

Since the introduction of cimetidine in 1977, an intensive treatment of peptic ulcers has begun (J Int MedRes 17 (suppl) 9A, 1989). As the availability of the H ₂ inhibitor, cimetidine, has been known, a number of derivatives have been developed, including ranitidine, famotidine, roxatidine, nizatidine, (Meth Find Exp Clin Pharmacol 11 (suppl 1) 87, 1989, NEng J Med 323: 1672, 1990), but a high recurrence rate has been a problem after the administration of drugs Intell Clin Pharm 21: 493, 1987, Gut 30: 449, 1989).

This is due to the fact that the mucosal and submucosal tissues healed by these attack factor inhibitors are weaker than normal tissues and are easily damaged by attack factors such as acidosis after the administration of the drug (JClin Gastroenterol 11 1) S34, 1989).

A relatively recently developed proton pump inhibitor is omeprazole, esomeprawole, lansoprazole, rabeprazole, pantoprazole, etc., and acid secretion in gastric wall cells (Yale J Biol Med 65: 649, 1992). However, the recurrence rate has not been reduced in patients with ulcer healing due to these agents, and it has been reported that Yanbian, diarrhea, fever, headache , Fatigue and other side effects have been reported.

Therefore, when H ₂ inhibitor and proton pump inhibitor alone are used for the inhibition of gastric acid secretion, the most important inhibitory effect on recurrence of peptic ulcer is not expected.

In the case of the gastric mucosal protective agent, it is known that the mucosal protective agent generally has a low short-acting effect, has a high dosage, and should be taken for a relatively long period of time. However, . Helicobacter pylori and non-steroidal anti-inflammatory drugs are known to play an important role in the recurrence of peptic ulcer (Scan J Gastroenterol 26 (suppl): 6, 1991) The recovery of the host factor, such as structural normalization, is very important for lowering the recurrence rate. Therefore, it is urgent to introduce treatment that can reduce the recurrence rate as well as shortening the duration of peptic ulcer healing, that is, improving the quality of ulcer healing.

1. Korean Patent Publication No. 10-2009-0131706

Disclosure of Invention Technical Problem [6] The present invention provides a novel pharmaceutical composition for improving the preventive and therapeutic effect of drugs for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer, and for reducing side effects.

According to an aspect of the present invention,

1) a drug for the treatment of gastroesophageal reflux disease and peptic ulcer; and a pharmaceutically acceptable salt thereof; And

2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To

The present invention also provides a pharmaceutical composition for prevention and treatment of gastroesophageal reflux disease and peptic ulcer.

In the pharmaceutical composition for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer according to the present invention, the drug for the treatment of gastroesophageal reflux disease and peptic ulcer is selected from the group consisting of an H ₂ inhibitor, a proton pump inhibitor and a colloidal bismuth compound May be one or more drugs selected.

The pharmaceutical composition of the present invention is composed of lactitol, esophagitis, gastritis, and a drug for the treatment of peptic ulcer, and is excellent in therapeutic effect against gastroesophageal reflux disease and peptic ulcer, and exhibits synergistic efficacy far superior to that of each drug.

In addition, lactitol is because it represented the mucosal protective effect such that it promotes maturation and normalization of the reproduction mucosa in ulcer healing process to help the recovery of the lesion, the pharmaceutical composition of the present invention peptic ulcer caused by H ₂ inhibitors, proton pump inhibitors It suppresses the recurrence rate, which is a problem in treatment, and shortens the treatment period. Lactitol is also used for edible purposes and has few adverse effects. By reducing the dose of these drugs when used in combination with an H ₂ inhibitor, a proton pump inhibitor, or a colloidal bismuth compound, the pharmaceutical composition of the present invention can further reduce the side effects Is a safe pharmaceutical composition.

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition for the prevention and treatment of peptic ulcer diseases such as gastroesophageal reflux disease and gastric ulcer and duodenal ulcer. The composition according to the present invention comprises lactitol and an H ₂ inhibitor, a proton pump inhibitor or an agonist A colloidal bismuth compound that inhibits reverse transcription factor and Helicobacter pylori inhibitory action, and a drug for the treatment of peptic ulcer disease. The inhibitory action against gastric acid-induced persistent lesion and pain and the secretion of mucus secretion And promotes endogenous prostaglandin synthesis to promote gastrointestinal lesion healing, thereby showing a synergistic effect in the treatment of gastroesophageal reflux disease and peptic ulcer.

The effects of a pharmaceutical composition comprising lactitol and an H ₂ inhibitor, a proton pump inhibitor or a colloidal bismuth compound on gastroesophageal reflux disease and peptic ulcer in an artificially induced esophagitis, gastritis and peptic ulcer animal model, I will explain in detail. The embodiments of the present invention are illustrative of the contents of the present invention, and the contents of the present invention are not limited thereto.

Example 1 Preparation of lactitol and H ₂ Synergism with inhibitors

The synergistic action of H ₂ inhibitor and lactitol on gastric lesions by indomethacin was studied. Famotidine, ranitidine and cimetidine were used as H ₂ inhibitors.

Seven weeks old male rats were fasted for 24 hours, and oral administration of each drug was followed by oral administration of indomethacin 40 mg / kg 1 hour later. All animals were slaughtered 6 hours after the administration of indomethacin, the stomach was excised and the ulcer area was measured and ascertained. The test results are shown in Tables 1 to 3.

The synergistic action of the pharmaceutical composition comprising lactitol and famotidine on the indomethacin-induced gastric ulcer is shown in Table 1, and the synergistic action of the pharmaceutical composition comprising lactitol and ranitidine is shown in Table 2, Are shown in Table 3. < tb > < TABLE >

Administered group Capacity (mg / kg) Number of animals Ulcer area (mm ² ) Lesion inhibition rate (%) Presence or absence of synergy Control group 12 21.8 ㅁ 3.2 - U
72.3> 59.8
Famotytin 5.3 12 8.3 ㅁ 1.9 59.8 Lactitol +
Famotidine 100 + 5.3 12 3.6 ㅁ 1.2 72.3

Administered group Capacity (mg / kg) Number of animals Ulcer area (mm ² ) Lesion inhibition rate (%) Presence or absence of synergy Control group 12 21.8 ㅁ 3.2 - U
72.8> 60.2
Ranitidin 5.3 12 7.9 ㅁ 1.3 60.2 Lactitol +
Lanitidine 100 + 5.3 12 3.5 ㅁ 2.5 72.8

Administered group Capacity (mg / kg) Number of animals Ulcer area (mm ² ) Lesion inhibition rate (%) Presence or absence of synergy Control group 12 21.8 ㅁ 3.2 - U
72.1> 59.2
Cimetitine 5.3 12 8.1 ㅁ 2.3 59.2 Lactitol +
Cimetidine 100 + 5.3 12 3.9 ㅁ 1.6 72.1

As can be seen from Tables 1, 2 and 3, the pharmaceutical composition comprising lactitol, famotidine, lactitol and lanitidine, lactitol and cimetidine showed excellent elevation in the indomethacin-induced gastric model Effect.

Example 2 Synergism of Lactitol with Proton Pump Inhibitor

The uptake of omeprazole and lactitol as a representative proton pump inhibitor and the synergistic action of esomeprazole and lactitol on gastric lesions by absolute ethanol were examined.

Seven-week-old male rats were fasted for 24 hours, and each drug was orally administered. After 1 hour, anhydrous ethanol was orally administered at 1.5 ml per mouse. After 1 hour of ethanol administration, all animals were slaughtered and the stomach was excised and the lesion area was measured and ascertained synergy. The results of the test show the synergistic action of omeprazole and lactitol in Table 4, and the synergistic action of esomeprazole and lactitol in Table 5.

Administered group Volume
(mg / kg) Number of animals Ulcer area
(mm ² ) Lesion incidence rate
(%) Synergistic effect
The presence or absence Control group 10 92.8 ㅁ 16.3 100 Omeprazole 0.1
0.3
1.0 10
10
10 69.9 14.8
58.9 ㅁ 10.1
48.8 7.9 74.5
62.8
52.0
Lactitol +
Omeprazole 100 + 0.1
100 + 0.3
100 + 1.0 10
10
10 40.4 ㅁ 12.7 *
33.9 ㅁ 8.3 *
19.8 ㅁ 4.2 * 43.1
36.1
21.1 U
U
U *: Significant difference compared to control (p <0.05)

Administered group Volume
(mg / kg) Number of animals Ulcer area
(mm ² ) Lesion incidence rate
(%) Synergistic effect
The presence or absence Control group 10 92.8 ㅁ 16.3 100 Esomeprazole 0.1
0.3
1.0 10
10
10 68.9 ㅁ 11.5
57.2 ㅁ 10.5
47.2 ㅁ 11.2 73.1
61.5
52.1
Lactitol +
Esomeprazole 100 + 0.1
100 + 0.3
100 + 1.0 10
10
10 40.1 ㅁ 11.5 *
33.2 * 8.6 *
18.8 ㅁ 4.3 * 42.9
35.1
20.2 U
U
U *: Significant difference compared to control (p <0.05)

As can be seen in Tables 4 and 5 above, the pharmaceutical compositions comprising lactitol and opilezol, and the pharmaceutical compositions comprising lactitol and esomeprazole, exhibit synergistic effects on the gastric lesion induced by anhydrous ethanol in all dose groups And the lesion development rate is decreased synergistically.

Example 3 Synergism of Lactitol with Colloidal Bismuth Compound

The synergistic action of bismuth subcitrate, a typical colloidal bismuth compound, with lactitol was studied for stomach lesions by ethanol-HCl. Seven weeks old male rats were fasted for 24 hours, and each drug was orally administered. After 1 hour, an ethanol-hydrochloric acid mixture was orally administered at 1.0 ml per mouse. One hour after the administration of ethanol-hydrochloric acid, all animals were slaughtered and the stomach was excised and the area of the lesion was measured to confirm the synergy. The test results are shown in Table 6.

Administered group Volume
(mg / kg) Number of animals Ulcer area
(mm ² ) Lesion incidence rate
(%) Synergistic effect
The presence or absence Control group 10 147.5 ㅁ 12.6 100 Bismuth
Percept rate 2.0
4.0
8.0 10
10
10 110.2 ㅁ 10.7
100.2 ㅁ 15.4
92.8 * 14.6 * 74.7
67.8
62.9 Lactitol +
Bismuth
Percept rate 100 + 2.0
100 + 4.0
100 + 8.0 10
10
10 80.5 ㅁ 14.1 *
72.3 ㅁ 8.8
66.3 ㅁ 10.8 54.6
49.0
44.9 U
U
U *: Significant difference compared to control (p <0.05)

As can be seen in Table 6 above, the pharmaceutical composition comprising lactitol and bismuth subcortrate shows synergistic reduction of the gastric ulcer area induced by ethanol-hydrochloric acid in all dose groups and a synergistic reduction of the lesion expression rate have.

These results indicate that lactitol has a synergistic effect in combination with H ₂ inhibitor, proton pump inhibitor or colloidal bismuth compound in comparison with animal models of gastroesophageal reflux disease and peptic ulcer, It is possible to introduce safe and useful peptic ulcer treatment method by reducing side effects of the above-mentioned drugs by decreasing dose as well as excellent therapeutic effect and suppression of recurrence rate.

The compositions according to the present invention may be included in solid or liquid pharmaceutical preparations together with conventional pharmaceutical auxiliaries and / or carriers.

Examples of solid formulations are those that can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or optionally suppository. Such preparations may contain conventional pharmaceutical inorganic and / or organic carriers such as talcum, lactose or starch, and may additionally contain conventional pharmaceutical adjuvants such as lubricants, tablet disintegrants, have.

Liquid preparations such as suspensions or emulsions may generally contain diluents, such as suspensions, such as water, oils and / or polyethylene glycols. Other adjuvants such as preservative, taste corrective and the like may optionally be added.

The composition according to the present invention can be formulated to be mixed with pharmaceutical adjuvants and / or carriers by known methods. May be mixed with, for example, adjuvants and / or carriers, and may be dry or wet granulated, in a conventional manner, for preparation in solid pharmaceutical form. The granules or powders are put into the capsule directly or compressed into tablets in a conventional manner. These can be coated if necessary.

Claims (6)

1) a drug for the treatment of gastroesophageal reflux disease and peptic ulcer; and a pharmaceutically acceptable salt thereof; And
2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To
Or a pharmaceutically acceptable salt thereof, for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer.
The pharmaceutical composition for the prevention and treatment of gastroesophageal reflux disease and peptic ulcer according to claim 1, wherein the agent for treating gastroesophageal reflux disease and peptic ulcer comprises an H ₂ inhibitor.
The pharmaceutical composition according to claim 2, wherein the H ₂ inhibitor is at least one selected from the group consisting of famotidine, ranitidine, and cimetidine, and a pharmaceutical composition for preventing and treating peptic ulcer disease.
The pharmaceutical composition for prevention and treatment of gastroesophageal reflux disease and peptic ulcer according to claim 1, wherein the agent for treating gastroesophageal reflux disease and peptic ulcer comprises a proton pump inhibitor.
5. The method according to claim 4, wherein the proton pump inhibitor is any one selected from the group consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole for prevention and treatment of gastroesophageal reflux disease and peptic ulcer A pharmaceutical composition.
The pharmaceutical composition for prevention and treatment of gastroesophageal reflux disease and peptic ulcer according to claim 1, wherein the agent for treating gastroesophageal reflux disease and peptic ulcer comprises a colloidal bismuth compound.