KR20210126951A - Pharmaceutical composition for preventing or treating ileus comprising Ilaprazole - Google Patents

Abstract

The present invention relates to a composition for preventing or treating ileus containing ilaprazole as an active component. More specifically, when ilaprazole is administered to an animal model in which intestinal obstruction is induced after surgery, it is confirmed that the antioxidant and anti-inflammatory activity is improved, and gastrointestinal motility disorders induced by intestinal obstruction are recovered, so that the composition containing the ilaprazole as the active component can be provided as a preventive or therapeutic agent for ileus after surgery, and can be provided as a composition for improving gastrointestinal motility.

Description

TECHNICAL FIELD [0001] Pharmaceutical composition for preventing or treating ileus containing ilaprazole as an active ingredient;

The present invention relates to a composition for preventing or treating ileus containing ilaprazole as an active ingredient.

Intestinal obstruction (ileus) is a disease in which food, digestive juices, gas, etc. cannot escape due to blockage of the small intestine or part of the large intestine. Intestinal obstruction can be divided into mechanical ileus due to intestinal adhesions and paralytic ileus in which intestinal motility is paralyzed due to disorders occurring in organs other than the intestine.

Mechanical ileus is caused by the adhesion of the intestine and pulling the intestine every time it moves, causing pain.

Hyperthyroidism occurs, most often due to abdominal surgery. During laparotomy, damage to tissues in the abdominal cavity such as the peritoneum or intestine may occur, and as this area heals, inflammation occurs, and during the fibrosis process, the intestines adhere to each other and intestinal obstruction may occur. It may appear within a few days after surgery or may appear years later. In addition, mechanical ileus can occur due to hernias, tumors, abscesses, inflammatory diseases such as Crohn's disease or intestinal tuberculosis, intestinal hematoma due to trauma, and intestinal torsion.

In most cases of paralytic ileus, it appears after abdominal surgery, and intestinal movement is temporarily paralyzed due to anesthesia and surgery, but recovery is possible within a few days. In addition, it can be caused by gastric or duodenal ulcer perforation, acute peritonitis, acute pancreatitis, acute cholecystitis, and peritoneal irritation due to abdominal trauma.

When a patient who has undergone open surgery has an intestinal obstruction after such surgery, the patient's physical pain as well as the length of hospitalization and cost can be greatly increased. In case of ileus, medical treatment is given first, and when symptoms do not improve or when obstruction is due to tumor, etc., surgical treatment is performed. Therefore, prompt diagnosis and first aid are necessary.

Republic of Korea Patent Publication No. 10-2005-0008949 (published on Jan. 24, 2005)

An object of the present invention is to provide a composition containing ilaprazole as an active ingredient as a composition for preventing or treating intestinal obstruction or gastrointestinal motility disorder after surgery.

The present invention provides a pharmaceutical composition for preventing or treating ileus containing ilaprazole as an active ingredient.

The present invention provides a health food for preventing or improving intestinal obstruction containing ilaprazole as an active ingredient.

The present invention provides a pharmaceutical composition for preventing or treating gastrointestinal motility disorders containing ilaprazole as an active ingredient.

In addition, the present invention provides a health food for preventing or improving gastrointestinal motility disorder containing ilaprazole as an active ingredient.

According to the present invention, when ilaprazole is administered to an animal model in which intestinal obstruction is induced after surgery, it is confirmed that antioxidant and anti-inflammatory activity is improved and gastrointestinal motility disorder induced by intestinal obstruction is recovered. A composition containing ilaprazole as an active ingredient may be provided as an agent for preventing or treating ileus caused by surgery, and may be provided as a composition for improving gastrointestinal motility.

1 is a result confirming the effect of restoring gastric motility according to administration of 2 mg/kg of mosapride and 1, 3, and 10 mg/kg of ilaprazole as a control group in an animal model in which intestinal obstruction is induced after surgery.
Figure 2 is the result of confirming the effect of recovering small intestine motility according to the administration of mosapride 2 mg/kg and ilaprazole 1, 3, and 10 mg/kg as a control group in an animal model in which intestinal obstruction was induced after surgery.
Figure 3 shows the change in expression of inflammatory cytokine TNF-α (Tumor necrosis factor-α) after administration of 2 mg/kg of mosapride and 1, 3, and 10 mg/kg of ilaprazole as a control to an animal model induced after surgery. is the result of checking
Figure 4 confirms the expression change of the inflammatory cytokine IL-1β (Interleukin-1β) after administration of 2 mg/kg of mosapride and 1, 3, and 10 mg/kg of ilaprazole as a control to an animal model induced after surgery. is the result
5 is hematoxylin & eosin (H&E) staining results confirming the level of tissue damage recovery after administration of 2 mg/kg of mosapride and 1, 3, and 10 mg/kg of ilaprazole as a control group to an animal model induced after surgery. , Fig. 4A is a control group, Fig. 4B is a vehicle group, Fig. 4C is a mosapride (mosa) group, Fig. 4D is a ilaprazole 1 mg/kg administration group, Fig. 4E is a ilaprazole 3 mg/kg administration group, and Fig. 4F Ilaprazole 10 mg/kg administration group.
6 is a result confirming the change in the level of the antioxidant enzyme SOD (superoxide dismutase) according to the administration of ilaprazole 1, 3, and 10 mg/kg in an animal model in which intestinal obstruction was induced after surgery.
7 is a result confirming the change in the level of the antioxidant GSH (Glutathione) according to the administration of ilaprazole 1, 3, and 10 mg/kg in an animal model in which intestinal obstruction is induced after surgery.
8 is a result confirming the change in the level of MDA (malondialdehyde) according to the administration of ilaprazole 1, 3, and 10 mg/kg in an animal model in which intestinal obstruction was induced after surgery.

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

The inventors of the present invention found that ilaprazole, a benign pump inhibitor used as a treatment for dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and duodenal ulcer, is Mosapride, a drug that increases gastrointestinal strength in an animal model in which intestinal obstruction is induced after surgery. (mosapride) improved small intestine motility compared to the administration group, confirmed the effect of recovering the tissue damage to the small intestine due to inflammation induced by intestinal obstruction, and completed the present invention.

The present invention can provide a pharmaceutical composition for preventing or treating ileus containing ilaprazole as an active ingredient.

The ileus may be post-operative ileus.

The ilaprazole may increase the motility of the stomach and small intestine reduced by intestinal obstruction.

According to an embodiment of the present invention, as shown in FIGS. 1 and 2, a decrease in gastric and small bowel motility was confirmed in the sham POI induction model in which only laparotomy was performed without intestinal manipulation, whereas 5-TH4 that increases gastrointestinal motility Significant exercise capacity recovery was confirmed in the experimental group administered with the receptor antagonist Mosapride 2 mg/kg, and it was confirmed that the exercise capacity was restored to a level similar to that of Mosapride in the experimental group administered with 10 mg/kg ilaprazole.

In addition, according to another embodiment of the present invention, histological damage appears due to inflammation in the small intestine induced by intestinal obstruction after surgery. As a result, as shown in FIG. 5, histological damage and defect of villi were confirmed in the control group and the vehicle group, whereas the histological damage was recovered in the group administered with Mosapride and 10 mg/kg ilaprazole.

The pharmaceutical composition may include 0.01 to 10 parts by weight of ilaprazole based on 100 parts by weight of the total pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition for preventing or treating intestinal obstruction containing ilaprazole as an active ingredient is prepared according to a conventional method for injection, granule, powder, tablet, pill, capsule, suppository, gel, suspension, emulsion. , any one formulation selected from the group consisting of drops or liquids may be used.

In another embodiment of the present invention, the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetening agent, coating agent, swelling agent, lubricant, flavoring agent, antioxidant, buffer, bacteriostatic agent, diluent, It may further include one or more additives selected from the group consisting of dispersants, surfactants, binders and lubricants.

Specifically, carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules. agent and the like, and such a solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base material for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

According to an embodiment of the present invention, the pharmaceutical composition is administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject.

The preferred dosage of ilaprazole may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to an embodiment of the present invention, although not limited thereto, the daily dose may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be administered in several divided doses, thereby not limiting the scope of the present invention.

In the present invention, the 'subject' may be a mammal including a human, but is not limited to these examples.

The present invention can provide a health food for preventing or improving intestinal obstruction containing ilaprazole as an active ingredient.

The health food is used together with other foods or food additives other than the ilaprazole, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.

The effective dose of the compound contained in the health food may be used according to the effective dose of the therapeutic agent, but in the case of long-term intake for health and hygiene or health control, it may be less than or equal to the above range, It is clear that the ingredient can be used in an amount above the above range because there is no problem in terms of safety.

The type of health food is not particularly limited, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

The present invention may provide a pharmaceutical composition for preventing or treating gastrointestinal motility disorders containing ilaprazole as an active ingredient.

In addition, the present invention provides a health food for preventing or improving gastrointestinal motility disorder containing ilaprazole as an active ingredient.

Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Example 1> Postoperative ileus (Postoperative ileus) induced animal model production

7-week-old (200-250 g) SD rats were fasted for 24 hours and then anesthetized. After opening the abdominal cavity of anesthetized rats by 2-3 cm, take out the small intestine and cecum on gauze soaked in normal saline, massage with a cotton swab for 1 minute, and take care not to dry the intestine for 15 minutes. After that, the intestine was put back into the abdomen and the open part was sewn up to produce an ileus-induced animal model after surgery.

The 36 rats used in the experiment were randomized into 6 groups: Control group, vehicle group, mosa group, ilaprazole 1 mg/kg group, ilaprazole 3 mg/kg group, and ilaprazole 10 mg/kg group.

After abdominal surgery was performed on the rats in the remaining groups except for the control group, the control group was orally administered with 4 ml/kg of 0.5% CMC-Na aqueous solution 24 hours before euthanasia, and in the vehicle group, 4 ml after 30 minutes of surgery /kg 0.5% CMC-Na aqueous solution was orally administered. In the Mosa group and the ilaprazole administration group, each drug was orally administered 30 minutes after surgery by suspension in 4 ml/kg of 0.5% CMC-Na aqueous solution.

<Example 2> Confirmation of gastric motility recovery effect through gastric emptying

Gastric emptying (%) is one of the indicators to evaluate the exercise capacity of the digestive tract, and is suitable for evaluating the degree of recovery and decrease in the motility of the stomach in the digestive tract. When performing laparotomy or manipulation of the digestive tract, gastric motility decreases and gastric emptying becomes an indicator to identify abnormalities in gastric motility. The effect of restoring the upper locomotion ability according to the administration of Ilaprazole was confirmed.

Referring to FIG. 1 , a decrease in exercise capacity was confirmed in the sham POI induction model in which only the laparotomy was performed without intestinal manipulation. On the other hand, significant motor recovery was confirmed in the experimental group administered with mosapride 2 mg/kg, a 5-TH4 receptor antagonist that increases gastrointestinal motility, and in the experimental group administered with 10 mg/kg ilaprazole, it was superior to Mosapride. It was confirmed that there was a recovery effect.

From the above results, it was confirmed that ilaprazole exhibits an effect of restoring the decrease in gastric motility due to intestinal obstruction after surgery.

<Example 3> Confirmation of effect of recovery of small intestine motility through mean geometric center analysis

In the postoperative intestinal obstruction induced animal model according to Example 1, the effect of ilaprazole administration on the recovery of movement ability of the small intestine was confirmed.

The average geometric center of gravity is one of the indicators to evaluate the motility of the digestive tract. When laparotomy is performed and manipulation of the digestive tract occurs, the motility of the small intestine is greatly reduced. have.

Referring to FIG. 2 , while a decrease in the mean geometric center was confirmed in the postoperative ileus-induced model, significant exercise capacity in the experimental group administered with Mosapride 2 mg/kg, a 5-TH4 receptor antagonist that increases gastrointestinal motility Recovery was confirmed, and even in the experimental group administered with ilaprazole 1, 3, and 10 mg/kg, it was confirmed that the exercise capacity of the small intestine was improved to a level similar to that of Mosapride.

From the above results, it was confirmed that ilaprazole restores the decreased intestinal motility due to intestinal obstruction after surgery.

<Example 3> Confirmation of TNF-α reduction effect by ilaprazole

After the administration of ilaprazole in the postoperative ileus induced animal model according to Example 1, the expression change of the inflammatory cytokine TNF-α was confirmed.

TNF-α is an inflammatory cytokine that promotes the acute state of inflammation, and TNF-α increases vascular permeability, thereby re-enrolling macrophages and neutrophils to the site of infection. In addition, it induces inflammation through biologically broad regulation, including cell proliferation, differentiation, and apoptosis. This mechanism is used as an inflammatory marker of the affected area when a disease occurs.

Referring to FIG. 3 , it was confirmed that the level of TNF-α rapidly increased in the ileum tissue of the postoperative intestinal obstruction induced animal model in the postoperative intestinal obstruction induced animal model. On the other hand, in the experimental group administered with 1, 3 and 10 mg/kg of ilaprazole, the level of TNF-α was significantly decreased, and in particular, it was confirmed that TNF-α was reduced the most in the experimental group administered with 10 mg/kg. .

<Example 4> Confirmation of IL-1β reduction effect by ilaprazole

The expression change of the inflammatory cytokine IL-1β (Interleukin 1β) after ilaprazole administration in the postoperative ileus induced animal model according to Example 1 was confirmed.

IL-1β is an inflammatory cytokine belonging to the IL-1 family. It is a monokine produced by monocytes and macrophages. Similar to TNF-α, it is possible to confirm the acute state of inflammation, and the proliferation and differentiation of T cells and B cells. , fibroblast proliferation, prostaglandin E2 production, fever, etc., act extensively on inflammation and immune responses in vivo. These mechanisms are used as indicators of acute inflammatory disease in the onset of disease.

Referring to FIG. 4 , it was confirmed that the level of IL-1β sharply increased in the ileal tissue of the model in which intestinal obstruction was induced after surgery. On the other hand, it was confirmed that the IL-1β level was significantly decreased in the experimental group administered with 1 mg/kg, 3 mg/kg and 10 mg/kg ilaprazole.

<Example 5> Confirmation of histological changes in ileus after surgery according to ilaprazole administration

In the postoperative ileus induced animal model according to Example 1, the histological damage results according to ilaprazole administration were confirmed.

When ileus occurs after surgery, histological damage occurs due to inflammation in the small intestine. To confirm this, the ileum was stained with H&E and histological findings were confirmed.

As a result, as shown in FIG. 5 , compared to the control group, histological damage and defect of the villi were confirmed in the vehicle group, and it was confirmed that the histological damage was recovered in the mosa group and the ilaprazole 10 mg/kg group.

<Example 6> Confirmation of SOD activity change according to ilaprazole administration

Changes in the antioxidant enzyme SOD (superoxide dismutase) by ilaprazole administration in the postoperative ileus induced animal model according to Example 1 were confirmed.

SOD (Superoxide dismutase) is an enzyme that catalyzes the disproportionation reaction that converts superoxide ions into oxygen and hydrogen peroxide. It is known that SOD acts as an antioxidant defense mechanism in almost all cells exposed to oxygen. Anti-oxidative effect) is used as an indicator.

Referring to FIG. 6 , it was confirmed that the activity level of SOD rapidly decreased in the ileum tissue of the model induced with intestinal obstruction after surgery. On the other hand, it was confirmed that the SOD activity was significantly increased in the experimental group administered with ilaprazole 1, 3 and 10 mg/kg.

<Example 7> Confirmation of changes in glutathione according to ilaprazole administration

Changes in the antioxidant enzyme GSH (Glutathione) by ilaprazole administration in the postoperative ileus induced animal model according to Example 1 were confirmed.

Glutathione (GSH) is a non-enzymatic antioxidant that is biosynthesized in most organisms and prevents cell damage caused by free radicals, ROS such as peroxides and lipid peroxides, and heavy metals. This GSH acts as a reducing agent that provides electrons and is known to act as an antioxidant defense mechanism, so it is used as an indicator of the antioxidant effect.

Referring to FIG. 7 , it was confirmed that the level of GSH in the ileum tissue of the ileal tissue induced after surgery was rapidly decreased, whereas in the experimental group administered with 10 mg/kg ilaprazole, it was confirmed that the level of GSH was greatly increased. .

<Example 8> Confirmation of changes in malondialdehyde according to ilaprazole administration

Changes in malondialdehyde (MDA) according to ilaprazole administration in the postoperative ileus induced animal model according to Example 1 were confirmed.

Reactive oxygen species (ROS) generated during inflammation react with lipids to produce malondialdehyde (MDA), a lipid peroxide, which is well known as an indicator of oxidative stress.

Referring to FIG. 8 , it was confirmed that the MDA concentration level rapidly increased in the ileum tissue of the ileus-induced model after surgery. On the other hand, it was confirmed that the MDA concentration significantly decreased in the experimental group administered with 1, 3 and 10 mg/kg of ilaprazole.

From the above results, it was confirmed that ilaprazole can be used for the treatment of intestinal obstruction disease after surgery.

As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

A pharmaceutical composition for preventing or treating intestinal obstruction containing Ilaprazole as an active ingredient. The pharmaceutical composition according to claim 1, wherein the ileus is postoperative ileus. The pharmaceutical composition according to claim 1, wherein the ilaprazole increases the motility of the stomach and small intestine lowered by intestinal obstruction. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 0.01 to 10 parts by weight of ilaprazole based on 100 parts by weight of the total pharmaceutical composition. A health food for preventing or improving intestinal obstruction containing ilaprazole as an active ingredient. A pharmaceutical composition for preventing or treating gastrointestinal motility disorders containing ilaprazole as an active ingredient. A health food for preventing or improving gastrointestinal motility disorders containing ilaprazole as an active ingredient.

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