KR20010045320A - Pharmaceutical composition for Acute and Chronic Gastritis and Petic Ulcer - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing sphingolipids having an effect for the treatment of acute and chronic gastritis and gastric ulcer and inhibiting gastric acid secretion is provided, which can be used as material helpful for protection of detriment of the stomach and the duodenum from gastric acid secretion. CONSTITUTION: This pharmaceutical composition contains sphingolipids selected from the group consisting of phytosphingosine, sphingosine and sphinganine as an active component. The composition can be formed into a tablet, granules and fine granules by using starch and lower substituted hydroxypropylcellulose as an auxiliary substance, hydroxypropylcellulose or carboxymethylcellulose as a binding agent, magnesium stearate or starch as a lubricant and other additives. It is orally administered at a daily dose of 100 to 1,000kg three times a day.

Description

Pharmaceutical composition for Acute and Chronic Gastritis and Petic Ulcer

The present invention relates to a pharmaceutical composition containing as an active ingredient, spinolipids, a human lipid component having a therapeutic effect against acute gastritis and gastric injury and removing excess gastric acid.

Korean people have many digestive diseases such as gastritis and gastric ulcer due to eating habits, and these diseases have high recurrence rate after initial treatment. Antacids, H₂antagonists, Proton pump inhibitors, Cytoprotectives, etc. have been developed for this purpose, but the improvement of side effects and accumulation effects for long-term use and the development of more effective and safe drugs As the need for medical treatment increases, efforts are being made to develop the medicine with drugs applied in private or oriental medicine. Accordingly, the present inventors found that spinolipid, a human lipid component, has a high therapeutic effect on gastritis and gastric ulcers, and suggests a possibility as a therapeutic agent for ulcers.

The present inventors found that spinolipid, a human lipid component, has a high therapeutic effect on acute gastritis and gastric ulcer and has a function of removing excess gastric acid, and found a possibility as a ulcer therapeutic agent.

Peptic ulcer is a disease in which a circular, elliptical or linear ulcer develops in a part of the gut mucosa. Peptic ulcers are called because of the presence of strong digestive gastric juice in contact with the lower esophagus, gastric antrum, proximal part of the duodenum, Mckel diverticulum and gastrointestinal sutures. Most cases occur in the stomach and duodenum, so it is generally called stomach or duodenal ulcer.

Pathologically, the presence of ulcers on the mucous membranes of the stomach and intestine is called hemorrhagic erosion or acute superficial ulcer. Superficial ulcers reach muscularis mucosa and pass through submucosa to muscularis. In severe cases, the damaged area reaches the serosa and gastric fluid leaks into the abdominal cavity, causing severe pain and requiring surgical intervention. Peptic ulcers can cure naturally without any symptoms, but most ulcer patients complain of heartburn or sintrim.

Pepsin is a proteolytic enzyme that can digest almost any kind of protein ingested by meal. It is most active under acidic conditions, and this environment is exposed to hydrochloric acid (HCl) in gastric juice. Provided by When gastric ulcers occur due to the various causes mentioned, pepsin acts on the ulcers while the food is digested in the stomach, causing digestion and even strong acid hydrochloric acid, causing severe pain.

Peptic ulcers are caused by a number of factors, including mental and physical stress, medications (primarily anti-inflammatory drugs), and traumas that break down the equilibrium between homeostasis and attackers on the gastrointestinal mucosa. Attack factors include hydrochloric acid secreted from parietal cells of gastric glands and pepsin, a digestive enzyme secreted from chief cells. The acid in the gastric juice plays an important role as an attacker of ulcers. Most patients with stomach and duodenal ulcer are accompanied by symptoms such as sintrim due to excessive stomach acid. Bile acid in bile is recognized as an attack factor because it damages the gastric mucosa like alcohol or anti-inflammatory analgesics, or destroys the mucose barrier that prevents mucosal damage by the release of secreted hydrochloric acid into the mucosa. Protective factors include mucosa, mucin surrounding the surface of the mucosal mucosa, blood flow in the mucosa, and prostaglandin (PG), which constitutes the mucosa.

In general, peptic ulcer disease is stabilized and the symptoms are promptly improved by taking medication, but it is known that the recurrence is difficult to cure frequently. It is also a factor unless the patient stops taking medication because it is judged that the patient has completed the self-recognition symptom and stops taking the medication. It is true. There are many causes of all illnesses, but the cause of the disease is explained by the imbalance between the attacker and the defender. No matter how strong the attacker is, even if the defender is strong, the disease does not occur. Also, if you are poor, you will get sick. Thus, the essence of medicine in the treatment of diseases is to construct a rational formula that enhances the defensive factor and at the same time disables the attacker.

The pain-causing factor in most ulcers is gastric acid (hydrochloric acid), which is a strong acid with a pH of 1-2, which is essential for digesting protein, the main nutrient. The stomach wall of a healthy person is surrounded by mucous membranes and is protected from gastric acid. However, if erosions or ulcers occur on the gastric mucosa due to the causes listed above, hydrochloric acid acts on these areas and the wound becomes worse and painful.

Most of the ulcer treatments so far have been based on drugs such as antacids and acid secreting agents because of the action of hydrochloric acid. As long as a person is alive, gastric acid will continue to be secreted, and if the ulcer is formed by this gastric acid, you will have to take acid suppressants or antacids for life. However, these drugs only control the hydrochloric acid attacking the ulcer rather than treating the ulcer, so you can feel a little bit of comfort only when you stop taking it. Cause.

The antacids commonly used in these peptic ulcers, sodium bicarbonate and calcium carbonate, have strong antacid abilities, but secondary acidic stimulation of the stomach wall by carbon dioxide generated after gastric acid neutralization produces more acid in the stomach. High doses of sodium and calcium have side effects such as alkalosis, hypercalcemia and hypertension. In addition, the acid secretion inhibitor (H₂antagonist) cimetidine may inhibit the central nervous system in the elderly, and the anti-androgen effect may reduce side effects such as breast enlargement and libido and other drugs. It also works to increase. Eliminating external factors that cause ulcers (stress, drinking, irritating food, irregular meals, etc.) is, of course, an important but cure for finding the underlying cause.

Spinolipids have structural functions as a major component of cell membranes as well as the underlying physiological activity of regulation of cell growth and differentiation. The biological activity of various spinolipids reported so far is very diverse. However, these various properties are due to the difference in the specificity of structure and function between spinolipids present in more than 300 derivatives.

The present invention relates to a pharmaceutical composition containing Spinolipids, an active ingredient in human body, having a therapeutic effect against acute gastritis and gastric injury and removing excess gastric acid as an active ingredient.

Spinpholipid can be divided into phytosphingosine, spingosine, and spinganine. Their chemical structural formula is as follows.

1.Phytospinosine Structural Insertion

2. Spingosin Structural Insertion

3. Spinganine Structural Insertion

These are precursors of ceramide, which is known as an important ingredient to prevent moisture loss of the skin and to restore the damaged skin protection layer. It is an antibiotic that keeps the skin in a normal state from microorganisms present in the skin. Became known. However, spinrolipid has not yet been found to function as a therapeutic agent for gastritis and gastric ulcers. However, the present inventors have studied the gastric mucosa as well as the skin, and thus, the spinolipid has a significant effect on wound healing due to gastrointestinal inflammation or ulcer. It turned out that In addition, it was found that spinolipide, combined with gastric acid, has an antacid effect and affects gastric mucosal blood flow and prostaglandin, which functions to regulate acid secretion. In other words, spinolipide can protect gastric acid, a gastric ulcer attack factor, and exhibit a two-sided therapeutic effect of activating prostaglandin, a protective factor. Therefore, in the present invention, the spinoids (sphingoid = sphingolipid long chain base), such as spinosine, phytospinosine, and spinganine, which are basic skeletons of all spinolipids, are sufficient as therapeutic substances effective for acute gastritis and gastric injury. It has been proved to have very low toxicity.

The pharmaceutical composition of the present invention can be administered orally, for example, in tablets, capsules, granules, granules. Such formulations may be prepared by conventional pharmaceutical techniques using starch as a excipient, lower substituted hydroxypropyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose as binders, magnesium stearate or starch as lubricants, colorants as additives, coagulants and fragrances as additives. It is possible to manufacture.

Spinolipide is preferably administered orally three times a day within the range of 100 mg to 1000 mg. The dosage can be adjusted according to the degree of gastritis and ulcer and / or age of the patient.

Hereinafter, the present invention will be described in detail by examples according to the present invention. The content of the present invention is not limited to these examples, and the embodiments can be modified in various ways.

Example 1 Preparation of Soft Capsule

According to the conventional method for preparing soft capsules in the general formulation of the pharmacopeias, the following ingredients are contained in one capsule.

Example 2: Preparation of Capsule

Example 3: Preparation of Tablets

Example 4: Preparation of Fine Granules

4800 g of spinolipid are mixed with 6720 g of lower-substituted hydroxypropyl cellulose. The resulting mixed powder is kneaded after adding an aqueous solution in which 360 g of hydroxy cellulose is dissolved as a binder. The resulting mixture is treated and granulated, sifted into 0.5 mm sieves, dried and sifted again. The granules prepared are mixed with 120 g of dried corn powder to obtain a fine granule containing 40% spinolipid.

Experimental Example 1 Acute Toxicity Test

The purpose of this study is to examine the toxicity of spinolipids by visually observing the toxicity in experimental animals by oral administration of a large amount of samples.

10 male mice with 20-30 g body weight (breed: ICR) were used as a group, and spin lip feed (phytospinosine, spin gosin, or spinganine) was orally administered at 3000 mg / kg body weight for abnormal behavior. Acute toxicity was observed by measuring the number of deaths up to 72 hours.

The results of the acute toxicity test up to 72 hours after phytospinosine administration are shown in Table 1 below. In other words, there was no mortality and the minimum lethal dose of phytospinosine was 3000 mg / kg and no behavioral abnormalities were observed during the observation period.

Table 1. Acute Toxicity Test Results of Phytospinosine

Experimental Example 2 HCI-ethanol gastric damage test

This experiment is an experimental model using the Okabe method (Parmacometrics 12: 759,1976). This is an experimental method of damaging the gastric wall by direct administration of free hydrochloric acid, which is an attacking factor.

The experimental results are measured by measuring the area of gastric ulceration under the low magnification microscope (10 times magnification) in terms of width and length in millimeters, and adding the area of the entire stomach area. And the treatment rate is calculated as follows.

Treatment rate (%) = [(control ulcer area-drug ulcer area) / control ulcer area] * 100

Six Sprague-Dawley male rats weighing 150-180 g were used as a group and fasted for 24 hours or more with water freely supplied, followed by oral administration of the sample, and 30 minutes after the hydrochloric acid-ethanol solution (60 1 ml of 150 mM HCl) was orally administered to% ethanol. After standing for 1 hour under water-saving, the stomach was removed by lethality with ether, and the stomach was fixed with 2% formalin solution. As a control drug, scrawlate (sucralfate), which is used as a coating agent (gastric wall protecting agent), was used. In this experiment, phytospinosine had a significant protective effect by inducing gastric injury by the administration of free hydrochloric acid, which can be inferred from the increase of mucus secretion and the presence of a defense factor against HCl. .

Table 2. Protective effect against hydrochloric acid-ethanol gastric injury

Table 2 shows the gastric damage protective effect of each spin concentration of each concentration. As shown in Table 2, it can be seen that the gastric defense effect of spin cycle feed is clear. In particular, phytospinosine showed a significant effect even at low concentrations (10 mg / kg administration) and higher therapeutic effect with sucralate, an ulcer drug. Spinocin and spinganine showed a significant effect in the group administered more than 100 ㎎ / ㎏, it was found that the protective effect of phytospingosin gastric wall.

Experimental Example 3 Indomethacin Gastric Injury Experiment

This experiment was an experimental model by Yamagaki et al. That an experimental model of gastric ulceration was induced by suppressing the synthesis of prostaglandin, a gastric wall protective factor, when an excessive amount of nonsteroidal anti-inflammatory drugs were administered (Yamakaki K, et al. 1989, JAP J). Pharmacol., 49: 441-448.) Therefore, the protective effect of gastric damage in this experiment affects the action of prostaglandin and the protective effect of gastric wall (Robert, A., Zamis, JENE). , Lan caster, C. and Hancher, AF: Cytoprotection by prostaglandins in Rats.Gastroenterology, 77,433-443 (1979))

Six SD male rats weighing 200-250 g were used as a group and fasted for 24 to 48 hours with free supply of water, followed by oral administration of the specimens, and 30 mg of indomethacin (indomethacin) subcutaneously. . After 7 hours of subcutaneous injection, the stomach was removed by lethal injection with ether, followed by fixation of the stomach with 2% formalin solution.

Treatment rate was measured in the same manner as the hydrochloric acid-ethanol gastric injury experiment. Cimetidine was used as a control drug. Nonsteroidal analgesic agents, such as indomethacin and aspirin, cause gastric ulcers by inhibiting the synthesis of prostaglandins in large doses. Therefore, it can be seen that phytospingosin affects the action of prostaglandin, which shows a gastric protective effect in this experiment.

Table 3. Protective effect against indomethacin gastric injury

Table 3 shows the gastric protective effect of spin cycle feed at each concentration.

As can be seen in Table 3, it can be seen that the gastric protective effect of phytospingosin is most pronounced. In particular, phytospinosine showed a significant effect even at low concentrations (10 mg / kg administration) and showed a higher therapeutic effect than cimetidine, an acid secretion inhibitor. Spinocin and spinganine showed a significant effect in the group administered more than 100 ㎎ / ㎏ could confirm that the gastric protective effect of phytospingosin is better.

Experimental Example 4 Acetic Acid Ulcer Test

Acetic acid ulcer experiments are designed to measure the effectiveness of treatment for chronic ulcers and to indirectly measure the effects of prostaglandins on ulcers (Takagi K, et al, 1969, Jap J Pharmacol 199: 418). -426.)

Six SD male rats weighing 200-250 g were grouped as one group, and the stomach was exposed under ether anesthesia and exposed to 0.05 ml of 10% acetic acid at the grandular of the anterior wall. Inject into the sub-serosal layer using a micro-syringe and then suture. After that, the animals were fed with normal feeding and watering, and the samples were orally administered once a day at a predetermined time for 10 days from the second day after the operation. On the 12th day after surgery, the stomach was removed by ether, followed by fixation of the stomach with 2% formalin solution for 5 minutes. Treatment rate was measured in the same manner as the hydrochloric acid-ethanol gastric injury experiment. Thus, as shown in Table 4, phytospinosine and spinosine among spinolipids showed a significant treatment rate in chronic ulcer caused by acetic acid.

Table 4. Healing Effect on Acetic Acid Ulcer

Reports of natural therapeutic effects and production of prostaglandins on acetic acid ulcers (Uchida, M., Kawano, O., Misaki, N. and Irino, O .: Healing process of acetic acid-induced gastric ulcer and gastric mucosal prostaglandin E generation level in rats.Jap. J. Pharmacol., 50, 366 (1989).), The treatment effect of acetic ulcers was said to be due to an increase in prostaglandin-E2. Thus, phytospinosine and spinosine were thought to be involved in the production of prostaglandins.

According to the above experiment, spinolipide has very low toxicity, has an excellent gastric protective effect against gastric acid, affects the production of prostaglandin, a gastric protective defensive factor, and promotes rapid recovery of chronic ulcers. As a therapeutic agent, it was found that the substance was inferior.

Phytospinosine, spinosine and spinganine of the present invention can be applied to the purpose of treating and preventing gastric ulcer and duodenal ulcer in humans and animals. In particular, it protects the gastric mucosa from acute gastritis and gastrointestinal injury, protects the stomach and duodenum from excessive secretion of gastric acid, and can be used as a substance to help restore the cell membrane of damaged gastrointestinal mucosa.

The pharmaceutical composition of the present invention can be administered orally, for example, in tablets, capsules, granules, granules. Such formulations may be prepared by the corresponding pharmaceutical techniques using starch as a excipient, lower substituted hydroxypropyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose as binders, magnesium stearate or starch as lubricants, colorants as additives, flavoring agents and fragrances as additives. It is possible to manufacture.

Claims (3)

A pharmaceutical composition for the treatment of acute gastritis and peptic ulcer, containing spinolipide as an active ingredient. The pharmaceutical composition for treating acute gastritis and peptic ulcer according to claim 1, wherein the spinolipid is selected from the group consisting of phytospinosine, spinosine and spinganine. The pharmaceutical composition for treating acute gastritis and peptic ulcer according to claim 1, wherein the spinolipid is orally administered three times a day within the range of 100 mg to 1,000 mg.