JP4950551B2 - Gastrointestinal mucosa protective agent - Google Patents

Description

  The present invention relates to a gastrointestinal mucosa protective agent, particularly a prophylactic / therapeutic agent for peptic ulcer caused by gastric hyperacidity.

  A peptic ulcer is a defect in the local tissue of the gastrointestinal mucosa that is exposed to gastric juice. As for the cause of this, the relationship with Helicobacter pylori, a gram-negative bacilli (Non-patent Document 1), and Shay's balance theory (Non-patent Document 2), which is caused by an imbalance between the attack and defense factors, are known. It has been.

  Among the above factors, the mechanism of peptic ulcer caused by Helicobacter pylori was thought to be because ammonia generated in the stomach due to the strong urease activity of Helicobacter pylori damages the gastric mucosa. Various studies have been made since then, and it has been reported that Helicobacter pylori is also involved in the generation of monochloramine and the production of interleukin 8, which also causes gastric mucosal damage (non-patent literature). 3, Non-Patent Document 4).

  Therefore, antibiotics having anti-Helicobacter pylori activity (for example, penicillin, ampicillin, erythromycin, clarithromycin, streptomycin, tetracycline, etc.) and bismuth preparations are used for the treatment of peptic ulcer caused by Helicobacter pylori. .

  On the other hand, peptic ulcers caused by an imbalance of attack and defense factors such as hyperacidity have a different mechanism from that of Helicobacter pylori described above. This includes stress, heavy drinking and eating, smoking, taking non-steroidal anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, indomethacin, ethenamide, tranexamic acid, loxoprofen, etc.), protecting the digestive tract mucosa (stomach / duodenal mucosa, etc.) This is because gastric acid, which is an attacking factor, becomes relatively excessive due to a decrease in force, etc., and damages the gastrointestinal mucosa.

  For this reason, gastric acid secretion inhibitors and anti-pepsin agents that are attack factor inhibitors, or mucosal protective agents and tissue repair promoters that are defense factor enhancers are used for this treatment.

  Generally, the cause of ulcers in the upper stomach and relapsed refractory ulcers found in elderly people is often a decrease in protective factors, and it is desired to provide an excellent protective factor enhancer.

  On the other hand, yam is called Zanthoxylum piperitum and is a plant belonging to the genus Salamander. The fruit is pungent and has an effect of stimulating gastrointestinal tract and improving metabolic function, and has been widely used as a spice for promoting appetite since ancient times. In addition, what is obtained by drying the mature fruit of a yam is called a koji or koji in Oriental medicine, and it is known as a drug that warms the body and leaves cold. In order to stimulate the gastrointestinal tract and promote new-line metabolic function, yam is used as an aromatic gastrointestinal agent to improve gastric drooping, gastrointestinal cold pain, and gastric dilatation, as well as roundworm extermination, diuresis, anti-inflammation, local stimulant, and toothache prevention. ing.

  Furthermore, it is known that the sun shawl contained in yam has a bactericidal action, and its use as an anti-Helicobacter pylori activator of yam is also known (Patent Document 1).

  However, yam is not used for inflammatory or ulcer diseases because it is a irritating herbal medicine and enhances gastrointestinal function and promotes gastric acid secretion. Moreover, in order to mix | blend a yam with an antacid, it is recommended to mix | blend as 1/10 or less of the daily maximum amount mainly for the purpose of taste-masking.

Marshall BJ, Warren JR: Lancet, 16; 1, 1311-1315 (1984) Harry Shay M.D .: Am. J. Dig. Dis, 4, 847-870 (1959) Koji Tonokatsu, June issue of Clinical Gastroenterology, 66 (1994) Japan Pharmacists Association, Illness and Drug Revision 4th Edition, 159-172 (2003) JP 07-196522 A

  An object of the present invention is to provide a medicament that has a protective factor enhancing action, protects the mucous membrane in the digestive tract, and has an excellent preventive / therapeutic action against peptic ulcer caused by gastric hyperacidity.

As a result of diligent studies to solve the above problems, the present inventors have surprisingly found that yam or its extract has an excellent gastrointestinal mucosal protective action, and against peptic ulcers caused by gastric hyperacidity. The present invention has been completed by finding that it has an excellent preventive and therapeutic effect.
Traditionally, it has been known that yam promotes gastric acid secretion, but rather is thought to damage the gastrointestinal mucosa, and thus such findings found by the present inventors are extremely surprising.

  That is, the present invention provides a gastrointestinal mucosa protective agent containing yam or an extract thereof as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, the chemical | medical agent which has the outstanding digestive tract mucosa protective effect can be provided, and it can be used as a prophylactic / therapeutic agent which has the outstanding prophylactic / therapeutic effect with respect to the peptic ulcer caused by excessive gastric acidity.

  The yam used in the present invention or an extract thereof means Zanthoxylum piperitum belonging to the genus Citrusaceae or an extract thereof. The yam can use leaves, flowers, bark, branches, fruits, pericarp or roots as they are or after pulverization, but it is preferable to use fruits or pericarps for a more excellent gastrointestinal mucosa protective effect. In addition, the extract of yam is extracted at room temperature or under heating, or extracted by using an extractor such as a Soxhlet extractor, various solvent extracts, diluted solutions thereof, concentrated solutions thereof or dried products thereof. It means the end.

  As the extraction solvent for obtaining the extract of yam used in the present invention, either a polar solvent or a nonpolar solvent can be used. For example, water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; tetrahydrofuran and diethyl ether Linear and cyclic ethers such as polyethylene; polyethers such as polyethylene glycol; hydrocarbons such as squalane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene; halogenated carbonization such as dichloromethane, chloroform and dichloroethane And hydrogen dioxide; and carbon dioxide, and the like, and these can be used alone or as a mixture. In order to have a better gastrointestinal mucosa protective action, it is preferable to use an extract containing an acetone-containing solvent, that is, an acetone-containing solvent extract. The acetone-containing solvent can contain, for example, 10 to 50% by volume of water in addition to acetone.

  The anti-ulcer test described later confirmed that the yam or its extract has an excellent gastrointestinal mucosal protective effect. Therefore, yam or an extract thereof can be used as a protective agent for gastrointestinal mucosa and as a prophylactic / therapeutic agent for peptic ulcer caused by gastric hyperacidity. Examples of gastrointestinal mucosa include gastric mucosa and duodenal mucosa. Excessive stomach acid is a state in which stomach acid serving as an attack factor is relatively excessively present in the stomach or duodenum. Therefore, even if the secretion amount of gastric acid, which is an attack factor, is normal, gastric acid is excessive if the protective ability of the stomach or duodenal mucosa, which is a protective factor, is reduced. Causes of gastric hyperacidity include stress, binge eating, smoking, nonsteroidal anti-inflammatory drugs (eg aspirin, acetaminophen, ibuprofen, indomethacin, etenzamide, tranexamic acid, loxoprofen, etc.), gastrointestinal mucosa (stomach / duodenum) Reduction of the protective ability of the mucous membrane and the like), but may be caused by causes other than these. However, it is preferably not due to Helicobacter pylori. The present invention is a peptic ulcer prophylactic / therapeutic agent applicable to Helicobacter pylori negative patients.

  The agent for protecting the digestive tract mucosa of the present invention, the preventive / therapeutic agent for peptic ulcer caused by excessive acidity in the stomach (hereinafter referred to as the drug of the present invention) can be used as it is, or a pharmaceutically acceptable The carrier may be contained in the form of a pharmaceutical composition or the like.

  The compounding amount of the yam or its extract in the pharmaceutical composition in the case of the pharmaceutical composition is not particularly limited, but is 0.1 to 20% by mass, preferably 0.5 to 16% by mass in terms of the active ingredient based on the total amount of the pharmaceutical composition. %.

  In addition to yam or an extract thereof, other medicinal active ingredients can also be added to the drug of the present invention. Other active pharmaceutical ingredients are not particularly limited as long as they do not cause any trouble when formulated as a preparation. Preferred medicinal active ingredients include methylmethionine sulfonium chloride, processed carp, carrot, red ginseng, bamboo ginseng, seven ginseng, elephant carp, ginger, dried ginger, ryokan, turmeric, gadget, sojutsu, peanut, hop and the like However, it is not limited to these.

Of these, Ryo is Alpinia officinarum Hance from Zingiberaceae. By including Ryokan or an extract thereof in the drug of the present invention, it is possible to maintain an excellent gastrointestinal mucosal mucosal protective action while reducing the blending amount of yam or its extract. The irritation caused by can be suppressed. Ryoji can use leaves, flowers, bark, branches, fruits, pericarp, roots, rhizomes, etc. as they are or after pulverization, but it uses rhizomes because it has a better protective effect on the digestive tract mucosa. preferable. The extract means various solvent extracts obtained by extraction at room temperature or under heating, or extraction using an extraction device such as a Soxhlet extractor, a diluted solution thereof, a concentrated solution thereof or a dried powder thereof. Is. As the extraction solvent, a solvent similar to the solvent used for the extraction of the above-mentioned yam can also be used. It is preferred to use an extract. The acetone-containing solvent can contain, for example, 10 to 50% by volume of water in addition to acetone.
When Ryokan is used, the compounding amount of Ryokan in the drug of the present invention is 0.1 to 75% by mass, preferably 1 to 60% by mass in terms of bulk drug substance. The blending mass ratio of Ryokan and Yam is preferably 1: 2 to 6: 1 in terms of drug substance, from the viewpoint of expression of blending effects.

  The dosage form of the medicament of the present invention is preferably an orally administered preparation. Specific examples of the orally administered preparations include tablets, granules, capsules, drinks, jelly preparations, and the like, and these can be produced by known conventional techniques.

  Orally administered preparations can be prepared using components such as commonly used excipients, binders, disintegrants, disintegration inhibitors, absorption enhancers, humectants, adsorbents, lubricants and the like. Specifically, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch solution, shellac, Binders such as potassium phosphate; disintegrating agents such as dried starch, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; Disintegration inhibitors such as stearin, cocoa butter and hydrogenated oil; absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbent: purified talc, stearate Boric acid powder, lubricant and the like such as polyethylene glycol can be exemplified.

  The dose of the drug of the present invention varies depending on the target disease, patient's symptoms, severity, patient age, complications, etc., but is usually a raw drug of yam or its extract per day for adults The converted amount is 10 mg to 3000 mg, preferably 50 mg to 1500 mg, more preferably 100 mg to 1200 mg, which can be administered orally. If the dose is within the range of 10 mg to 3000 mg per day for an adult, it has an excellent gastrointestinal mucosal protective effect.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

Production Example 1 Preparation of yam extract 1066 g of persimmon skin was immersed in 80% by volume water-containing acetone (consisting of 20% by volume water and 80% by volume acetone, the same applies hereinafter) and left at room temperature for 1 day. Then, this was filtered and the filtrate was collect | recovered. The same operation was further repeated 3 times for the residue. The collected filtrate was dried under reduced pressure to obtain 203 g (yield 19.1%) of 80% by volume hydrous acetone extract of yam.

Example 1. Effect on ethanol-induced gastric mucosal damage Test substance (80% by volume aqueous acetone extract of yam obtained in Production Example 1) suspended in various concentrations with gum arabic powder (however, only gum arabic powder in the control group) is SD Male male rats (body weight of about 250 g, fasted for 24 hours) were orally administered (5 ml / kg), and after 1 hour, 99.5 vol% ethanol was administered at 1.5 ml / animal. After 1 hour, the stomach was removed and fixed with 1.5% by volume formalin, then the stomach was cut open, and the length of damage (damage factor) occurring in the gastric mucosa was measured. The results are shown in Table 1 according to the dose (mg / kg) per rat of the administered yam extract.

Example 2 Effect on indomethacin-induced gastric mucosal damage Test substance (80% vol. Acetone extract of yam obtained in Production Example 1) suspended in gum arabic powder at various concentrations (however, only gum arabic powder in the control group) is SD Male male rats (body weight of about 250 g, fasted for 24 hours) were orally administered (5 ml / kg), and after 1 hour, indomethacin was administered at a dose of 20 mg / kg. After 4 hours, the stomach was removed and fixed with 1.5% by volume formalin, and then the stomach was opened and the length of damage (damage factor) occurring in the gastric mucosa was measured. The results are shown in Table 1 according to the dose (mg / kg) per rat of the administered yam extract.

  As shown in Table 1, it has been recognized that the water-containing acetone extract of yam has a dose-dependent inhibitory effect on ethanol and indomethacin-induced gastric mucosal damage, and thus has a gastric mucosal protective action, and has excessive acidity in the stomach. It was found to be useful in the prevention and treatment of peptic ulcer caused by

Production Example 2 Preparation of Ryokan extract Ryokan 3000 g was dipped in 80% by volume aqueous acetone and left at room temperature for 1 day. Then, this was filtered and the filtrate was collect | recovered. The same operation was further repeated 3 times for the residue. The collected filtrate was dried under reduced pressure to obtain 288 g (yield 9.6%) of 80% by volume water-containing acetone extract.

Example 3 FIG. Effect of Japanese yam and Ryoji on ethanol-induced gastric mucosal damage Except that the test substance was 80% by volume hydrous acetone extract of Japanese yam obtained in Production Example 1 and 80% by volume aqueous acetone extract of Ryoji obtained in Production Example 2 The length of damage (damage coefficient) generated in the gastric mucosa was measured by the same method as in Example 1. The results are shown in Table 2 according to the dose (mg / kg) per unit weight of the rat yam extract and Ryokan extract administered.

  As shown in Table 2, it was found that even when the water-containing acetone extract of yam and the water-containing acetone extract of Ryokan were blended, a significant inhibitory action was observed against ethanol-induced gastric mucosal damage. It was proved that the combination had a gastric mucosal protective action and was useful for the prevention and treatment of peptic ulcer caused by gastric hyperacidity.

Formulation Example 1 In 20 mL of liquid prescription purified water, carrot dry extract 54.7 mg (raw substance equivalent 816.4 mg), yam extract 30.0 mg (raw drug equivalent 157.9 mg), oxoamidin powder 40.0 mg, Rakuyu extract 0.3 mL (raw drug equivalent) 300.0mg), dried hop extract 10.6mg (powder equivalent 150.5mg), assembly extract 3.0mg (powder equivalent 15.0mg), peppermint oil 6.0mg, dipotassium glycyrrhizinate 5.0mg, sucrose fatty acid ester (DK ester) SS (Daiichi Kogyo) 5.0 mg and citric acid 30 mg were added and dissolved by stirring. Sodium citrate was added to adjust the pH to 5.5, and an appropriate amount of purified water (room temperature) was added to make a total volume of 30 mL to produce an internal solution.

Formulation Example 2 Granules formulation methyl methionine sulfonium chloride, 30 parts hydrogenated oil 120 parts by weight of glycerin 20 parts by mass monostearate, 800 parts by weight of corn starch, ethanol 15 parts by mass of mixed powder consisting of carmellose calcium 50 parts by mass of A kneaded product was made. The kneaded product was extruded and granulated (φ0.8 mm), dried, sized and classified to obtain granules (hereinafter referred to as A granules).
In addition, carnitine chloride 300 parts by weight, carrot powder 300 parts by weight, licorice extract powder 70 parts by weight (concentration of crude drug 490.0 parts by weight), polyvinyl alcohol 70 parts by weight, carmellose calcium 30 parts by weight, crystalline cellulose 40 parts by weight, xylitol 800 parts by mass of 70% ethanol by which 90.9 parts by mass of yam extract (478.4 parts by mass in terms of crude drug) and 166.7 parts by mass of Rakuji extract (1736.5 parts by mass in terms of drug substance) were dispersed in advance in a mixture consisting of 1602.4 parts by mass In addition, a kneaded product was produced. The kneaded product was extruded and granulated (φ0.8 mm), dried, sized and classified to obtain granules (hereinafter referred to as B granules).
Further, 6 parts by mass of L-menthol was adsorbed on 24 parts by mass of magnesium aluminate metasilicate to obtain a fragrance powder (hereinafter referred to as C fragrance powder).
300 parts by mass of A granule, 2670 parts by mass of B granule and 30 parts by mass of C fragrance powder were mixed with a mixer, and further packaged with a packaging machine to obtain a granule having a single dose of 1.0 g.

Claims (6)

Stomach for Helicobacter pylori-negative patients, containing yam or its extract as an active ingredient and used for oral administration of 50 mg to 1500 mg per day as an active ingredient of yam Or a duodenal mucosa protective agent. Pepper or extracts thereof, gastric or duodenal mucosa protective agent according to claim 1, wherein the acetone-containing solvent extract of Japanese pepper. The gastric or duodenal mucosal protective agent according to claim 1 or 2, further comprising bean or extract thereof. Containing pepper or extracts thereof as an active ingredient, characterized Rukoto used to be 50mg~1500mg orally administered as a virgin drug equivalent amount of pepper per day for an adult, peptic gastric caused by hyperacidity Or a preventive / therapeutic agent for duodenal ulcer. The agent for preventing or treating digestive stomach or duodenal ulcer caused by excessive gastric acid according to claim 4 , wherein the yam or an extract thereof is an acetone-containing solvent extract of yam. The prophylactic / therapeutic agent for digestive stomach or duodenal ulcer caused by gastric hyperacidity according to claim 4 or 5, further comprising Ryoji or an extract thereof.