JP2745555B2 - Gastrointestinal drug - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a gastrointestinal drug containing a licorice methanol extract, which is excellent in treating and preventing various gastrointestinal diseases.

Problems to be Solved by Conventional Techniques and Inventions Licorice has been incorporated into many Chinese herbal formulas since ancient times, and the Japanese Pharmacopoeia contains licorice, licorice powder, licorice extract and licorice crude extract, and other licorice-style extracts It has been known. These are dried licorice,
It is an extract of water or boiling water, and is used as an expectorant, intestinal medicine, demulcent, etc. In addition, it is known that gastric secretion is suppressed without suppressing parasympathetic nerve, and is used for treatment of gastric ulcer and duodenal ulcer in foreign countries.

However, the symptoms of gastrointestinal diseases vary greatly from individual to individual and present various and diverse symptoms, but there is a problem that it is difficult to cope with such various symptoms of gastrointestinal diseases widely.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a licorice methanol extract-containing gastrointestinal drug that is excellent in safety and has a wide range of efficacy against various symptoms of gastrointestinal diseases.

Means and Action for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and as a result, a methanol extract of licorice having a different mechanism of action against gastrointestinal diseases, Combination use of antacids such as citrate, magnesium aluminate silicate, magnesium carbonate, etc. and mucosal repair agents such as L-glutamine, azulene, etc., results in a gastric acid secretion inhibitory action and a mucosal repair action of a methanol extract of licorice. Acid synergistic effect of gastric acid neutralizing action, mucosal covering action, gastrointestinal mucosal repair accelerating action, mucus production / secretion action, and mucosal protection action of mucosal repair agents, showing superior and widespread effects on gastrointestinal diseases Therefore, they have found that they can respond to various symptoms of gastrointestinal diseases widely, and have accomplished the present invention.

Therefore, the present invention relates to sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, methanol extract of licorice.
Synthetic aluminum silicate, aluminum hydroxide gel, magnesium silicate, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitated product, aluminum glycinate, volley, funnel extract, synthetic hydrotal Site, at least one antacid selected from the group consisting of magnesium aluminate silicate and magnesium aluminate metasilicate, and sorbitol sulfate, dextran, carboxymethyl ester, methyl methionine sulfonium chloride, sodium copper chlorophyllin, potassium potassium chlorophyllin , Aldioxa, gastric mucin, dextran sulfate aluminum salt, L-glutamine, water-soluble azulene, sucrose sulfate aluminum The combination of at least one or more of the mucosal repair agent selected from the group consisting of a is to provide a gastrointestinal agents characterized by.

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

The gastrointestinal drug of the present invention contains a methanol extract of licorice, an antacid and a mucosal repair agent as described above.

Here, as the methanol extract of licorice, those obtained by extracting licorice with methanol, and those obtained by extracting with methanol and then fractionating and purifying with an alkali, an acid or the like are suitably used. Extraction and fractionation methods from licorice are described, for example, in Japanese Patent Publication No. 41-15714.
A known method such as the method described in JP-B-42-4674 can be used.

Further, the antacids to be incorporated in the gastrointestinal drug of the present invention include sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, synthetic aluminum silicate, aluminum hydroxide gel, magnesium silicate, aluminum hydroxide / magnesium carbonate mixed dry gel, water Aluminum oxide / magnesium carbonate / calcium carbonate coprecipitated products, aluminum glycinate, borei, funnel extract, synthetic hydrotalcite, magnesium silicate aluminate and magnesium metasilicate aluminate are used. Synthetic aluminum silicate, aluminum hydroxide gel, magnesium silicate, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitation product,
Aluminum glycinate, volley, synthetic hydrotalcite, magnesium aluminate silicate and magnesium aluminate metasilicate are preferably used, and funnel extract, which is not non-absorbable, is also preferably used. Furthermore,
Among these, synthetic hydrotalcite, which also has a mucosal coating effect, magnesium aluminate silicate,
Magnesium aluminate metasilicate is more preferably used.

Further, as mucosal repair agents, sorbitol sulfate, dextran, carboxymethyl ester, aluminum salt of dextran sulfate having an anti-pepsin action, methylmethionine sulfonium chloride having a tissue repair promoting action, sodium or potassium copper chlorophyllin, aldioxa, mucosal protection Gastric mucin having an action, L-glutamine having a mucus production and secretion promoting action, water-soluble azulene having a mucous membrane covering and astringent action, and sucrose sulfate aluminum salt having an ulcer lesion protecting action are used. Methyl methionine sulfonium chloride, which has a tissue repair promoting action,
Copper chlorophyllin sodium or potassium, ardioxa, sorbitol sulfate with anti-pepsin activity,
Dextran, carboxymethyl ester, aluminum salt of dextran sulfate, gastric mucin having mucosal protective action, L-glutamine having mucosal production and secretion promoting action, water-soluble azulene having mucosal coating and astringent action, ulcer lesion protecting action The sucrose sulfate aluminum salt having is preferably used. Further, among these, L-glutamine, which has a mucus production and secretion promoting action that prevents gastric juice, which is a strong acid, from entering the gastric mucosa in the gastric cavity, has a mucosal coating and astringent action. Water-soluble azulene, sucrose sulfate aluminum salt having an ulcer lesion protection effect, and the like.

The amount of each of the above components is not particularly limited, but if the daily dose of the gastrointestinal drug of the present invention is 3600 to 4500 mg / day, the amount of the licorice methanol extract is 8 to 45% (% by weight or less). The same), particularly preferably 13 to 35%. Similarly, the amount of the antacid is not limited, and is appropriately selected depending on the type and the like. However, it is preferably 0.5 to 70%, more preferably 8 to 45%, and also the compound of the mucosal repair agent. There is no limitation on the amount, and the amount is appropriately selected according to the type and the like.
Preferably it is 0.04 to 60%, more preferably 0.06 to 35%.

Here, what is most important for improving the pharmacological effect by using an antacid and a mucosal repair agent together with the methanol extract of licorice is the mixing ratio of these agents. Its compounding ratio is preferably 1: 0 by weight based on the licorice methanol extract.
01 (antacid): 0.001 (mucosal repair agent) to 1: 3.5: 3.5, particularly preferably 1: 0.03: 0.005 to 1: 2.7: 2.7.

In addition, the gastrointestinal drug of the present invention contains, as shown in Examples described later, other gastric stricters, analgesics,
Flavors and the like may be blended.

The dose to the human body (adult) is usually 600 to 1600 mg / day for the licorice methanol extract, and the antacids and mucosal repair agents are the daily doses at the time of clinical use for image transmission. It should be noted that specific examples of the prescription will be shown in Examples described later.

The dosage form of the gastrointestinal drug of the present invention is not particularly limited, and can be formulated into various dosage forms such as tablets, granules, capsules, liquids, and dry syrups.

In the case of producing tablets, in addition to the above-mentioned components, components usually used in producing tablets, for example, sugars such as lactose, mannitol and sucrose, celluloses such as microcrystalline cellulose, calcium sulfate, calcium phosphate, sedimentation Inorganic salt agents such as calcium carbonate, excipients such as starch such as corn starch and potato starch, and various types of starch microcrystalline cellulose, carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, etc. as disintegrants Cellulose derivatives, Explotab (trade name), starch derivatives, etc., and magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated vegetable oil, and the like can be used as lubricants. In addition,
When a binder is required, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, starch paste and the like are used as a binder, and if necessary, sweeteners such as sucrose, glucose, and saccharin sodium,
A sour flavoring agent such as citric acid, tartaric acid and malic acid and a flavoring agent such as a flavor may be added. In addition, as the tableting method, a direct tableting method in which the main component and the above-mentioned additives are simply mixed and tableted is also used, and after kneading into dry granules by compression molding or by adding a mixed solvent such as water, the mixture is kneaded. After granulation, drying and wet granulation,
An indirect tableting method for producing a compressed tablet may be used, or a method combining these methods may be used. Furthermore, tablets can be film-coated or sugar-coated to mask the taste of the tablets.

In order to produce granules, dry granules or wet granules can be obtained by the granulation method described in the above-mentioned tablet production method.

In the case of a capsule, even if only the main drug component is filled in a capsule, or an appropriate amount of an excipient, a lubricant is added to the capsule, or after filling into a capsule as in the above tablet,
Capsules can also be filled.

When a liquid preparation is used, it can be produced by dissolving and dispersing the component of the present invention in an aqueous solution containing a sweetener, a thickener, a surfactant, an antifoaming agent, a preservative, a flavor and the like. Also,
Granules containing the above components, such as dry syrup, can be prepared in advance and dissolved and dispersed in water when taken. Here, specific examples of the above additives include sugars such as sucrose, D-mannitol, glucose, and fructose, and synthetic sweeteners such as saccharin sodium and aspartame, and a thickener such as methylcellulose. ,
Cellulose derivatives such as sodium carboxymethylcellulose and hydroxypropylcellulose; synthetic high molecular compounds such as polyvinylpyrrolidone, sodium polyacrylate and polyvinyl alcohol; sodium alginate;
Natural polymer substances such as gelatin, xanthan gum, guar gum, tragacanth gum, and gum arabic;
Examples of surfactants include oral surfactants such as polysorbate 80 and HCO-60, and examples of antifoaming agents generally include silicones, and examples of preservatives include sodium benzoate, methyl parahydroxybenzoate, and propyl paraoxybenzoate. Are used. Further, it is possible to add an appropriate sterilization operation such as steam sterilization or intermittent sterilization to the prepared liquid preparation.

The additives that can be added to the gastrointestinal drug of the present invention are not limited to those described above, and other additives can be used according to the purpose and the like.

Effect of the Invention As described above, the gastrointestinal drug of the present invention has better efficacy against gastrointestinal diseases as compared to the case where a methanol extract of licorice is used alone, and has usefulness against gastrointestinal diseases. It is suitable as a drug with a high level of odor.

Next, examples will be shown, and the effects of the present invention will be specifically described.

Experimental Example 1 (Effect on Acceleration of Healing of Acetic Acid Ulcer) Sprague-Dawley male 6-week-old rats were fasted overnight and then opened under ether anesthesia.
30μ of acetic acid was injected locally using a microsyringe below the serosa at the pyloric gastric body border. The stomach was replaced and the abdomen was sutured. The drugs shown in Table 1 were orally administered every day (once a day) for 11 days from the next day. The day after the last administration, the stomach was removed, and the area (mm ² ) of the ulcer was measured. The results are shown in Table 1. Each drug was used after being dissolved in a 0.5% carboxymethylcellulose sodium salt solution (CMC-Na).
The control group received only a 0.5% CMC-Na solution.

The purified product of the licorice methanol extraction fraction was FM-100.
(Trade name: Asparon, manufactured by Nippon Gunpaku Co., Ltd.) was used.

As is evident from the results in Table 1, the purified licorice methanol extract fraction showed a tendency to reduce the ulcer area in a dose-dependent manner, and the synthetic hydrotalcite as an antacid and the L-glutamine and azulene as mucosal repair agents showed a tendency to decrease. 13.1, 14.5, 19.2 respectively
% Of the ulcer area, but when the purified licorice methanol extract fraction and these synthetic hydrotalcites, L-glutamine, and azulene were used in combination, they acted synergistically and exhibited a high healing promoting effect. Was shown.

That is, conventionally, the additive and synergistic actions have been considered only to be ideal and difficult to handle quantitatively.
um (“Pharmacology,” Oxford University Press Londo
n, 1953.) provides an empirical study method,
Using this, many investigators examined the interaction of the two-drug combination and theoretically supported empirical decisions. According to that, when the A and B drugs are used in combination, if the corresponding amounts of the two drugs exhibiting the same effect are (A) and (B), respectively, If so, it is concluded that if the left and right sides are equal, it is an additive action. Based on the same theory, the effect of the combined use of the purified licorice methanol extract and the antacid or mucosal repair agent was examined as shown in Table 1. As a result, 100 m of the purified licorice methanol extract was purified.
When combined use of g / kg with synthetic hydrotalcite, L-glutamine, and azulene 1/2 day amount resulted in inhibition rates of 25.5, 24.3, and 31.6%, each exceeding the inhibition rate alone, and a synergistic effect was confirmed.

The effect of the combination of the three drugs is described by Takagi et al. (Pharmaceutical Magazine, 88
According to the theoretical formula (6), 779.1968), for the two drugs A and B, 1/3 or 2/3 of the mixture (a / 3 + 2b / 3) consisting of a / 3 and 2b / 3.
And 2c / 3 or c / 3 of the third drug C,
A method was adopted in which the compounding ratio of the A and B drugs was reversed to 2a / 3 + b / 3, and a third drug was added in the same ratio as before, and the licorice methanol extract fractionated purified product 67 mg / kg + synthesis As a result of conducting an experiment in a combination group of hydrotalcite 178 mg / kg + L-glutamine 67 mg / kg, the effect is more synergistic than the two-drug combination which was more synergistic than alone,
A synergistic effect with the combination of the three drugs was confirmed. In addition, when a significant difference test (t-test) was performed on the ulcer healing promoting effect of each drug administration group with respect to the control group, only the three-drug combination group had a significant difference of 99% or more in reliability (p <0.01) Only with the combination of the three drugs, a significant ulcer healing promoting effect was observed with respect to the control.

This is thought to be due to the synergistic effects of different pharmacological actions on the tissue re-performance of the damaged site necrotized by acetic acid, but this acetic acid ulcer experiment was a good preclinical model of human peptic ulcer. Therefore, it is considered to be highly correlated, and it is more useful to promote the healing of peptic ulcer by taking a purified licorice methanol extract fractionated product and adding an antacid and a mucosal repair agent such as L-glutamine. In addition to high potency, the dose of the licorice methanol extract fractionated purified product is reduced, leading to a reduction in side effects.

Experimental Example 2 (Protective effect of hydrochloric acid / ethanol against acute gastric mucosal damage) Using a 7-week-old Donryu male rat, after fasting overnight, orally administering the drugs shown in Table 2, and 30 minutes after that, gastric mucosal damage 5 ml / kg of 150 mM hydrochloric acid / 60% ethanol solution
Was orally administered. After leaving for 1 hour, remove the stomach,
The length of the band-like bleeding injury that occurred in the glandular stomach mucosa was measured. The results are shown in Table 2.

Each drug was used after being dissolved in a 0.5% carboxymethylcellulose sodium salt solution (CMC-Na).

The control group received only a 0.5% CMC-Na solution.

As shown in Table 2, the licorice methanol-extracted and purified fraction prevented the mucosal damage caused by the mucosal necrotic substance, hydrochloric acid / ethanol, in a dose-dependent manner, and the inhibition rates were 44.1 and 76.6%, respectively. In addition, among the antacids, magnesium metasilicate aluminate, which has a mucosal covering effect, and synthetic hydrotalcite alone have a significant mucosal damage preventive effect with a reliability of 99% or more (p <0.01) in the t-test against the control. Although magnesium carbonate showed a tendency to prevent mucosal damage, it was confirmed that a synergistic effect was exhibited by using these drugs in combination with the purified licorice methanol extract fraction.

That is, as a result of examining the combined effect of the two and three drugs using the same theory as in Example 1, the group in which magnesium metasilicate aluminate was added to the purified licorice methanol extract fractionation showed a significant prevention rate of 75.3%. An effect was shown, which was a stronger inhibition rate than each of the single effects. Such an effect was also observed in the group in which magnesium carbonate and synthetic hydrotalcite were used in combination with the purified licorice methanol extract fraction. Magnesium aluminate was 4/9 and azulene was 2/9, but the suppression rate was 80.6
% And the two-drug combination are more synergistic, and such an effect is considered to be due to the synergistic addition of the mucosal covering effect and the mucosal repairing effect to the gastric mucosal cell protective effect of the purified licorice methanol extract. A clinically useful preventive and therapeutic effect on gastric mucosal damage caused by drugs, alcohol, and stress was confirmed.

Hereinafter, prescription agents and formulation examples are shown as examples, but the present invention is not limited to the following formulation examples and formulation examples. In each prescription example, the amount of each drug was shown in terms of daily dose. The purified licorice methanol extract fraction used in each example is the same as that used in the above experimental examples.

Formulation Example 1 Licorice methanol extract fractionated purified product 800 mg Magnesium aluminate silicate 1200 Roth extract 30 L-glutamine 1200 Clove oil 10 Lemon oil 15 Total 3255 mg / day Formulation example 1 30 g of roast extract, 10 g of clove oil and 15 g of lemon oil It was added to 345 g of microcrystalline cellulose and mixed well to produce an adsorbed powder. On the other hand, a solution prepared by dissolving 24 g of polyvinylpyrrolidone (K-30) in 140 g of water was added to 1.2 kg of L-glutamic acid, kneaded with a kneader, crushed and granulated, and dried at 40 ° C. for 16 hours to produce granules. . 400 g of the above adsorbed powder, granules 12
24 g and licorice methanol extraction fraction purified product 800 g, magnesium aluminate 1.2 kg, crystalline lactose 450 g, potato starch 100 g, magnesium stearate 26 g were mixed,
One tablet (350 mg) was tableted using this mixed powder to obtain a tablet according to the above-mentioned Formulation Example 2.

Formulation Example 2 Licorice methanol extract fractionated purified product 800 mg Synthetic hydrotalcite 1200 L-glutamine 900 Dimethylpolysiloxane 60 l-Menthol 60 Biodiastase 120 Kankyo powder 200 Fried powder 72 Total 3412 mg / day Formulation example 2 Synthesized with 60 g of dimethylpolysiloxane Hydrotalcite 1
200 g was mixed to produce a trituration. To 1260 g of this trituration, 800 g of a purified product of the licorice methanol extract, L-glutamine 900
g, l-menthol 60 g, biodiastase 120 g, kankyo powder 200 g, fennel powder 72 g, lactose 300 g, potato starch 200 g, talc 50 g, magnesium stearate 30 g, and after mixing, use a capsule filling machine to make a No. 0 capsule.
490 mg was filled to produce a capsule according to Formulation Example 4 above.

Formulation Example 3 Licorice methanol extract fractionated purified product 900 mg Polymigel 600 Magnesium carbonate 420 L-Glutamine 900 Dust powder 180 Ginger powder 90 Gentiana powder 60 l-menthol 30 Total 3180 mg / day Formulation example 3 Distilled water 20 in sucrose 5 kg, D-sorbitol solution (70
%) 10 kg, sodium benzoate 250 g, sodium carboxymethylcellulose 200 g, polyvinylpyrrolidone 100
g, 50 g of polysorbate 80 and 100 g of fragrance were added and dissolved. Then, 1060 g of the mixture of the components shown in Formulation Example 5 above was added and mixed. The total amount was 50, and the mixture was homogenized with a TSK homogenizer. did. After filling, the suspension was sealed with an aluminum cap and sterilized in an autoclave at 121 ° C. for 20 minutes to produce a suspension.

Formulation Example 4 Licorice methanol extract fractionated product 600 mg Synthetic hydrotalcite 1500 azulene 6 thump 300 mint 200 lipase AP6 30 Total 2636 mg / day Formulation example 5 Licorice methanol extract fractionated product 800 mg Roth extract 30 Gastric mucin 800 Dry water Aluminum oxide gel 600 Glucose 300 Cellulase 60 Total 2590 mg / day Formulation Example 6 Licorice methanol extract 900 mg Aldioxa 150 Synthetic hydrotalcite 450 Calcium carbonate 630 Biodiastases 1000 60 Wig powder end 45 Caulis end 210 Total amount 2445 mg / day Prescription example 7 Licorice Purified product of methanol extraction fractionation 810 mg Magnesium aluminate metasilicate 900 Calcium carbonate 600 Aldioxa 120 Takasutase 90 Kankyo powder 150 Total 2670 mg / day

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/725 A61K 31/725 33/06 33/06 33/08 33/08 33/10 33/10 35/56 35/56 35/78 35/78 R ACL ACLJ (56) References JP-A-48-88213 (JP, A) JP-B-48-8485 (JP, B1) JP-B-46-13035 (JP, B1)

Claims (1)

(57) [Claims] 1. A methanol extract of licorice is added to sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, synthetic aluminum silicate, aluminum hydroxide gel, magnesium silicate, a mixed dry gel of aluminum hydroxide and magnesium carbonate, aluminum hydroxide. Magnesium carbonate
At least one or more antacids and sorbitol sulfates selected from the group consisting of calcium carbonate coprecipitate, aluminum glycinate, boray, funnel extract, synthetic hydrotalcite, magnesium aluminate silicate and magnesium aluminate metasilicate Dextran, carboxymethyl ester, methyl methionine sulfonium chloride, copper chlorophyllin sodium, copper chlorophyllin potassium, aldioxa, gastric mucin, dextran sulfate aluminum salt, L
-A gastrointestinal drug comprising a combination of at least one mucosal repair agent selected from the group consisting of glutamine, water-soluble azulene and sucrose sulfate aluminum salt.