JPH07316062A - Medicinal composition - Google Patents

Abstract

PURPOSE:To obtain a medicinal composition having more excellent effect than the case in which the compound is alone used and useful as a medicine for treating and preventing gastrointestinal diseases such as anorexia and indigestion by adding a compound useful as a ulcer treating agent and an various kinds of gastrointestinal crude drugs. CONSTITUTION:This medicinal composition contains (A) one or more kinds of crude drugs for gastrointestinal medicines [preferably one or more kinds of crude drugs selected from a group consisting of KANZOU(root of Glycyrrhiza glabra), KEIHI (bark of Cinnamomum cassia), UIKYOU(fruit of Foeniculum vulgare), NINJIN(ginseng), SHUKUSHA(fruit of Amomum xanthioides), RYOUKYOU(galanga root), OUREN(rhizome of Coptis japonica) and CHOUJI (bud of clove) and (B) a compound of the formula (Q is phenyl, p-halogeno- phenyl, o-alkoxy-p-formylphenyl, etc.) or its salt. Furthermore, the compound of the formula is preferably 4-(2-carboxyethyl)phenyl-trans-4- aminomethylcyclohexanecarboxylate hydrochloride(cetraxate hydrochloride).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition useful as a gastrointestinal drug.

[0002]

BACKGROUND OF THE INVENTION A compound represented by the general formula (I) or a salt thereof is conventionally known to be useful as a therapeutic agent for ulcer (see Japanese Patent Publication No. 56-32296), but a drug having a more excellent effect. Is desired.

[0003]

DISCLOSURE OF THE INVENTION As a result of intensive studies, the present inventors have found that by adding various gastrointestinal medicinal herbs to a compound represented by the general formula (I) or a salt thereof, the general formula (I) The present invention has been completed by finding that it is possible to provide a drug having a superior effect as compared with the compound shown or a salt thereof alone.

[0004]

The present invention provides one or more gastrointestinal herbal medicines, and general formula (I).

[0005]

[Chemical 2]

[In the formula, Q is a phenyl group, p-halogeno-
Phenyl group, o-alkoxy-p-formylphenyl group, bisphenyl group, p-carboxyvinylphenyl group, p-carboxyphenyl group, p- (β-aminocarboxyethyl) -phenyl group, p-carboxy lower alkylphenyl group Alternatively, it means a β-naphthyl group. ] The pharmaceutical composition containing the compound shown by these, or its salt,

[0007] One or more kinds of gastrointestinal herbal medicines selected from the group consisting of licorice, cinnamon, fennel, carrots, shukusha, ryokkyo, laurel and clove, and a compound represented by the general formula (I) or a salt thereof. A pharmaceutical composition containing

A pharmaceutical composition in which the compound represented by the general formula (I) or a salt thereof is 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate or a salt thereof.

A pharmaceutical composition in which the compound represented by the general formula (I) or a salt thereof is 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride (cetraxate hydrochloride),

Licorice, Keihi, Fennel, Carrot, Shuksha, Ryokyo, Ouren, Clove and 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate
A pharmaceutical composition containing hydrochloride (cetraxate hydrochloride),

1 part by weight of liquorice, 1 part by weight of cinnamon, 0.3 part by weight of fennel, 0.25 part by weight of carrot, 0.25 part by weight of shuksha, ryokyou
0.15 parts by weight, Ouren 0.1 parts by weight, clove
A pharmaceutical composition containing 0.01 part by weight and 1 part by weight of 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride (cetraxate hydrochloride), and the above-mentioned pharmaceutical composition. Regarding gastrointestinal medicine.

[0012] In general, "herbal medicines" include "herbal medicines" such as animals and plants themselves, parts of animals and plants, or their secretions.
And, the "extract" of the crude drug is meant, and in the present invention, "crude drug" means the crude drug or the extract of the crude drug alone or the mixture of the crude drug and the extract of the crude drug.

The form of the herbal medicines can be freely adjusted as required, and for animals and plants or parts thereof, they can be cut or crushed into small pieces, small pieces, or ground into powder. . The animal and plant secretions and crude drug extracts can be used as they are, or can be concentrated to a viscous liquid, and can be dried to be used as a solid.

[0014] Here, a powder of a certain crude drug is usually called "the crude drug powder".
For example, the powder of "Asenyak" is called "Asenyak powder". The oily substance (extracted oil) extracted from a certain crude drug is generally called "crude oil", and the extracted oil of "Fennel" is called "Fennel oil". An extract of a certain crude drug refers to a liquid leached by adding an appropriate leaching agent to a crude drug, or a liquid obtained by concentrating the leaching liquid, and specific examples thereof include "extract" and "tincture". Examples of the extract of "" include "Ginger extract" and "Ginger tincture". In particular, dried "extract" is usually called "dry extract". For example, dried extract of "liquorice" is "dried extract of licorice".
Say.

In general, crude drugs can have the same effect in any form as long as they have the same animal and plant origin.

The gastrointestinal medicinal herbs according to the present invention include:
Specifically, Acenyak, Anise fruit, Aloe, Fennel, Turmeric, Ubay, Uyaku, Engosaku, Enmeisou, Ogon, Owakaku, Ouren, Processed Ginger, Gajutsu, Cuckoo, Columbus Root, Kankyo, Licorice, Pheasant,
Kujin, keihi, ketsumeishi, gentian, genosho, kouzin, koboku, goshuyu, pepper, quintet,
Colombo, Conzurango, Hawthorn, Hawthorn, Yamana, Perilla, Peony, Shuksha, Ginger,
Owl, blue skin, red sprout, iris root, centaurium grass, zebrafish, soup, soybean, large incense, rhubarb, rhododendron, carrot, clove, chimpi, capsicum, spruce, animal gall (bear gall, beef gall), nigaki, nutmeg, carrot Mentioned herbs such as mint, mint, hijah, juniper, hops, homika, hyacinth leaves, mokko, yakchi, sardine, ryutan and ryekyo, and extracts of the listed herbs. The gastrointestinal medicinal herbs according to the present invention should not be limited to the above-mentioned herbs.

Among the gastrointestinal medicinal herbs according to the present invention, licorice, cinnamon, fennel, carrot, shuksha,
Preference is given to the crude drugs of Ryokyo, Chironomus and Clove, and extracts of these crude drugs.

Among the compounds represented by the general formula (I) or salts thereof according to the present invention, the most preferable one is 4-
(2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride, whose general name is cetraxate hydrochloride,
It is a compound represented by the following chemical structural formula.

[0019]

[Chemical 3]

In the pharmaceutical composition of the present invention, one or more kinds of herbal medicines for gastrointestinal administration selected from the group consisting of licorice, cinnamon, fennel, carrot, shukusha, ryokkyo, laurel and clove, and the general formula ( A pharmaceutical composition containing the compound represented by I) or a salt thereof is preferable.

[0021] One or more kinds of herbal medicines selected from the group consisting of licorice, cinnamon, fennel, carrot, shukusha, ryokkyo, laurel and clove, and 4- (2-carboxyethyl) phenyl trans. Particularly preferred is a pharmaceutical composition containing 4-aminomethylcyclohexanecarboxylate hydrochloride (hereinafter referred to as cetraxate hydrochloride).

Specific examples of preferred pharmaceutical compositions include:
For example, a pharmaceutical composition containing licorice and cetraxate hydrochloride, a pharmaceutical composition containing cinnamon and cetraxate hydrochloride, a pharmaceutical composition containing fennel and cetraxate hydrochloride, a pharmaceutical composition containing carrot and cetraxate hydrochloride, A pharmaceutical composition containing Shuksha and cetraxate hydrochloride, a pharmaceutical composition containing Ryokyo and cetraxate hydrochloride,
Pharmaceutical composition containing laurel and cetraxate hydrochloride, clove and pharmaceutical composition containing cetraxate hydrochloride, licorice, carrot, lauren and pharmaceutical composition containing cetraxate hydrochloride, licorice, cinnamon, carrot, lauren and cetraxate hydrochloride A pharmaceutical composition containing fennel, fennel, chrysanthemum, Ryokyo, clove and a pharmaceutical composition containing cetraxate hydrochloride, cinnamon flesh, fennel, Shuksha, Ryokyo and a pharmaceutical composition containing cetraxate hydrochloride, cinnamon, fennel, Pharmaceutical composition containing Shuksha, Ryokyo, clove and cetraxate hydrochloride, and licorice, cinnamon, fennel, carrot, Shuksha, Ryokyo, Coptis, clove and setra hydrochloride And the like pharmaceutical composition containing insert.

As the most preferable pharmaceutical composition, there can be mentioned a pharmaceutical composition containing licorice, cinnamon, fennel, carrot, Shuksha, Ryokyo, laurel, clove and cetraxate hydrochloride.

As preferred forms of gastrointestinal medicinal herbs in a preferred pharmaceutical composition, licorice is dried licorice extract, keihi is keihi powder, fennel is fennel powder, carrot is carrot powder, and shukusha is shukusha powder. Ryokyo can be Ryokyo powder, Oren can be Oren powder, and Clove can be Clove powder. The form of the crude drug for gastrointestinal medicinal product in the present invention should not be limited to these.

In a preferred pharmaceutical composition of the invention,
As a substitute for carrot, ginseng or Chixectus carrot may be used, as a substitute for lauren, Oataku or Colombo may be used, and as a substitute for Shuksha, Ozaku or Yakuchi may be used.

The pharmaceutical composition of the present invention can be administered orally or parenterally, preferably orally.

The pharmaceutical composition of the present invention can be formulated into various dosage forms by known formulation techniques, and appropriate formulation additives can be added to the formulation. Specific examples of formulation additives Examples thereof include excipients, binders, disintegrants, emulsifiers, suspending agents, preservatives, antioxidants, corrigents and flavors.

The formulation additives that can be added to the formulation must be harmless to the living body such as the human body at the dose of the formulation, and do not impair the effects of the active ingredients of the formulation.

Excipients that can be used include lactose, starch, crystalline cellulose and light anhydrous silicic acid.

Examples of binders that can be used include gum arabic powder, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose and polyvinyl alcohol.

Examples of disintegrants that can be used include starch, carboxymethyl cellulose and carboxymethyl cellulose calcium.

Examples of emulsifiers that can be used include polysorbate 80 and cholesterol.

Examples of suspending agents that can be used include sodium alginate and polyvinylpyrrolidone.

Preservatives that can be used include ethyl paraoxybenzoate, butyl paraoxybenzoate and the like.

Examples of antioxidants that can be used include ascorbic acid and tocophenol.

Examples of flavoring agents that can be used include sucrose, honey and the like.

Specific examples of formulations include powders, fine granules,
Oral preparations such as granules, pills, tablets, capsules, suspensions, syrups, elixirs and limonades can be mentioned. Preference is given to powders, fine granules and granules.

The composition ratio of the pharmaceutical composition of the present invention is preferably 0.001 to 100 parts by weight, more preferably 0 to 100 parts by weight, with respect to 1 part by weight of cetraxate hydrochloride, each crude drug for gastrointestinal medicinal drug is a crude drug. 0.005 to 10 parts by weight, more preferably 0.01 to 3 parts by weight.

In the most preferred pharmaceutical composition of the present invention, the composition ratio of each component of licorice, cinnamon, fennel, carrot, shukusha, ryekyo, weren, clove and cetraxate hydrochloride is as follows: It is as follows. That is,

The amount of licorice is preferably 0.05 to 10 parts by weight, more preferably 0.1 to 5 parts by weight, and still more preferably 0.25 to 2 parts by weight.

The content of Keihi is preferably 0.1 to 15 parts by weight, more preferably 0.2 to 6.5 parts by weight, and still more preferably 0.5 to 2.5 parts by weight.

The amount of fennel is preferably 0.02 to 4 parts by weight, more preferably 0.05 to 2 parts by weight, and still more preferably 0.1 to 0.8 parts by weight.

The amount of carrot is preferably 0.02 to 4 parts by weight, more preferably 0.05 to 2 parts by weight, and still more preferably 0.1 to 0.8 parts by weight.

The amount of shukusha is preferably 0.02 to 4 parts by weight, more preferably 0.04 to 2 parts by weight, and further preferably 0.1 to 0.8 parts by weight.

The amount of Ryokyo is preferably 0.01 to 2.5 parts by weight, more preferably 0.02 to 1.5 parts by weight,
It is more preferably 0.05 to 0.5 parts by weight.

The amount of the oren is preferably 0.01 to 2.5 parts by weight, more preferably 0.02 to 1.5 parts by weight.
05 to 0.5 parts by weight.

Clove is preferably 0.001 to 2.5 parts by weight, more preferably 0.002 to 1.5 parts by weight,
It is more preferably 0.005 to 0.5 part by weight.

Among them, 1 part by weight of licorice and Keihi
1 part by weight, fennel 0.3 parts by weight, carrot 0.
A pharmaceutical composition containing 25 parts by weight, 0.25 parts by weight of Shuksha, 0.15 parts by weight of Ryokyo, 0.1 parts by weight of lauren, 0.01 parts by weight of clove and 1 part by weight of cetraxate hydrochloride is highly preferred.

The dose of the pharmaceutical composition of the present invention depends on the dose of cetraxate hydrochloride, which is one component of the pharmaceutical composition of the present invention, and the dose of cetraxate hydrochloride is usually 100 per adult / day. ~ 2000 mg is suitable, preferably 200-800 mg.

In order to take the pharmaceutical composition of the present invention orally, it should be divided into 1 to 4 doses, and
It can be taken between meals, after meals, or before going to bed. The dose can be appropriately increased or decreased depending on the age, body weight and symptoms.

The pharmaceutical composition of the present invention is used as a prophylactic drug for treating gastrointestinal diseases, preferably as a gastrointestinal drug. , Stomach weakness, eating too much, drinking too much, heartburn,
Examples include stomach upset, chest tightness, vomiting (nausea, nausea) and belching.

The present invention will be described in more detail below with reference to Examples and Test Examples, but the present invention should not be limited to these.

[0053]

【Example】

 1. Example 1 A fine granule (1 package) was prepared according to the following formulation.

Ingredients Cetraxate hydrochloride 200 mg Licorice dry extract 40 mg Keihi powder 200 mg Fennel powder 60 mg Carrot powder 50 mg Shuksha powder 50 mg Ryokyo powder 30 mg Ouren powder 20 mg Clove powder 2 mg Formulation additive 648 mg Total 1300 mg Dried licorice extract 40 mg
Equivalent to mg.

2. Examples 2 to 23 Various additives were added to the compositions shown in Table 1 and Table 2 to prepare a composition.

[0056]

[Table 1]

[0057]

[0058]

[Table 2]

[0059]

[Test example]

1. Effects on rat hydrochloric acid / ethanol gastric injury model 6-week-old Kbl: Wist fasted under water for 24 hours
Ar rats (weighing 204 to 248 g, Kitayama Labes Co., Ltd.) were divided into 10 groups so that the average weight was almost uniform in each group, and hydrochloric acid / ethanol (80% ethanol containing 150 mM hydrochloric acid) 5 ml / kg was orally administered. One hour after the administration of hydrochloric acid / ethanol, the rat was sacrificed by cervical dislocation and the stomach was excised. The excised stomach excretes the contents, and the cardia is ligated with an arterial clamp to remove saline 1
After injecting 0 ml, the pylorus side was ligated with a clip, and 2 more
Fixed in% formalin solution. Next, an incision was made along the large incision, and the length (mm) of each lesion expressed in the glandular stomach was measured per animal, and the lesion lengths were totaled. The drugs in the table were orally administered 30 minutes before the administration of hydrochloric acid / ethanol. The results are shown in Tables 3 and 4. The damage occurrence rate and the inhibition rate in the table were calculated by the following formulas.

Damage occurrence rate (%) = (number of animals expressing damage / number of animals used) × 100

Inhibition rate (%) = (1-average value of damage coefficient of test drug / average value of damage coefficient of vehicle control) × 100

[0062]

[Table 3]

[0063]

[Table 4]

As is clear from Table 3, in the composition group in which the gastrointestinal medicinal herbs were added to cetraxate hydrochloride, the suppression of damage expression was recognized as compared with the group to which cetraxate hydrochloride was administered alone. Especially, a gastrointestinal herbal medicine mixture consisting of dried licorice extract, cinnamon powder, carrot powder and laurel powder, or gastrointestinal tract consisting of licorice dried extract, cinnamon powder, carrot powder, laurel powder, fennel powder, shuksha powder, ryokkyo powder and clove powder The composition group in which the medicinal herb mixture was added to cetraxate hydrochloride showed excellent suppression of damage expression. Therefore, it was confirmed that the blending of the gastrointestinal medicinal herb mixture and cetraxate hydrochloride had a synergistic effect as compared with each of them alone.

In the results of the experiment shown in Table 3, excellent suppression of the expression of gastric damage was recognized, and cetraxate hydrochloride, dried licorice extract, cinnamon garlic powder, carrot powder, laurel powder, fennel powder, shukusha powder, ryokkyo powder and clove powder were found. The composition ratio of the components in the composition was made constant, and the dose of the composition was examined (Table 4). As is clear from Table 4, cetraxate hydrochloride 12 mg / kg, licorice dried extract 2.4 mg / k
g, cinnamon powder 12 mg / kg, carrot powder 3 mg / k
g, Ouren powder 1.2 mg / kg, Fennel powder 3.6
mg / kg, Shuksha powder 3 mg / kg, Ryokyo powder 1.8 mg / kg, and Clove powder 0.12 mg / k
g, and cetraxate hydrochloride 40 mg
/ Kg, licorice dried extract 8mg / kg, cinnamon powder 4
A composition consisting of 0 mg / kg, carrot powder 10 mg / kg, laurel powder 4 mg / kg, fennel powder 12 mg / kg, Shuksha powder 10 mg / kg, Ryokyo powder 6 mg / kg and clove powder 0.4 mg / kg was excellent. Inhibition of damage was observed.

2. Effect on Patient's Subjective Symptoms and Objective Findings (Human Clinical Trial) 162 human patients with chronic gastritis and the like having subjective symptoms such as anorexia, heartburn, leaning, and stomach / abdominal distension were used as subjects. The test formulation of Example 1 was orally administered to a test subject once a day, three times a day (three packets a day, total 3900 mg) before meals, and the administration was continued for 1 to 4 weeks. Subjective symptoms and objective findings were examined before and after administration. The results are shown in Table 5.

[0067]

[Table 5]

As is clear from Table 5, administration of the pharmaceutical composition of the present invention resulted in nausea, belching / belching, anorexia, heartburn, epigastric pain, epigastric tenderness, leaning / stomach heaviness and abdominal distention. The symptoms of patients with symptoms such as feeling were improved.

[0069]

The pharmaceutical composition of the present invention comprises rat hydrochloric acid
It showed excellent effects in ethanol gastric injury model and human clinical trials. Therefore, these results show that the pharmaceutical composition of the present invention is excellent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 35/78 W 8217-4C 31/215 ACL 9455-4C // (A61K 35/78 31: 235 )

Claims (7)

[Claims] 1. One or more kinds of herbal medicines for gastrointestinal medicinal purposes,
And the general formula (I): [In the formula, Q is a phenyl group, a p-halogeno-phenyl group,
o-alkoxy-p-formylphenyl group, bisphenyl group, p-carboxyvinylphenyl group, p-carboxyphenyl group, p- (β-aminocarboxyethyl)-
It means a phenyl group, a p-carboxy lower alkylphenyl group or a β-naphthyl group. ] The pharmaceutical composition containing the compound shown by these, or its salt. 2. One or more gastrointestinal herbal medicines selected from the group consisting of licorice, cinnamon, fennel, carrot, shukusha, ryokkyo, laurel and clove, and a compound represented by the general formula (I) or Pharmaceutical composition containing the salt 3. A pharmaceutical composition in which the compound represented by the general formula (I) according to claim 1 or 2 or a salt thereof is 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate or a salt thereof. Composition 4. The 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate or the salt thereof according to claim 3, is 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate. Pharmaceutical composition which is hydrochloride (cetraxate hydrochloride) 5. Licorice, cinnamon, fennel, fennel, carrot, shukusha, ryokkyo, laurel, clove and 4- (2-carboxyethyl) phenyl trans-
Pharmaceutical composition containing 4-aminomethylcyclohexanecarboxylate hydrochloride (cetraxate hydrochloride) 6. A kanzo (1 part by weight), a keihi (1 part by weight), a fennel (0.3 part by weight), a carrot (0.25 part by weight), a shukusha (0.25 part by weight), and a ryokyou.
0.15 parts by weight, Ouren 0.1 parts by weight, clove
Pharmaceutical composition containing 0.01 part by weight and 1 part by weight of 4- (2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride (cetraxate hydrochloride) 7. A gastrointestinal drug comprising the pharmaceutical composition according to any one of claims 1 to 6.