JPH0413629A - New remedy for anaphilaxia of intestinum crassum - Google Patents

Abstract

PURPOSE:To obtain a remedy for anaphilaxia of intestinum crassum containing beta-eudesmol as an active ingredient and having activities derived from both of calcium antagonism and anticholin action. CONSTITUTION:The aimed remedy containing beta-eudesmol contained in Atratylodes lancea important as crude drugs for stomach as an active ingredient. Dose of beta-eudesmol is preferably 100-1000mg/adult day. beta-Eudesmol can be isolated by extracting Atratylodes Lancea with an organic solvent such as lower alkyl ketone, lower fatty acid ester or lower fatty acid ether and subjecting the concentrate of the extract to column chromatography using silica gel, alumina, etc., as an absorbent, recrystallization, molecular distillation, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel therapeutic agent for large intestine hypersensitivity containing β-eudesmol as an active ingredient.

<Problems to be solved by conventional technology and invention> β-
Although it has been known since ancient times that eudesmol is contained in an important herbal medicine for stomach health, it was not known that β-eudesmol has a therapeutic effect on colon hypersensitivity.

There is a constant need for new and useful therapeutic agents for colon hypersensitivity.

<Means for solving the problem> Traditionally, opium alkaloids such as morphine and papaverine, or anticholinergic drugs such as athrobin were the mainstream antidiarrheal agents, but in recent years calcium blockers that are more selective for the intestine have been used. CF, V, Defeud, etc. are attracting attention.
is arid M,O,Christen Tren
dsin Pharmacological 5cie
nces 10.170-172 (1989)].

The present inventors are conducting a screening test to find a drug that has both the anticholinergic effect that has traditionally been said to be associated with natural products, especially crude drugs used in Chinese herbal medicine, and the calcium antagonistic effect that has recently attracted attention as a mechanism of action. Atratylode has been important as a stomachic herbal medicine since ancient times.
It has been found that β-eudesmol, which is contained in plants such as S. Lancea, rhizomes of the Asteraceae family, is an active ingredient.

The present invention, which was completed as a result of the above findings, relates to a therapeutic agent for colon hypersensitivity containing β-eudesmol as an active ingredient.

β-eudesmol is extracted from the blue spores using organic solvents such as lower alcohols, lower alkyl ketones, lower fatty acid esters, and lower aliphatic ethers, and the concentrated extract is subjected to column chromatography using silica gel, alumina, etc. as an adsorbent. It can be isolated by subjecting it to , recrystallization, molecular distillation, etc. Recrystallization can be performed using, for example, 50% methanol water.

Examples of lower alcohols include methanol and ethanol, examples of lower alkyl ketones include acetone and methyl ethyl ketone, examples of lower fatty acid esters include ethyl acetate, and examples of lower aliphatic ethers include ethyl ether and isopropyl ether. .

The therapeutic agent for colon hypersensitivity of the present invention can be in the form of a tablet, capsule, powder, granule, or liquid form such as a sterile solution or suspension for oral or parenteral administration.

Tablets, granules, and powders are suitable for oral administration of the active ingredient of the present invention, and granules and powders can be made into unit dosage forms as capsules, if necessary. Orally administered solid preparations contain conventional excipients (anhydrous silicic acid, synthetic aluminum silicate, lactose, sugar, corn starch, microcrystalline cellulose, etc.), binders (gum arabic, gelatin, polyvinylpyrrolidone, etc.), and lubricants (stearic acid magnetic acid, etc.). jade, talc, silica, etc.), disintegrants (potato starch, carboxymethyl cellulose calcium, etc.)
, wetting agents (polyethylene glycol, sorbitan monooleate, sodium lauryl sulfate, etc.). The tablets may be coated according to conventional methods. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, etc., or may be dry products that can be redissolved in a suitable vehicle prior to use. Such liquid formulations contain commonly used emulsifiers (lecithin, sorbitan monooleate, etc.), emulsifying aids (turpinto syrup, methylcellulose, gelatin, etc.), non-aqueous vehicles (
(coconut oil, peanut oil, etc.), antioxidants, colorants, flavorings, etc.

Liquid preparations may be obtained by dissolving or suspending them in sterile vehicles for use in parenteral administration. Solutions are prepared by dissolving the active compound in an injection vehicle, filtering sterilization, and sealing in ampoules.

The pharmaceutical composition of the present invention containing β-eudesmol as an active ingredient is effective in treating large intestine hypersensitivity. The dosage of this pharmaceutical composition varies depending on the degree of colon hypersensitivity, the patient's constitution and age, the administration method, etc., but approximately 100 μg to approximately 1000 a+g of β-eudesmol per day for adults is appropriate. .

<Example> Next, a production example, a colon hypersensitivity treatment test example, a safety test example, and a dehiscence example of β-eudesmol will be shown.

Production Example Production of β-Eudesmol 3 kg of blueberries were immersed in 15ff of acetone, left to stand for 3 days, and then filtered. The filtrate residue was subjected to the same operation twice more, and all the filtrates were combined and concentrated and dried under reduced pressure at below 40°C to obtain 144 g of extract. The extract was subjected to silica gel chromatography [Silica gel 60, manufactured by Merck & Co., Ltd., developing solvent: n-hexane:ethyl acetate-15:1 (
volume)] and crudely fractionated into 5 fractions. TLC (silica gel 60Fzs-1 developing solvent: n-
Hexane: Ethyl acetate = 10:1 After confirming the volume, the two fractions were combined and subjected again to silica gel chromatography [Silica gel 60, manufactured by Merck & Co., Ltd., developing solvent: n-hexane: Ethyl acetate = 10:1 ( 20.6 g of β-eudesmol was obtained.

Test example: CaC1z and cha in isolated guinea pig ileum
Effect of rbachol on contraction Experimental method To prepare a guinea pig ileum specimen, kill the guinea pig by exsanguination, remove the ileum approximately 40 cm in length from about 15 cm above the ileocecal region, wash the contents with nutrient solution at 37°C, and remove the ileum. About 2
1 specimen. The specimen was prepared by applying a load of 1 g to the ileum9.
Krebs vented with a mixed gas of 5%0□-5%COt
-) It was hung in a 25.D Magnus tank (kept at 37°C) filled with Lenseleit solution. The resulting changes in muscle tone were recorded on a polygraph via an isometric transducer. In the following tests, β-eudesmol was dissolved in 99.5% ethanol, and the influence of the solvent was evaluated as a control. The obtained results are expressed as the standard error above the mean (S, E,) for each group, and the significant difference from the control group is expressed as s tu
den t- was tested using the test.

Test Example I Effect on CaCf2 contraction KCf (5
Ca containing EGTA (0,1mM) plus
C1! The test drug was added to the isolated guinea pig ileum in the Z removal solution. 10 minutes later CaCfz (0,1-2
, 5a+M) was added cumulatively to obtain a dose-effect curve. The contraction rate was calculated by setting the average value of the contraction force in the control group when 2.5 mM of CaClt was added as 100%.

The results are shown in FIG.
M completely inhibited this contraction.

Test Example 2 Effect of carbachol on contraction In isolated guinea pig ileum, carbachol was 10-7
Shows contraction action from M or above 3X10-' to 10-4
showed the maximum contraction response. Therefore, carbachol
The effects of β-eudesmol treatment for 10 minutes were investigated by creating a dose-response curve by cumulatively adding the doses until the maximum response was obtained from lo-'M. The contractile response was compared with carbachol in the control group.
The average value of shrinkage force when adding 10-5M is 100
Calculated as %.

The results are shown in FIG. 2, and β-eudesmol suppressed the maximum contraction of the carbachol dose-response curve more than 3×10 −5 M in a dose-dependent manner.

Although not shown in the diagram, a similar study was conducted using guinea pig aorta, but the reaction was much weaker than that in the ileum.

Test Example 3 Acute toxicity test - group 10 of DA-Y male mice (body weight 20-22 g)
β-eudesmol was orally administered to the rats at a dose of 2,000 mg/kg, and their survival was observed for one week, but no deaths were observed.

Formulation Example 1 Tablets Tablets were prepared by mixing the following ingredients and molding the resulting mixture with a tablet press.

Amount per tablet (mg) β-Oides Mall 50 Cornstarch 60 Crystalline cellulose 100 Carboxymethyl cellulose 65 Formulation example 2 Granules Granules were prepared using the following ingredients and following a conventional method.

β-Eidesmol 50 ■ Crystalline Cellulose 20 ■ Silicic Anhydride
10 ■ Magnesium stearate 130 ■
Effects of the Invention> The present invention provides a therapeutic agent for colon hypersensitivity whose activity is derived from both calcium antagonistic action and anticholinergic action.

[Brief explanation of the drawing]

Figure 1 shows the therapeutic effect of β-eudesmol on colorectal hypersensitivity (antagonistic effect on CaCfz contraction in the ileum). Figure 2 and 4 show the therapeutic effect of β-eudesmol on colorectal hypersensitivity (
(antagonistic effect on carbachσl contraction in the ileum). Patent applicant RiRa Co., Ltd.

Claims (1)

[Claims] A therapeutic agent for colon hypersensitivity containing β-eudesmol as an active ingredient.