JPS59106421A - Cholagogue - Google Patents

Abstract

PURPOSE:To provide a low-toxic cholagogue containing atractylodine as an active component. CONSTITUTION:SOJUTSU is the rhizome of Atractylodes lancea or its variety belonging to Compositae family, and is a crude drug used from ancient times as a stomachic, a drug for controlling intestinal function, diuretic, and diaphoretic. It has been found that atractylodine which is a main component of SOJUTSU has cholagogic action. Atractylodine can be prepared e.g. by extracting SOJUTSU with an organic solvent (e.g. methanol), treating the extract by silica gel column chromatography, eluting with n-hexane,distilling out the solvent, and recrystallizing the remaining yellow solid with methanol. Preferable effective dose as cholagogue for adult is usually 25-50mg of atractylodine per dose, and the drug is administered once a day. The toxicity is considerably low; i.e. its acute toxicity is >=3,000mg/kg of LD50 for mouse.

Description

[Detailed description of the invention] The present invention relates to choleretic agents.

Sojura [Ao, N] is a member of the Asteraceae family (Compositae).
)'s Hongbaokela (Attract71odes 1a
It is the rhizome of ncea De CanmdoL or its variants, and is a herbal medicine that has been used since ancient rice as a stomachic, intestinal regulator, diuretic, and diaphoretic.

The Ministry of the Invention has discovered that atrafuthyrosin, a product of Soudura, exhibits choleretic effects, and has completed the present invention based on this new knowledge. It is a choleretic agent.

Atrafuthyrosin, which is the active ingredient of the choleretic agent of the present invention, is
For example, the extract obtained by extracting 100 mg of molasses, which can be obtained as follows, using methanol, ethanol, diethyl ether, acetone, ethyl acetate, etc. in an organic bath (Shi), is subjected to column chromatography using silica gel, One yellow solid obtained by bathing with n-hexane and distilling off the bathing agent is recrystallized with methanol to obtain pale yellow columnar crystals σ) atrafuthyrosine. Extraction is performed at room temperature.
It can be heated for 4 hours, but 30~goCVc
It is preferable to carry out heating.

le) A specific example of the production of atraftyrosin is shown below.
It is as follows: 0 Ingredients 1 example 1 S amount of Sodura 30, i.e. isomb methanol, ethanol (9,5-1), diethyl ether, acetone, ethyl acetate, etc.Q) Organic bath agent is added. Then, the organic bath agent to be used Q) is heated under reflux for 1 hour at a temperature S to 10C lower than the boiling point (digested when using diethyl ether),
Filter the extract, then dry the filtrate and roll up the dried extract powder with silica gel. The bath agent was subjected to column chromatography using 4-layer chromatography, developed with n-hexane, and fractionated into lomb portions. One bottle of atrafuthyrosin'``on'&?!
Then, it was recrystallized from methanol to obtain 720 m9 of atrafuthyrosin as pale yellow columnar crystals.

The properties of atraftyrosin obtained as described above were as follows, and were consistent with the literature values [Pharmaceutical Journal, Shima, 1999].

Atraftyrosin Color, Properties: Light yellow columnar crystals Melting point; S0~53° Ratio T69K: Ca]', 0+0° (C= /
-00, MeOIH) Elemental analysis value (C10H,.0) Calculated value C%) C: g! ;, ≦9. H:3. ! ;3Q
:g, 7g Actual value (%) C:gk-73,H;j,jjQ:g
, 70 Next, the fact that atraftyrosin exhibits a choleretic effect will be explained with reference to experimental examples and their results.

Example weight 300! Wistar spotted rats before and after iI-7
A group of 70 animals was used. After this rat was fasted for an hour and a half, the abdomen was incised, a polyethylene cannula was inserted into the bile duct, and after a 7-hour stabilization period, atrafuthylodine, which was prepared in Example 1 of 'AIM' described above, was inserted into the duodenum. /
00 m97Mf, and 700 m/ml of sodium V-dehydrocholate were administered, and the bile volume 30 minutes before administration was taken as a factor of 100, and the amount of bile effluxed from then on was determined.As a control, the above-mentioned Using the same rats as
The above-mentioned colleague inserted a polyethylene cannula into the bile duct and measured the amount of bile without administering drugs. The choleretic effect of atraftylodine was compared with that of the control and the administration of sodium tehydrochol. The results are shown in the figure. Note that the results in the drawings show the average of 0 rats from 7 groups. From the results shown in the drawings, it was confirmed that atraftyrosin has a remarkable choleretic effect in the same manner as sodium dehydrocholate.

Next, the acute effects of atraftyrosin will be explained by showing experimental examples and their results.

Example dd-Y 70 male mice were used in 7 groups, and the drugs described in the central experiment and z'c were administered to these mice. The number of deaths was observed for two days after administration, and the LD50 value was calculated from the number of deaths. I asked for it. However, food and water were provided ad libitum during the observation period.

The results are shown in Table 1. In addition, L in Table 1
The Dso value shows the average value of 7 groups lθ animals.

Table 1 From the results shown in Table 1, the LD5o value of atraftyrosin is 3000 mLi/L or more, while the LD50 value of sodium dehydrocholate is 10! ;0rfL
9/2, which indicates that the toxicity of atraftyrosin is quite low. Although it varies depending on the patient's age, weight, and level of medical opinion, it is usually administered as atrafuthyrosin per dose for adults.
25~somg, taken up to 7 times a day]j1%']
It is recognized that

Atraftyrosin can be used as it is as a choleretic agent, but it can also be used as a choleretic agent by adding excipients, adjuvants, etc. that are used in ordinary formulations and dispersing it according to the usual method of manufacturing formulations.
], granules, tablets, capsules, and other formulations.

Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 Atraftyrosin, jiP was mixed with lactose 9 and 5 and stearin late magnesium 7, and this mixture was compressed using a single-shot tablet machine to form tablets with a diameter of -011 nm and a weight of about -3. The slug tablets were taken, crushed with an oscillator, and sieved to obtain good granules with particles of 20 to SO mesh.

This granule is taken 7 times) to 2 times per day (equivalent to 2!i to S01η as atractylodine) depending on the symptoms.

Example 2 Atrafuthyrosin 23y- was mixed with crystalline cellulose 19S and stearin-coated magnesium, and this mixture was compressed using a single-shot tablet machine to form tablets with a diameter of 7 mW+, u u
A drug of SnL9 was prepared.

One tablet of Honmeishanri contains atraftyrosin. This tablet is taken 7 times to 2 tablets 787 times depending on the symptoms. Example 3 Attractylodine is mixed with potato starch, j/3
Mix with ノ, add water and knead, / mrh
The mixture is granulated using a screen having an S mesh to form granules. After drying, size the particles on the No./A mesh side.

Next, 109% of stearin magnesium is mixed with the granules and compressed into tablets. Manufacture of 01119 tablets.

This 7 tablets contain 2 atrafuthyrosin! ; Contains UK/. This tablet can be taken 7 times 7 times according to the symptoms.
Take 7 times.

Example 4 Atractylodin S, Lactose Retriever 3?2 and Steer 1J-
/[1 magnesium and 2 f were mixed and filled into hard capsules of 300 m9 each. Book Capsule 1] / Atrafuthyrosin in the capsule! ; Contains 01119. This capsule is to be taken once a day according to the symptoms.

[Brief explanation of the drawing]

Claims (1)

[Claims] A choleretic agent whose active ingredient is atraftyrosin.