JPH03123734A - Antipollakiuria agent - Google Patents

Abstract

PURPOSE:To obtain an antipollakiuria agent containing extract of a specific Chinese drug or active substance thereof as active ingredient and having anticholinergic and calcium antagonismic actions together. CONSTITUTION:The objective antipollakiuria agent containing extract of Atractylodes lancea or extract of Magnolia avabota extracted with a polar solvent such as lower alcohol, lower alkyl ketone, lower fatty acid ester or lower aliphatic ether or beta-eudesmol which is an active substance thereof as an active ingredient. Dose thereof is preferably 300-3000mg/adult/day (as dried extract) or 100-1000mg/adult/day (as beta-eudesmol).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an anti-urinary agent containing a specific herbal medicine extract or its active substance as an active ingredient.

[Prior art and problems to be solved by the invention] There are many Chinese herbal medicines that have been used since ancient times as anti-urinary agents, such as Gosha Kenkigan, Gorinsan, Shokenchuto, Dai Corporations, etc. are known.

However, the Chinese medicine Ao$ (Asteraceae, 8 tractyloids)
It was not known that extracts of Magnolia eslancea and related plants) and Magnolia avabota (Magnoliaceae, Magnolia avabota) have an anti-frequent urinary effect.

In addition, drugs with anticholinergic effects, such as oxybutynin, are currently used as anti-urinary agents, but because they act on the central nervous system and have side effects such as dry mouth, they are not specifically effective for the bladder. The development of drugs is desired. More specifically, in recent years, there has been a demand for drugs that exhibit specific antagonistic effects on bladder contraction as anti-urinary agents and also have anticholinergic and calcium antagonistic effects.

[Means to solve the problem]

As part of the process of evaluating Chinese herbal extracts from a modern pharmacological perspective, the present inventors conducted research in light of the recent interest in drugs that combine anti-acetylcholine and calcium antagonistic effects as anti-urinary agents. It was recognized that the extract obtained by extracting 3ft and Namibian with a polar solvent has both such properties, and that such an extract is also effective in a frequent urination model test on animals. Further examination of the active ingredients in this extract revealed that β-eudesmol (β-e
udesmol).

The present invention, which was completed as a result of the above findings, relates to an anti-frequent urinary agent containing as an active ingredient an extract of Aspergillus spp. As mentioned above, the anti-urinary agent of the present invention is prepared using an animal reagent (in vitro) using rats.
In vivo), it shows an antagonistic effect on bladder contraction and a significant antagonistic effect on carbachol and hyperpotassium contraction, and has anti-acetylcholine and calcium antagonistic effects in combination.

Next, the present invention will be explained in more detail.

The Aochi extract and the Koboku extract may be either the soft extract or the dry extract mentioned in the "Extract agent" section of the 11th revised Japanese Pharmacopoeia "General Preparations".

The production of Soshuang and Koboku extracts is carried out using lower alcohol,
It consists of extracting, for example, coarsely chopped Aspergillus or Namibaku with a polar solvent such as a lower alkyl ketone, lower fatty acid ester, lower aliphatic ether, etc., concentrating it, and drying as necessary to obtain a soft extract or dry extract. .

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. .

Isolation of β-eudesmol from Cangzhuang and Nakuboku is performed by first extracting with an organic solvent such as the lower alkyl ketone, lower alcohol, lower fatty acid ester, lower aliphatic ether, etc., and then applying the concentrate of this extract to silica gel, alumina, etc. This can be carried out by subjecting it to column chromatography, recrystallization, molecular distillation, etc. using as an adsorbent. For example, recrystallization is 50
% methanol in water. As a reference example, an example of extraction and separation from Aspergillus japonica is shown.

The anti-urinary agents of the present invention can be in liquid form such as tablets, capsules, powders, granules or sterile solutions or suspensions 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. Solid preparations for oral administration contain conventional excipients (silicic anhydride, synthetic aluminum silicate, lactose, sugar, cornstarch, microcrystalline cellulose, etc.) and binders (gum arabic,
gelatin, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, silica, etc.), disintegrants (potato starch, calcium carboxymethylcellulose, etc.), and wetting agents (polyethylene glycol, sorbitan monooleate, sodium lauryl sulfate, etc.). Can be done. 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 preparations contain commonly used emulsifiers (lecithin, sorbitan monooleate, etc.), emulsifying aids (sorbit syrup, methylcellulose, gelatin, etc.), non-aqueous vehicles (coconut oil, peanut oil, etc.), antioxidants, and colorants. agent,
It can contain flavoring agents and the like.

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, which contains the extract of Aspergillus orientalis as an active ingredient, is effective in treating frequent urination. The dosage of this pharmaceutical composition varies depending on the degree of frequent urination, the patient's constitution and age, the method of administration, etc., but it is approximately 3 ml of dry extract per day for adults.
00mg to about 3000mg.

or about 100 mg to about 1 as β-eudesmol
000mg is appropriate.

〔Example〕

Next, production examples, anti-urinary effect test examples, safety test examples, and formulation examples of extracts and β-eudesmol will be shown.

Fissure fl Preparation of Blue Persimmon Extract 3 kg of coarsely chopped Blue Persimmon was soaked in acetone 152, allowed to stand for 3 days, and then filtered. During this time, I stirred it occasionally.

The filtration residue was subjected to the same operation twice more, and all the filtrates were combined and concentrated under reduced pressure at 40° C. or lower to obtain 144 g of soft extract.

1.1 Example E. Preparation of β-eudesmol 3 kg of C. persica was immersed in acetone li, left for 3 days, and then filtered. During this time, I stirred it occasionally. The filtration residue was subjected to the same operation twice more, and all the filtrates were combined and concentrated and dried under reduced pressure 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 was crudely fractionated into 5 fractions.

After confirming that β-eudesmol was contained as a main component in the 4th and 5th fractions (confirmation of β-eudesmol was made using T, L, C, [Silica gel 60F) with the standard product. z s <, Merck & Co., developing solvent n-hexane:ethyl acetate 10:1 (volume)] and by matching the Rf values), the two parts were combined and subjected to silica gel chromatography again [Silica gel 60, Merck & Co., Ltd.]. Made by company,
Developing solvent: n-hexane:ethyl acetate=10:1 (volume)] to obtain 20.6 g of β-eudesmol.

Anti-frequent urinary effect of W upper extract [antagonistic effect on carbamylcholine contraction in the bladder] Wistar male rats (body weight 200 g) were placed in the midline of the lower abdomen under urethane (500 mg/kg, i, p) anesthesia. After making an incision, the bladder was exposed. A cannula is then inserted through the urethra, the urethra is tied off, and the intravesical pressure is reduced to 10 cm).
z.

Warmed Ringer's solution was injected into the bladder to prevent this from occurring, and a low-pressure transducer was connected to the other end of the cannula for measuring intracystic pressure, and changes in the bladder were recorded on a recorder via the low-pressure transducer. After the intravesical pressure became constant, the bladder was contracted with carbamylcholine (10-'M), and the height of contraction at that time was observed on a recorder.

Thereafter, the height of contraction after administration of Cangchuan extract and Koboku extract was expressed as contraction inhibition rate ('1) and evaluated.

The results are shown in Figure 1, and Wakasui extract and Koboku extract were found to have significant effects, indicating their usefulness for frequent urination.

m Anti-urinary action of β-eudesmol (antagonistic action against carbamylcholine contractile action in the bladder) Wistar female rats (body weight 200 g) were anaesthetized with urethane (500 mg/kg, i, p,) and their lower abdomen was injected in the midline. After making an incision, the bladder was exposed. Then, a cannula was inserted through the urethra, the urethra was tied off, and the intravesical pressure was reduced to 10 cm8.
Warmed Ringer's solution was injected into the bladder so that the pressure did not exceed 0, and a low-pressure transducer was connected to the other end of the cannula to measure intracystic pressure, and changes in the bladder were recorded on a recorder via the low-pressure transducer. . After the intravesical pressure became constant, the bladder was contracted with carbamylcholine (10-'M), and the height of contraction at that time was observed on a recorder. After that, β-eudesmol was suspended in gum arabic,
After intraperitoneal administration, the bladder was contracted with carbamylcholine every 5 minutes, and the height of contraction was observed on a recorder until 90 minutes after administration. Then, the contraction height before β-eudesmol administration was set to 100.
%, and the contraction height after administration of β-eudesmol was expressed as a contraction inhibition rate (%) and evaluated.

The results are shown in FIG. 2, and β-eudesmol was found to have a strong and significant inhibitory effect, indicating its usefulness for frequent urination. As a comparative example, oxyputinin, which is used as an anti-urinary agent, was used. The dosage was 300 mg/kg for both β-eudesmol and oxybutynin.

M Anti-urinary effect of β-eudesmol (antagonistic effect on ion contraction at high concentration in the bladder) The test method was conducted according to Example 1, and instead of carbamylcholine used in Example 1, KCI (50mM ) was used to contract the bladder, and the contraction height before β-eudesmol administration was set as 100%, and the contraction height after β-eudesmol administration was expressed as a contraction inhibition rate (%) for evaluation.

The results are shown in FIG. 3, and β-eudesmol was found to have a strong and significant inhibitory effect, indicating its usefulness for frequent urination. As a comparative example, oxybutynin, which is used as an anti-urinary agent, was used. The dosage was 300 mg/kg for both β-eudesmol and oxybutynin.

R3 supporting example D. Acute toxicity test - group 10 of aa-y male mice (body weight 20-22 g)
2,000 mg/kg of Aspergillus persica extract was orally administered to the rats, and their survival and death were observed for one week, but no deaths were observed. A similar test was conducted on Koboku extract and it was confirmed that it was safe.

Acute toxicity test Group 10 of day male mice (weight 20-22 g)
β-eudesmol was orally administered to the animals at 2000 mg/kg and their survival was observed for one week, but no deaths were observed.

Tablets are prepared by mixing the following ingredients and molding the resulting mixture using a tablet press.

Tablet Hikari no N (mg) Active ingredients 50 Corn starch 60 Crystalline cellulose
100 carboxymethyl cellulose 65 total
275 The active ingredient is Cangzhuang extract, Aobaku extract or β-eudesmol.

Sniper granules Granules are prepared using the following ingredients and following a conventional method.

Active ingredients: 50 mg crystalline cellulose 20 mg silicic anhydride
10 mg Magnesium stearate 130 mg Total 210 mg The active ingredients are Cangzhuang extract, Aobaku extract, or β-eudesmol.

〔Effect of the invention〕

The anti-urinary agent of the present invention is characterized in that its activity is derived from both anticholinergic action and calcium antagonistic action.

[Brief explanation of the drawing]

FIG. 1 shows the anti-frequent urinary effect (antagonistic effect on carbamylcholine contraction in the bladder) of Cangchuan extract and Koboku extract. FIG. 2 shows the anti-urinary effect (antagonistic effect on carbamylcholine contraction in the bladder) of β-eudesmol. FIG. 3 shows the anti-urinary effect of β-eudesmol (antagonistic effect on ion contraction at high concentrations in the bladder).

Claims (1)

[Scope of Claims] An anti-urinary agent containing as an active ingredient an extract of Aspergillus orum or β-eudesmol extracted with a polar solvent.