JPH01180824A - Treating and preventing agent for liver disease - Google Patents

Abstract

PURPOSE:To obtain a treating and preventing agent for liver disease containing cubebin as an active ingredient and having high safeness and excellent liver disorder protecting action. CONSTITUTION:Cubebin is incorporated as an active ingredient, blended with ordinary preparation carrier and prepared according to ordinary method to provide the aimed product. The agent can be prepared in form of oral use such as inhalant, granule, capsule or syrup and parenteral use such as suppository, injection, external medicine or drops. The agent is administered in dose of 0.1-1,000mg, preferably 5-100mg/adult once-several times daily. Cubebin can be extracted and isolated from Cinnamomum porrectum, but obtained also by synthesis, etc.

Description

[Detailed description of the invention] [Industrial application field] TECHNICAL FIELD The present invention relates to therapeutic and preventive agents for liver diseases.

[Background of the invention and prior art]

The etiology, pathological features, and pathophysiology of liver diseases are not uniform, and there are many unknown points. Therefore, it is currently extremely difficult to develop therapeutic agents for liver diseases.

Glycyrrhizin preparations are currently widely used and clinically evaluated for the treatment and prevention of liver diseases. However, although glycyrrhizin preparations are said to be effective in treating liver disorders, cirrhosis, hepatitis, and liver protection after surgery, their medicinal efficacy is not very strong, and they also have the problem of steroid-like side effects. Furthermore, although glycyrrhizin preparations are intravenous preparations, they have the disadvantage of being ineffective when administered orally.

Under these circumstances, there is a strong desire for the development of new liver disease treatment and prevention agents that are highly safe and have clear medicinal efficacy.

In view of these circumstances, the present inventors undertook exploratory research in order to develop a new therapeutic agent for liver diseases.

The present inventors used plants used in the private sector as materials,
After extensive research over a long period of time, we have surprisingly discovered that cubebin, which will be described later, exhibits a protective effect against liver damage and is therefore useful as a treatment and prevention agent for liver diseases, leading to the completion of the present invention.

Therefore, an object of the present invention is to provide a novel agent for treating and preventing liver diseases.

[Structure and effects of the invention]

The cubebin used in the present invention has the following structural formula (1).

Qubebin, for example, Cinnamomum porre
Qubebin can be extracted and isolated from Ctum, but in the present invention, cubebin obtained by extraction, synthesis, or any other method can also achieve the purpose of the present invention.

The physicochemical properties of cubebin, the active ingredient of the present invention, obtained by the following extraction method are as follows.

(1) Melting point mp(t); 133-134 colorless needle crystals (methanol) (2) Nuclear magnetic resonance PMR (90 MHz, ds-DMS
O) δppm; 1.7-2.8 (6H, m), 3
', 3 (LH, s, -DH), 3.3 to 4.0 (2H
, m), 5.0 (IH, d), 5.92 (4H, s
.

-0CH20-, X2), 6.4 to 6.9 (6 days,
m) (3) Infrared absorption IR (v: RA o L,
cm-+); 3320 (OH), 160
5 (4) Mass spectrometry FD-MS (ff, /Z); 37
9 (M''+Na), 356 (An example of a method for extracting cubebin, the active ingredient of Maa's invention, is as follows.

Extraction> Dried leaves of Cinnamomum porrectum 1
0 kg was immersed in methanol 4H at 60° C. for 5 hours and then filtered to obtain a methanol extract. The extraction residue was further immersed in methanol 40β at 60°C for 5 hours, and then filtered.
A methanol extract was obtained.

The resulting exudates from both sleeves were combined and the solvent was distilled off under reduced pressure on a water bath at 50°C to obtain 1.6 kg of a dark green residue.

After dissolving 1.6 kg of the obtained residue in ethyl acetate IH, 20β of water was added, stirred, and then heated overnight to separate the ethyl acetate layer. The obtained ethyl acetate solution was distilled off under reduced pressure on a 50°C water bath to obtain about 900 g of a residue.

Using 200 g of the obtained residue, silica gel column chromatography was performed using chloroform-methanol (30:1) as a developing solvent, and the residue was divided into five fractions.

Add chloroform-methanol (3
0:1) as a developing solvent, the mixture was divided into three parts by silica gel column chromatography. The second two fractions were recrystallized with dichloromethane-methanol to obtain 13 g of cqbebin as colorless needle crystals.

Next, in order to explain the effects of the present invention in detail, the effect of cubebin on a D-galactosamine liver injury model will be shown.

(1) Experimental animal Fischer strain (F344) male Usoto, 7 weeks old,
Each group had a body weight of 170 to 180 g, 8 mice in the control group, and 4 mice in the test drug group.

(2) Preparation of liver damage land D -(+)-Galactosamine hydrochloride was dissolved and diluted in physiological saline, and the final concentration was adjusted to 250 mg/- by adjusting the pH of 10N-Na ice water solution to 2-/kg. It was administered once subcutaneously.

(3) Preparation and administration method of test drug The test drug was suspended in 1%-7 Tween 80 and administered orally by force twice, 1 hour before and after D-galactosamine administration.

(4) Measuring method of liver damage and expression of activity 48 hours after administration of D-galactosamine, 50 μβ blood was collected from the tail vein of the rat. Transfer to a spiran containing 50 μl of 3.2% sodium citrate aqueous solution, mix well, and then rotate at 3000 rpm.
, followed by cold centrifugation for 5 minutes. The P-GOT value of the obtained plasma was measured using the measurement kit "Iatrozyme TA-LQ J (enzyme method). In addition, the blood clotting time of whole blood collected from the rat tail vein was measured using the hepaplastin test. .

The results are shown in Table 1.

The activity of each sample was expressed as the inhibition rate of liver damage caused by D-galactosamine administration.

Table 1 From the above pharmacological experiment examples, it is clear that cubevin, the active ingredient of the present invention, has a protective effect on liver damage.

The rat acute liver injury model prepared above using D-galactosamine as the inducing drug is histologically very similar to that of human viral hepatitis, and is used clinically to treat chronic hepatitis. It has been reported that glycyrrhizin preparations suppress acute liver injury in rats induced by D-galactosamine (for example, Kiwami Okita et al., Liver.

16 (9), 42 (1975)), it is an extremely reliable model.

In addition to the D-galactosamine liver injury model, the cubevin of the present invention can also be used in the carbon tetrachloride liver injury model, Propionibacterium acnes-lipopolysaccharide (P,
It also showed inhibitory activity against a model of fulminant hepatitis (acnes-LPS).

Furthermore, cubebin used in the present invention is highly safe (300 mg/kg of cubebin was orally administered to mice, but no toxicity was observed).

Therefore, due to the nature of the disease, the present invention often requires continuous administration over a long period of time, but the present invention is also of high value in this sense.

When cubebin, the active ingredient of the present invention, is administered as a liver disease treatment/prevention agent, it may be administered orally as a powder, granule, capsule, syrup, etc. Although it may be administered parenterally as an external preparation or infusion, it is usually administered orally. The dosage varies significantly depending on the severity of symptoms, age, type of liver disease, etc., but is usually about 0.1 to 1000 mg, preferably 2 to 500 mg, and more preferably 5 to 100 mg per day for adults.
Administer in one to several divided doses per day.

When formulating the drug, it is produced by a conventional method using a conventional pharmaceutical carrier.

That is, when preparing a solid preparation for oral use, excipients are added to the crude drug, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent,
After adding flavoring agents and the like, it is made into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.

Examples of excipients include lactose, cornstarch, white sugar,
Glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., and binders include, for example, polyvinyl alconope polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, seratin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, Dextrin, pectin, etc. are used as lubricants, such as magnesium stearate, talc, polyethylene glycol,
Silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint, aromatic acid, peppermint oil, dragonbrain, cinnamon powder, etc. are used. It will be done. Of course, these tablets and granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

Applicant's agent Kaoru Furutani

Claims (1)

[Claims] A liver disease treatment/prevention agent containing cubebin as an active ingredient.