JPH032122A - Glycyrrhizin suppository - Google Patents

Abstract

PURPOSE:To increase the transferability of glycyrrhizin in blood to improve the usefulness thereof as a hepatic disease remedy by administrating the glycyrrhizin as a suppository. CONSTITUTION:A glycyrrhizin suppository such as an ordinary anal suppository or a suppository prepared by filling a suspension of the glycyrrhizin in a liquid oily basic agent or an ointment-like mixture thereof in a soft capsule or tube is administered in a rectum. The content of the glycyrrhizin in the suppository is preferably 10-500mg and the suppository is administered one-several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to a suppository containing glycyrrhizin or a salt thereof, and a therapeutic agent for liver disease characterized by administering the suppository.

``Prior art, problems to be solved by the invention, and means to solve the problems'' Glycyrrhizin or its salts, alone or in combination with amino acids, can be used to treat liver diseases such as hepatitis, liver damage, drug eruptions, and allergic bronchitis. It is used in oral and injectable forms to treat allergic diseases such as inflammation and various types of inflammation.

However, it has been reported that when administered orally, glycyrrhizin is not detected in the blood due to decomposition by gastric acid and metabolism during the first pass through the liver (Therapeutics, 7 (5) 704
(1981)). In addition, when injections require administration over a long period of time, such as in patients with liver disease, the burden on the patient becomes large. For this reason, it was necessary to investigate a method for increasing the blood concentration of glycyrrhizin while minimizing the burden on patients even when administering glycyrrhizin for a long period of time.

The inventors of the present invention have conducted intensive studies on this problem and have found that this problem can be solved by using glycyrrhizin or its salts as a suppository.

"Disclosure of the Invention" The present invention relates to a suppository containing glycyrrhizin or a salt thereof, and a therapeutic agent for liver disease characterized by administering the suppository.

The above-mentioned salts may be any pharmaceutically acceptable salts, and include, for example, metal salts such as potassium and sodium salts, ammonium salts, and the like.

In addition, the liver disease referred to in the present invention refers to alcohol, viruses,
Liver diseases and disorders caused by various factors such as drugs, poisons, bile duct obstruction, and disorders of the hepatic circulatory system. Glycyrrhizin or its salts are used alone or in combination with amino acids in the form of oral preparations or injections to treat liver diseases such as hepatitis and liver failure, pharmacology, allergic diseases such as allergic bronchitis, and various inflammations. There is.

However, it has been reported that when administered orally, glycyrrhizin is not detected in the blood due to decomposition by gastric acid and metabolism during the first pass through the liver (Therapeutics, 7(5), 704(1).
981)). In addition, when injections require administration over a long period of time, such as in patients with liver disease, the burden on the patient becomes large. For this reason, it was necessary to investigate a method that would reduce the burden on patients even when administering glycyrrhizin for a long period of time and also increase the blood concentration of glycyrrhizin.

As a result of intensive studies on this problem, the present inventors have found that this problem can be solved by using glycyrrhizin or its salts (hereinafter collectively referred to as glycyrrhizin) as the main ingredient.

As a method for examining whether a certain drug is absorbed through the rectum, a method is used in which a solution of the drug is administered into the rectum of a rat (Biopharmaceutical Experiments, p. 162, published by Seishi Chikuin, 1985). Detailed data will be discussed in the section on absorption experiments, but glycyrrhizin was not detected in plasma after oral administration or duodenal administration.
Glycyrrhizin was detected in plasma after rectal administration.

From these experiments, the present inventors discovered that glycyrrhizin is absorbed from the rectum and migrates into the blood, and found that the effects of glycyrrhizin can be effectively exerted by forming it into a base ingredient.

For patients with chronic hepatitis who require long-term administration of drugs, the use of injections was painful and required hospital visits, which placed a heavy burden on the patients. However, since the main drug can be administered by oneself and is painless, it is clear that the burden on the patient will be reduced.

It has already been mentioned that glycyrrhizin is useful for the treatment of many diseases such as liver diseases, allergic diseases, and various types of inflammation.As a representative example, we conducted an experiment to determine whether the main agent of glycyrrhizin of the present invention is effective for liver diseases. I did it.

One of the methods to examine the usefulness of drugs for liver diseases is the acute liver failure model (Ferruga J.

et al, Agent and Actions*
9.566 (1979)). Therefore, as a result of an investigation using this model, detailed data will be described in the section on pharmacological studies, the mortality rate due to acute liver failure was halved in those administered rectally with glycyrrhizin compared to controls. The effect of intrarectal administration of glycyrrhizin on an acute liver failure model revealed that the main glycyrrhizin agent of the present invention is useful as a therapeutic agent for liver diseases.

As a representative example of the pharmacological effects of the glycyrrhizin base agent of the present invention, the effect on liver diseases was shown, but the base agent of the present invention is also useful for treating allergic diseases and inflammation, for which glycyrrhizin is known to be effective. be.

The glycyrrhizin content of the main agent in the present invention is not particularly limited as long as it exhibits medicinal efficacy, and varies depending on symptoms, age, etc., but is preferably 10 to 500 μg, and can be administered once to several times a day. .

The type of glycyrrhizin main agent of the present invention includes the usual '
Examples include 14s-portal suppositories and suspensions or ointments in which glycyrrhizin is dispersed in a liquid oil base and filled into soft capsules or tubes.

The glycyrrhizin base agent of the present invention may be prepared using a known manufacturing method, for example, by dispersing glycyrrhizin in a base such as cacao butter, Witepsol ■ (Dynamite Nobel), polyethylene glycol, etc. Agents, absorption enhancers, etc. may be added. Also,
It may also be used as a combination drug by adding other medicinal ingredients such as glycine, methionine, and cysteine.

Examples of formulations are shown below.

"Examples" Example 1 Glycyrrhizi/By is ground into a fine powder, purified cocoa butter 192y is added thereto, and the mixture is kneaded on a 60°C water bath.

All the ingredients were put into a dosage form and slowly cooled to form a base ingredient for one 2y.

Example 2 After melt-mixing 58y of polyethylene glycol 1000 and 22y of polyethylene glycol 4000 at 45°C, glycyrrhizin 5y1 cysteine 5y, glycine 1
Add 02, disperse, and add to the 1.5y total dosage form, being careful not to settle. After solidifying in ice water, it was separated from the mold.

Using the same method as in Example 2, the content per base ingredient was 75 Mf of glycyrrhizin, 75 Mf of methionine, and 100 Mf of glycine.
q were prepared.

Example 3 After melting Witepsol 150y at 60°C, glycyrrhizin 50y is added and stirred thoroughly until uniform. The mixture was poured into a total dosage form of 2y and cooled to obtain a main ingredient.

In the same manner as in Example 3, glycyrrhizin contents of 10 caps, 50 W, 100 da, and 200 μg per base ingredient were prepared.

Example 4 After melting Witepsol 145y at 60°C, dipotassium glycyrrhizinate 5y is added and stirred to become uniform. The mixture was put into a 1.5y total dosage form and cooled to obtain a main ingredient.

[Absorption experiment]

A known method for examining the rectal absorption of drugs is to administer a solution of the drug into the rectum of a rat and examine its absorption (Biopharmaceutical Experiments, p. 162, published by Seishi Shoin, 1985). Therefore, the absorption from the rectum was investigated using an aqueous solution of glycyrrhizic acid.

(Experimental method) Add dipotassium glycyrrhizinate to 0.00% of a sunset view. After dissolving in physiological saline containing IN sodium hydroxide, add hydrochloric acid to p
Adjust to H7.0 and add physiological saline to give a concentration of sow/d.

After rectally administering a 20W/Ky glycyrrhizic acid solution to rats under ether anesthesia using an oral probe, the liniment was sealed with biological adhesive to prevent leakage, and 15 minutes after administration.
Blood was collected at 30 minutes and 1.2.3 hours, and the glycyrrhizin concentration in plasma was measured by high performance liquid chromatography. For comparison, plasma glycyrrhizin concentrations were also calculated for rats given oral administration and duodenal administration.

(result) The experimental results are shown in Table 1.

Table 1 Glycyrrhizin concentration in plasma after rectal administration (unit: μy/d, average value of 3 cases) N, D,: Below detection limit (0.5p9/m/) 1 oral administration as shown in Light 1 Glycyrrhizin was not detected in the plasma of those administered into the duodenum, but it was detected in those administered rectally.

From this result, it was found that glycyrrhizin is absorbed through the rectum, and the usefulness of the glycyrrhizin base agent of the present invention was discovered.

[Pharmacological test]

One of the methods to examine the usefulness of drugs for liver diseases is the acute liver failure model (Ferruga J.

et al.Agents and Actions
, 9+ 566 (1979)). Using this model, the usefulness of the glycyrrhizin base agent of the present invention was investigated.

(Experimental method) According to the above literature, 8-week-old male BALB/c mice were infected with Propionibacterium acnes.
, '7''y/mouse was administered intravenously. After 7 days, dipotassium glycyrrhizinate suspended in 1-timethylcellulose solution was administered intrarectally at 100 q/kg to prevent leakage. The anus was sealed with bioglue. One hour after administration, Lipopolysaccharid
25 μy/mouse was administered intravenously, and the presence or absence of death was observed for up to 24 hours. In addition, 1-th methyl cellulose solution was used as a control.

(result) The experimental results are shown in Table 2.

As shown in Figure 2, in the control group, 67% of the mice died due to acute liver failure, whereas in the dipotassium glycyrrhizinate administration group, the mortality rate was reduced by half to 33%. Based on this, it has been found that the glycyrrhizin base agent of the present invention is useful as a therapeutic agent for liver diseases.

"Effects of the Invention" The present invention exhibits the effect of increasing the blood circulation of glycyrrhizin by rectally administering glycyrrhizin as a main ingredient, and therefore is useful as a therapeutic agent for liver diseases.

Claims (2)

[Claims] (1) Suppositories containing glycyrrhizin or its salts that are administered rectally and have improved blood circulation. (2) A therapeutic agent for liver disease characterized by administering a suppository containing glycyrrhizin or its salts.