JP2003160496A - Oral medicine of glycyrrhizine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral medicine of glycyrrhizine, easily absorbable as the glycyrrhizine, and having enhanced absorptivity of the glycyrrhizine. <P>SOLUTION: This oral medicine of the glycyrrhizine contains the glycyrrhizine and/or at least one kind of a pharmacologically acceptable salt thereof as a principal ingredient. The medicine contains at least one kind of chenodeoxycholic acid, deoxycholic acid and/or a pharmacologically acceptable salt thereof as an absorption promoter, and is coated with an enteric coat. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an oral administration agent for glycyrrhizin containing, as a main ingredient, at least one of glycyrrhizin and / or a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art Conventionally, glycyrrhizin and its salts are used alone or in combination with amino acids such as glycine, methionine and cysteine as injections or oral administrations to improve liver function in chronic hepatitis, allergic properties such as eczema and dermatitis. It has been used to treat disease. As for the improving effect on liver function, it is known that injection is superior to oral administration (clinical and study 66, 253, 1988) (clinical and study 66, 2629, 1989).

In the treatment of chronic hepatitis with an injection, glycyrrhizin is administered in an amount of 80 to 120 mg per day, up to 2 times as needed.
It is administered intravenously up to 00 mg for a long period of 3 months to 1 year. Since this injection is administered 40 mL to 100 mL at a frequency of 3 to 5 times a week, it often damages a patient's vein or surrounding tissues. In addition, long-term intravenous injection is a heavy burden because the patient is limited in time to maintain the same lifestyle as a healthy person.

Therefore, as a means for compensating for the above-mentioned drawbacks of the injectable preparation, it has been desired to create an orally-administered preparation exhibiting an effect comparable to that of the injectable preparation.

By the way, glycyrrhizin and its salts show a clearly different in-vivo behavior between an injection and an orally administered drug. When 40 mg to 120 mg of glycyrrhizin monoammonium is intravenously administered to healthy subjects, 10 μg / mL to 50 μg / m immediately after administration
After exhibiting a blood concentration of L, it disappears with a half-life of 3 to 5 hours.
Oral administration of 100 mg of glycyrrhizin monoammonium to healthy subjects showed almost no transfer of glycyrrhizin to the blood (500 ng / mL or less) and the metabolite glycyrrhetic acid was 1
After 12 hours at much lower concentrations (100 ng / mL-200 ng / m
L) Appears only in blood (J. Pharm. Sci., 81, 10
42, 1992). It is considered that this is because glycyrrhizin is partially hydrolyzed in the liver, but mainly glycyrrhizin is decomposed into glycyrrhetinic acid by microorganisms in the intestine and absorbed.

Glycyrrhizin, which was orally administered to rats, appears in the blood as glycyrrhetinic acid or unmetabolized glycyrrhizin after being metabolized to glycyrrhetinic acid by microorganisms in the stomach, cecum and large intestine in a considerable amount. In this case, the bioavailability as glycyrrhetinic acid is almost 100%, and the bioavailability as glycyrrhizin is approximately 4% (Chem. Pharm. Bull. 35 (2) 705 (1987); Biol.
Pharm. Bull. 17 (10) 1399 (1994); J.Pharm.Pharmaco
l.48 902 (1996)).

By the way, there is a rectal administration agent as a dosage form similar to the oral administration agent. For this, a rectal administration agent containing glycyrrhizin (Japanese Patent Laid-Open No. 3-2122), a method of dispersing glycyrrhizin in Witepsol, Miglyol and the like and administering it to the rectum (Japanese Laid-Open Patent No. 3-123731), polyoxyethylene to glycyrrhizin Preparations containing salts of medium chain fatty acids such as lauryl ether, capric acid or caproic acid (JP-A-4-
261117), nonionic surfactants such as polyoxyethylene alkyl ether and glycyrrhizin, and capric acid,
Preparations containing organic acids such as citric acid and malonic acid
Patents such as 5-97680), a preparation in which sodium caprate, a pH adjuster, and / or ursodesoxycholic acid are added to glycyrrhizin (JP-A-7-82155) are disclosed. However, it has been difficult to obtain a blood concentration of glycyrrhizin sufficient for the treatment of chronic hepatitis by using these preparations at a normal dose. Moreover, long-term administration of rectal preparations was not preferred by patients.

As an orally administered agent, glycyrrhizin is mixed with an ester of a medium chain fatty acid such as stearic acid or caprylic acid mono-, di- or triester and coated with an enteric coating (JP-A-3-255037), Glycyrrhizin was added to a fat emulsion consisting of phospholipids such as egg yolk lecithin, fats and oils such as soybean oil and water, and further, a nonionic surfactant, a salt or glyceride of a medium chain fatty acid such as stearic acid or capric acid, and the mixture were dried. Then, a formulation coated with an enteric coating (JP-A-6-192107), capric acid, caprylic acid, caproic acid or the like or a salt thereof is added to glycyrrhizin, polyethylene glycol, propylene glycol, hydrogenated hydrogenated castor oil (HCO-60 ) And / or a formulation in which a composition dissolved in water and added with a pH adjuster or the like is placed in a capsule or the like and coated with an enteric coating (JP-A-10-226650), etc. It is known. However, none of these preparations was sufficient to obtain a blood concentration of glycyrrhizin sufficient for treating chronic hepatitis. In addition, these preparations are not practical because their manufacturing methods are complicated.

Chenodeoxycholic acid is used as a solubilizer for cholesterol gallstones in pharmaceuticals, and sodium deoxycholate is used as a solubilizer for pharmaceutical additives. In addition, chenodeoxycholic acid and deoxycholic acid promote insulin absorption (US1995-442).
358), chenodeoxycholic acid and deoxycholic acid promote oral absorption of the antibiotic cetriaxone (US Pat.
1986-916150) and sodium deoxycholate was Caco-
It is known to promote absorption of the anticancer drug epirubicin using two cell membranes (Biochem. Pharmcol. 59, 665, 20.
00).

However, these findings do not show that chenodeoxycholic acid and deoxycholic acid promote absorption of a large number of unspecified compounds. Further, it is not known at all that chenodeoxycholic acid, deoxycholic acid and / or their salts have an action of promoting absorption of glycyrrhizin.

[0011]

Therefore, the present invention is an orally administered glycyrrhizin containing at least one of glycyrrhizin and / or a pharmacologically acceptable salt thereof as a main ingredient, and has an excellent absorption rate of glycyrrhizin. An object is to provide an oral administration agent for glycyrrhizin.

[0012]

[Means for Solving the Problems] Glycyrrhetinic acid has been reported to be as effective as or better than glycyrrhizin in oral administration in drug-induced hepatitis in experimental animals (Japanese Journal of Pharmaceutical Sciences 9, 59, 1992). ) (Pl
anta Med. 60 136, 1994). However, in the treatment of human chronic hepatitis, as described above, the injection of glycyrrhizin exhibits a superior clinical effect as compared with the oral administration. Therefore, the present inventors believe that the liver function improving effect on human chronic hepatitis by intravenous administration of glycyrrhizin is because it is expressed by a synergistic or additive effect of glycyrrhizin and glycyrrhetinic acid, and is easy as glycyrrhizin. A study was conducted to create an orally-administered drug that can be absorbed by the skin.

The inventors of the present invention have conducted extensive studies on substances having an action of promoting absorption of glycyrrhizin in the duodenum, jejunum or ileum. As a result, chenodeoxycholic acid, deoxycholic acid and their salts were found to contain glycyrrhizin or glycyrrhizin. They have found that they have an action of promoting salt absorption, and have completed the present invention.

That is, the present invention is as follows. (1) Glycyrrhizin and / or an orally-administered glycyrrhizin containing at least one pharmacologically acceptable salt thereof as a main ingredient, chenodeoxycholic acid, deoxycholic acid, and / or their pharmacologically acceptable as an absorption promoter. Glycyrrhizin for oral administration, which contains at least one salt of glycyrrhizin and is coated with an enteric coating. (2) The oral administration agent for glycyrrhizin according to (1), which contains at least one of chenodeoxycholic acid and a pharmacologically acceptable salt thereof as an absorption enhancer. (3) The oral administration agent for glycyrrhizin according to (1), which contains at least one of deoxycholic acid and a pharmacologically acceptable salt thereof as an absorption enhancer.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

The oral administration agent for glycyrrhizin of the present invention contains at least one glycyrrhizin and / or a pharmacologically acceptable salt thereof as a main drug.

Glycyrrhizin of the present invention has the following general formula
In the chemical structural formula represented by (I), R ₁, R₂, R₃Is H
A compound is shown.

[0018]

[Chemical 1]

Further, the pharmacologically acceptable salt means a medical salt.
Only those that are physiologically acceptable as medicines
Although not specified, for example, sodium salt or potassium
Alkali metal salts such as um salts, calcium salts and magnesium
Alkaline earth metal salts such as ammonium salts, ammonium salts,
Organic amine such as ethylamine salt and triethanolamine salt
Basic amino acids such as quinone salt, lysine salt and arginine salt
Preferable examples are salts or choline salts. More concrete
In the chemical structural formula represented by the general formula (I),
R₁, R₂, R₃Is all NH_Four, Compounds such as Na, K,
Or R₁, R₂, R ₃1 or 2 is H, which
Substituents other than NH are NH_FourCompounds such as Na, K, etc.
Say.

The glycyrrhizin and / or the pharmacologically acceptable salt thereof of the present invention is contained as a main drug, and one kind or two or more kinds may be contained.

The chenodeoxycholic acid and deoxycholic acid of the present invention are compounds in which R is H in the chemical structural formulas represented by the following general formulas (II) and (III).

[0022]

[Chemical 2]

[0023]

[Chemical 3]

The pharmacologically acceptable salts are not limited to these as long as they are physiologically acceptable as pharmaceuticals, but for example, alkali metal salts such as sodium salts and potassium salts. Suitable are salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, organic amine salts such as triethylamine salts and triethanolamine salts, or basic amino acid salts such as lysine salts and arginine salts or choline salts. It can be illustrated. More specifically, the compounds in which R is NH ₄ , Na or K in the chemical structural formulas represented by the general formulas (II) and (III) are shown.

The chenodeoxycholic acid, deoxycholic acid and / or their pharmacologically acceptable salts of the present invention are
It is used as an absorption enhancer by adding an amount effective to exert the effect of the present invention. In addition, chenodeoxycholic acid, deoxycholic acid, and one kind selected from pharmacologically acceptable salts thereof may be contained, or two or more kinds of compounds selected from these may be contained in combination. Good.

The compounding ratio of glycyrrhizin and / or a pharmacologically acceptable salt thereof to chenodeoxycholic acid, deoxycholic acid and / or a pharmacologically acceptable salt thereof contained in the oral administration agent for glycyrrhizin of the present invention is The following is preferable.

Content of glycyrrhizin and / or its pharmacologically acceptable salt (calculated as the amount of glycyrrhizin)
And the content ratio of chenodeoxycholic acid, deoxycholic acid and / or their pharmacologically acceptable salts (calculated as the amount of chenodeoxycholic acid and / or deoxycholic acid) is 1: 0.1 to 1:20. , And more preferably,
It should be 1: 0.5 to 1:10.

However, this optimum mixing ratio varies depending on the dose of glycyrrhizin and / or its pharmacologically acceptable salt. Therefore, after considering the dose of glycyrrhizin and / or a pharmacologically acceptable salt thereof, the optimum compounding ratio is examined in each case, and chenodeoxycholic acid, deoxycholic acid and / or their pharmacologically acceptable salts are examined. By determining the content of the salt containing glycyrrhizin, an orally-administered glycyrrhizin agent exhibiting the effects of the present invention can be obtained.

When examining the above-mentioned optimum mixing ratio, which kind of chenodeoxycholic acid or deoxycholic acid, or whether any kind thereof is included, and the kind of chenodeoxycholic acid or deoxycholic acid to be contained are also taken into consideration. Then, an orally-administered glycyrrhizin agent exhibiting the effects of the present invention can be obtained.

As a more preferable blending ratio, a single dose of glycyrrhizin and / or a pharmacologically acceptable salt thereof is known as a safe and effective range of 1 to 8 mg /
In the case of kg, the compounding ratio may be 1: 0.75 to 1: 2.0.

Further, when the single dose of glycyrrhizin and / or its pharmacologically acceptable salt is 10 mg / kg, chenodeoxycholic acid and / or its pharmacologically acceptable salt The compounding ratio is preferably 1: 5 to 1:10.

When glycyrrhizin and / or a pharmacologically acceptable salt thereof is administered at a single dose of 10 mg / kg, deoxycholic acid and / or a pharmacologically acceptable salt thereof are used. The compounding ratio is preferably 1: 4 to 1: 8.

In the orally-administered glycyrrhizin of the present invention, the enteric coating agent used for forming the enteric coating is not particularly limited as long as it is pharmaceutically acceptable. For example, hydroxypropyl methyl cellulose phthalate, cellulose acetate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose trimellitate, methacrylic acid copolymer (Eudragid L,
Eudragit S), hydrogenated rapeseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated beef tallow, etc.

To perform coating using this enteric coating agent, glycyrrhizin and / or a pharmacologically acceptable salt thereof and chenodeoxycholic acid, deoxycholic acid and / or a pharmacologically acceptable salt thereof are used. The composition containing is made into a simple mixture or fine granules, granules or tablets, and these are dissolved in a solvent while flowing using appropriate equipment such as a coating pan and a fluidized bed coating device and formulation equipment by a conventional method. It can be performed by spraying the enteric coating agent little by little and repeating hot air drying.

Particularly when the enteric coating agent is hydrogenated rapeseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated beef tallow, etc.,
After melting these enteric coating agents at 60 ° C to 85 ° C, glycyrrhizin and / or a pharmacologically acceptable salt thereof and chenodeoxycholic acid, deoxycholic acid and / or
Alternatively, it can be carried out by simultaneously dispersing the pharmacologically acceptable salt and spray cooling.

Further, after dissolving the enteric coating agent in a solvent such as ethanol or methanol, glycyrrhizin and / or a pharmacologically acceptable salt thereof and chenodeoxycholic acid, deoxycholic acid and / or their pharmacology are dissolved in this solution. It is also possible to perform coating with an enteric coating agent by dispersing or dissolving the above-accepted salt, adding to vegetable oil or liquid paraffin, and heating and drying if necessary with vigorous stirring.

In addition to the methods described above, the enteric coating can be obtained by applying existing techniques such as a spray drying method or a microencapsulation method using supercritical carbon dioxide (Oleoscience, 1, 13, 2001). Coating with an agent can also be performed.

Furthermore, in order to coat glycyrrhizin and / or a pharmacologically acceptable salt thereof and chenodeoxycholic acid, deoxycholic acid and / or a pharmacologically acceptable salt thereof with an enteric coating, the method described above can be used. Glycyrrhizin and / or a pharmacologically acceptable salt thereof and chenodeoxycholic acid, deoxycholic acid and / or a pharmacologically acceptable salt thereof are packed into hard capsules or soft capsules, and then formed into fine particles, granules or tablets. In the above-mentioned method which is usually used, a method of forming an enteric coating on the outer wall of the capsule can be used.

Any of the above methods can be appropriately selected,
The manufacturing method is not particularly limited in the present invention.

The dose of the oral administration agent for glycyrrhizin of the present invention is not particularly limited as long as the drug effect can be expected.
1 adult glycyrrhizin and / or its pharmacologically acceptable salt (calculated as the amount of glycyrrhizin)
Oral administration of glycyrrhizin containing a dose of 50-250 mg once daily
It is preferred to administer ~ 3 doses.

[0041]

EXAMPLES The present invention will be described in more detail below with reference to examples.

[0042]

Example 1 <Evaluation of absorption promoting action on glycyrrhizin> The absorption promoting action on glycyrrhizin was evaluated using various sodium bile salts shown below.

An aqueous solution containing glycyrrhizin monoammonium and various sodium bile salts shown in Table 1 below was prepared as a sample solution. The formulations of these sample solutions are shown in Table 1.
As shown in.

[0044]

[Table 1]

The glycyrrhizin monoammonium column in Table 1 shows the content as glycyrrhizin in 1 mL of the sample aqueous solution, and each sodium bile salt column shows the content of sodium bile acid in 1 mL of the sample aqueous solution. The content is described.

SD rat (male, 8 weeks old, weight about 240 g to 260
g) was used. The rat was previously anesthetized by intraperitoneal administration of urethane, and laparotomy was performed to connect the pyloric region of the stomach with a surgical thread to prevent reflux of the duodenal contents into the stomach.

Taking the weight of each rat into consideration, the sample solutions described in Table 1 above were taken in an amount corresponding to the weight of each rat so that the ratio of glycyrrhizin was 10 mg / kg with respect to the weight of each rat. It was administered into the duodenum of rats. The number of animals per sample was 2 to 6.

As a control group, an aqueous solution containing only glycyrrhizin monoammonium containing no sodium bile acid was similarly administered.

0 (before administration), 0.25, 0.50, 1.00, 2.00,
Glycyrrhizin in serum after 3.00 hours was measured by the HPLC method of Mizukaki et al. (Biol. Pharm. Bull. 23 (8) 904 (2000)).

Glycyrrhizin monoammonium obtained by this measurement (10 mg / k as glycyrrhizin)
g) and the sodium salt of bile acid (25 mg / kg) were administered to the duodenum of rats, and the time course of the concentration of glycyrrhizin in serum is shown in FIG.
It shows in (a) and FIG.1 (b).

The abbreviations shown in FIGS. 1 (a) and 1 (b) correspond to the abbreviations of sodium bile salts shown in Table 1.

Further, the maximum concentration of glycyrrhizin in serum was observed when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and sodium salt of bile acid (25 mg / kg) was administered to the duodenum of rats. Table 2 shows the blood concentration (C _max ), the area under the blood concentration curve (AUC ₀ → 3 _hr. ), And the bioavailability (BA).
Shown in. Here, the area under the blood concentration curve (AUC ₀ → _3hr. )
Is the trapezoidal method for the area under the blood concentration curve from 0 to 3 hours, and the bioavailability (BA) is the glycyrrhizin monoammonium of AUC ₀ → 3 _hr. It was calculated as a percentage when divided by AUC ₀ → _3h (measured separately with 3 animals) at the time of intravenous administration.

[0053]

[Table 2]

From the above experiment, chenodeoxycholic acid,
It was confirmed that deoxycholic acid significantly enhances intestinal absorption of glycyrrhizin in rats.

It was found that chenodeoxycholic acid and deoxycholic acid have particularly strong absorption promoting effects on glycyrrhizin, and they become weaker in the order of chenodeoxycholic acid> deoxycholic acid> lithocholic acid> cholic acid≈dehydrocholic acid. In addition, glycocholic acid, taurocholic acid and ursodeoxycholic acid showed almost no absorption promoting action.

When glycyrrhizin was intravenously administered to rats, 81% of the dose of glycyrrhizin was excreted in bile in 48 hours, and the amount of glycyrrhizin excreted in bile was decreased.
79% have been reported to be reabsorbed from the intestinal tract (J. P.
harm. Sci., 75, 672, 1986).

In the human bile acid composition, cholic acid and chenodeoxycholic acid are 35%, deoxycholic acid is 25%, and the remaining 5% is other bile acids such as lithocholic acid (hepatobiliary pancreas 313, 39, 1999).

However, according to this experiment, among the bile acids, the compounds having an action of promoting the absorption of glycyrrhizin and exhibiting a good promoting action comparable to that of the injectable drug are limited to specific compounds. confirmed.

As is clear from the above experimental results,
Chenodeoxycholic acid, deoxycholic acid and salts thereof have an action of promoting absorption of glycyrrhizin, and therefore, a glycyrrhizin oral absorbent containing glycyrrhizin and / or a salt thereof and chenodeoxycholic acid, deoxycholic acid and / or a salt thereof. Can be effectively used as an oral administration agent of glycyrrhizin having an excellent absorption rate of glycyrrhizin.

By the way, the 7-position hydroxyl group of the steroid ring is bonded to the α-position in chenodeoxycholic acid and to the β-position in ursodeoxycholic acid. Both chenodeoxycholic acid and ursodeoxycholic acid show clear contrast in their absorption-promoting effects on glycyrrhizin because of the difference in the reactivity of these compounds with intracellular or extracellular receptors. It is believed that

[0061]

[Example 2] <Study of optimum mixing ratio of glycyrrhizin and chenodeoxycholic acid> An oral administration agent for glycyrrhizin, in which the absorption rate of glycyrrhizin is increased by adding chenodeoxycholic acid and / or its salt to glycyrrhizin and / or its salt In that case, if a mixing ratio of glycyrrhizin and chenodeoxycholic acid is taken into consideration at that time, a more effective oral administration agent of glycyrrhizin can be obtained. In the following experiment, the desirable mixing ratio was examined.

An aqueous solution containing glycyrrhizin monoammonium and sodium chenodeoxycholate having various contents shown in Table 3 below was prepared as a sample solution.
The formulations of these sample solutions are as shown in Table 3.

[0063]

[Table 3]

In the column of glycyrrhizin monoammonium in Table 3, the content as glycyrrhizin in 1 mL of the sample aqueous solution is described, and in each column of sodium chenodeoxycholate, sodium chenodeoxycholate in 1 mL of the sample aqueous solution is described. The content is described.

SD rat (male, 8 weeks old, body weight: about 260 g to 2
80 g) was used. The rat was previously anesthetized by intraperitoneal administration of urethane, and laparotomy was performed to connect the pyloric region of the stomach with a surgical thread to prevent reflux of the duodenal contents into the stomach.

Taking the weight of each rat into consideration, the sample solution described in Table 3 above was taken in an amount of 10 mg / kg as glycyrrhizin relative to the weight of each rat, and the amount corresponding to each weight was taken and injected. It was injected into the duodenum of rats by a needle. The number of animals per sample was 2 to 4.

0 (before administration), 0.25, 0.50, 1.00, 2.00,
Glycyrrhizin in serum after 3.00 and 4.00 hours was measured in Example 1
The measurement was performed by the HPLC method of Mizukaki et al.

Glycyrrhizin monoammonium obtained by this measurement (10 mg / k as glycyrrhizin)
FIG. 2 shows the time-dependent changes in the concentration of glycyrrhizin in the serum when each sample solution containing g) and each chemodeoxycholate sodium (mg / kg) was administered to the rat duodenum.

The numbers shown in FIG. 2 correspond to the doses of sodium chenodeoxycholate shown in Table 3.

Further, glycyrrhizin in serum when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and each compounding amount of sodium chenodeoxycholate (each mg / kg) was administered to the duodenum of rats Table 4 shows the maximum blood concentration (C _max ), the area under the blood concentration curve (AUC ₀ → _{4 hr} ) and the bioavailability (BA). Here, the bioavailability (BA) was determined in comparison with AUC ₀ → _4h (measured separately with 3 animals) after intravenous administration of glycyrrhizin monoammonium.

[0071]

[Table 4]

In the above experimental results, when the dose of glycyrrhizin was 10 mg / kg, the dose of sodium chenodeoxycholate was 75 mg / kg, and both C _max and AUC ₀ → ₄ showed the maximum values.

Also, the dose of glycyrrhizin was 10 mg / kg.
When 6 mg / kg was changed to 6 mg / kg and an experiment was conducted to examine the optimum mixing ratio by the same method as above, the highest C _max and AUC were obtained when sodium chenodeoxycholate was administered at 8 mg / kg.
Showed the value.

Thus, it was also confirmed that the optimum compounding ratio of sodium chenodeoxycholate to glycyrrhizin varied depending on the dose of glycyrrhizin.

As is clear from the above experimental results,
Taking into account the dose of glycyrrhizin and determining each dose so that the blending ratio of glycyrrhizin and chenodeoxycholic acid is the desired value, an effective oral dose of glycyrrhizin with a higher absorption rate of glycyrrhizin can be obtained. You can

[0076]

[Example 3] <Study of optimum mixing ratio of glycyrrhizin and deoxycholic acid> Oral glycyrrhizin and / or a salt thereof containing deoxycholic acid and / or a salt thereof has an increased absorption rate of glycyrrhizin. Although an administration agent is obtained, a more effective oral administration agent of glycyrrhizin can be obtained in consideration of the compounding ratio of glycyrrhizin and deoxycholic acid. In the following experiment, the desirable mixing ratio was examined.

An aqueous solution containing glycyrrhizin monoammonium and sodium deoxycholate having various contents shown in Table 5 below was prepared as a sample solution. The formulations of these sample solutions are as shown in Table 5.

[0078]

[Table 5]

The column of glycyrrhizin monoammonium in Table 5 shows the content as glycyrrhizin in 1 mL of the sample aqueous solution, and each column of sodium deoxycholate contains deoxycholic acid in 1 mL of the sample aqueous solution. The content of sodium is described.

SD rat (male, 9 weeks old, body weight: about 280 g
300 g) was used. The rat was previously anesthetized by intraperitoneal administration of urethane, and laparotomy was performed to connect the pyloric region of the stomach with a surgical thread to prevent reflux of the duodenal contents into the stomach.

Taking the weight of each rat into consideration, the sample solution described in Table 5 above was taken in an amount of 10 mg / kg of glycyrrhizin relative to the weight of each rat, and an amount corresponding to each weight was taken and injected. It was injected into the duodenum of rats by a needle. The number of animals per sample was 2 to 4.

0 (before administration), 0.25, 0.50, 1.00, 2.00,
Glycyrrhizin in plasma after 3.00 hours was measured by the ion pair-HPLC method described below.

That is, methanol was added to plasma, and the mixture was shaken vigorously and then centrifuged. A certain amount of this supernatant was collected, dried under reduced pressure, and dissolved in 5% methanol.
Glycyrrhizin was adsorbed in addition to VactC ₁₈ . Methanol was added to this to elute glycyrrhizin and the mixture was dried under reduced pressure. The residue was dissolved by adding a fixed amount of a water / methanol mixture (35:65) in which benzoic acid-n-butyl ester was dissolved as an internal standard. This solution was developed by ion pair-HPLC using a Pegasil ODS column with a water / methanol mixture (35:65) containing 5 mM tetra-n-butylammonium hydroxide as a mobile phase to analyze the glycyrrhizin content (Chem. Pharm. Bull. .33 (12) 5364 (198
Five)).

Glycyrrhizin monoammonium obtained by this measurement (10 mg / k as glycyrrhizin)
g) and each amount of sodium deoxycholate (each mg
/ Kg) is administered to the rat duodenum and the time course of plasma glycyrrhizin concentration is shown in FIG.

The numbers shown in FIG. 3 correspond to the content of sodium deoxycholate shown in Table 5.

When each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and each amount of sodium deoxycholate (each mg / kg) was administered to the duodenum of rats,
Maximum blood glycyrrhizin concentration in plasma (C _max ),
Table 6 shows the area under the blood concentration curve (AUC ₀ → 3 _hr ) and the bioavailability (BA). Where bioavailability (BA)
Is an intravenous administration of glycyrrhizin monoammonium
It was calculated in comparison with AUC ₀ → _3h (measured separately with 3 animals).

[0087]

[Table 6]

In the above experimental results, when the dose of glycyrrhizin was 10 mg / kg, the dose of sodium deoxycholate was 60 mg / kg, and both C _max and AUC ₀ → ₃ showed the maximum values.

As is clear from the second and third embodiments,
Even if the dose of glycyrrhizin is fixed and the dose of sodium chenodeoxycholate or sodium deoxycholate is increased, the amount of glycyrrhizin in serum or plasma does not simply increase.

The amount of glycyrrhizin is maximal at a particular dose ratio. Further, the dose ratio also varies depending on the dose of glycyrrhizin.

Therefore, a more effective oral administration agent of glycyrrhizin can be obtained by variously selecting the dose of glycyrrhizin and the compounding ratio of glycyrrhizin and chenodeoxycholic acid or deoxycholic acid.

From the above-mentioned experiments, it was confirmed that chenodeoxycholic acid, deoxycholic acid and salts thereof promote the absorption of glycyrrhizin or a salt of glycyrrhizin. Therefore, at least one of glycyrrhizin and / or a pharmacologically acceptable salt thereof is used as a main drug, and as an absorption enhancer, at least one of chenodeoxycholic acid, deoxycholic acid and / or a pharmacologically acceptable salt thereof is used.
The oral administration agent for glycyrrhizin in which the composition containing the seed is coated with the enteric coating agent can be effectively used as the oral administration agent for glycyrrhizin with higher absorption as glycyrrhizin.

[0093]

Industrial Applicability According to the present invention, it is possible to provide an oral administration agent for glycyrrhizin, which has an excellent absorption rate of glycyrrhizin which is easily absorbed as glycyrrhizin.

[Brief description of drawings]

FIG. 1 (a) Concentration of glycyrrhizin in serum when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and a sodium salt of bile acid (25 mg / kg) was administered to the duodenum of rats. FIG. (B) Time-dependent change in glycyrrhizin concentration in serum when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and sodium salt of bile acid (25 mg / kg) was administered to the duodenum of rats FIG.

FIG. 2 Glycyrrhizin concentration in serum when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and each amount of sodium chenodeoxycholate (each mg / kg) was administered to the duodenum of rats FIG.

FIG. 3 Glycyrrhizin in plasma when each sample solution containing glycyrrhizin monoammonium (10 mg / kg as glycyrrhizin) and each amount of sodium deoxycholate (each mg / kg) was administered to the duodenum of rats The figure which shows the time-dependent change of a density | concentration.

Continued front page    (72) Inventor Morimi Iwata             1-4 Nishikubo-cho, Hodogaya-ku, Yokohama-shi, Kanagawa             Nishikubocho Park Heights 1-1316 (72) Inventor Akiko Ishiguro             41-20 Tojogo Town, Sakae Ward, Yokohama City, Kanagawa Prefecture F-term (reference) 4C076 AA45 BB01 CC03 CC04 CC16                       CC18 DD70 FF25 FF34                 4C086 AA10 EA10 MA02 MA03 MA05                       MA52 NA10 NA11 ZA75 ZA89                       ZB11 ZB13

Claims (3)

[Claims] 1. An orally-administered glycyrrhizin containing at least one of glycyrrhizin and / or a pharmacologically acceptable salt thereof as a main ingredient, and chenodeoxycholic acid, deoxycholic acid and / or their pharmacological pharmacological properties as absorption promoters. An oral administration agent for glycyrrhizin, which contains at least one kind of an acceptable salt and is coated with an enteric coating. 2. The oral administration agent for glycyrrhizin according to claim 1, which contains at least one of chenodeoxycholic acid and a pharmacologically acceptable salt thereof as an absorption enhancer. 3. The oral administration agent for glycyrrhizin according to claim 1, which contains at least one of deoxycholic acid and a pharmacologically acceptable salt thereof as an absorption enhancer.