JPH03255037A - Glycyrrhizin pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain a glycyrrhizin preparation capable of quickly increasing the concentration of glycyrrhizin in blood by blending glycyrrhizin or salt thereof with a fatty acid glyceride and coating the blend with an enteric coating film. CONSTITUTION:Glycyrrhizin or salts thereof is blended with a fatty acid glyceride (e.g. mono, di or triglyceride of middle chain fatty acid such as stearic acid or caprylic acid) at a ratio of (1:1)-(1:10.0) and the blend is coated with an enteric coating film (e.g. hydroxypropylmethylcellulose phthalate) to provide a glycyrrhizin preparation having a form of tablet, granule, inhalant, capsule, etc. When the preparation is administered, glycyrrhizin is rapidly absorbed in the duodenum or small intestine, because the enteric coating film is dissolved in the duodenum and moved into blood to effectively exhibit the effect. Glycyrrhizin is effective in the therapy of liver disease, allergic disease, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The present invention relates to a glycyrrhizin preparation that has improved transferability into blood.

"Prior art, problems to be solved by the invention, and means for solving 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, pharmaceutical therapy, allergic bronchitis, etc. It is used in oral and injectable forms to treat allergic diseases 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 WRK and metabolism by the first-pass effect in the liver (Therapeutics, 7(5), 70).
4 (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 is large.

On the other hand, a formulation for rectal administration has recently been reported (Japanese Unexamined Patent Publication No. 1994-294619), but oral formulations are easier for patients to handle. It was necessary to consider ways to increase the concentration.

"Disclosure of the Invention" The present invention relates to a glycyrrhizin preparation characterized by blending fatty acid glyceride with glycyrrhizin or a salt thereof and coating the product with an enteric coating.

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.

Glycyrrhizin or its salts are used alone or in combination with amino acids, etc., in the form of oral preparations or injections for the treatment of liver diseases such as hepatitis and liver disorders, drug therapy, allergic diseases such as allergic bronchitis, and various inflammations. It is being

However, it has been reported that when administered orally, glycyrrhizin is not detected in the blood due to decomposition by gastric acid and metabolism by the first-pass effect in the liver (Therapeutics, 7 (5) 70
4 (1981)). However, injectable drugs place a heavy burden on patients when long-term administration is required, such as in patients with liver disease. On the other hand, a formulation for rectal administration has recently been reported (Japanese Unexamined Patent Publication No. 1994-294619), but oral formulations are easier for patients to handle. It was necessary to consider ways to increase the concentration.

As a result of intensive studies on this problem, the present inventors found that glycyrrhizin or its salts (hereinafter collectively referred to as glycyrrhizin) are blended with fatty acid glycerides and are coated with an enteric coating, thereby allowing the decomposition of glycyrrhizin. We found that it is possible to increase the medium concentration.

Experiments using rats were conducted to examine the absorption of the formulation of the present invention in the gastrointestinal tract. Detailed data will be described in the absorption experiment section, but even when glycyrrhizin dissolved in physiological saline was administered into the stomach or duodenum, almost no glycyrrhizin was detected in the blood. Furthermore, even when glycyrrhizin dispersed in fatty acid glyceride was administered to the stomach, no glycyrrhizin was detected in the blood. on the other hand,
When glycyrrhizin dispersed in fatty acid glyceride was administered into the duodenum, glycyrrhizin was detected in the blood. This result indicates that if glycyrrhizin is directly administered into the intestine and dispersed in fatty acid glyceride having a surfactant effect, glycyrrhizin will be absorbed due to its absorption promoting effect. Therefore, the present inventors formulated glycyrrhizin with fatty acid glyceride and coated it with an enteric coating, and as this coating dissolves in the duodenum, glycyrrhizin is rapidly absorbed in the duodenum and small intestine and transferred to the blood, allowing glycyrrhizin to be absorbed into the blood. It was discovered that the effect of the method can be effectively demonstrated.

Examples of fatty acid glycerides in the present invention include monoglycerides, diglycerides, and triglycerides of medium-chain fatty acids such as stearic acid, caprylic acid, and capric acid. Alternatively, a mixture of these fatty acid glycerides may be used.

The enteric coating used in the present invention may be one that is commonly used for pharmaceuticals, and examples thereof include hydroxypropyl methylcellulose hetatalate, cellulose acetate, hydroxyglobil methylcellulose acetate succinate, and the like.

The dosage form of the preparation of the present invention includes tablets, granules, powders, capsules, and the like.

The glycyrrhizin preparation of the present invention may be prepared using a known manufacturing method. For example, if it is a capsule, fatty acid glyceride is added to glycyrrhizin, and if necessary, excipients, binders, lubricants, surfactants, stabilizers, etc. The capsules may be filled with additives such as a curing agent, a solubilizing agent, a preservative, a melting point regulator, etc., and then coated with an enteric coating. Alternatively, capsules coated with an enteric coating may be filled in advance, or granules coated with an enteric coating may be filled into capsules.

The blending ratio of glycyrrhizin and fatty acid glyceride in the formulation of the present invention varies depending on the type of fatty acid glyceride, but is preferably 10:1 to 1:100, more preferably 1:1 to i:io,o.

Glycyrrhizin is also commercially available in combination with amino acids such as glycine, methionine, and cysteine.
The formulation of the present invention may also be used as a compounded drug by adding other medicinal ingredients such as these amino acids.

The glycyrrhizin content in the present invention is not particularly limited as long as it can exhibit medicinal efficacy, and varies depending on symptoms, age, etc., but preferably the single dose is 10 to 500115+, and 1
It can be administered once to several times a day.

Examples of formulations are shown below.

"Example" Example 1 (capsule) Formulation 1 Glycyrrhizin monoammonium salt 80 ■ Inviturf 42 320 - Hydroxypropyl methyl cellulose 7 tallate 60 ■ Manufacturing method Glycyrrhizin monoammonium salt 80 is monoglyceride and diglyceride of caprylic acid and capric acid Inviturf 42 (trade name:
Dynamite Nobel Co.) After dispersing to 320 towns, 1
Fill into No. capsule. After sealing the cancer joint using gelatin, it was coated with hydroxypropyl methylcellulose phthalate dissolved in a mixture of methylene chloride and ethanol.

Formulation 2 Glycyrrhizin monoammonium salt sogI9 Inviturf 42 320 ■Hydroxyglobil methylcellulose acetate saccharide, 1-) 60'myProduction method Glycyrrhizin monoammonium salt 80q is dispersed in Inviturf 42 320■. The dispersion liquid was filled into enteric-coated empty capsules molded using hydroxypropyl methylcellulose acetate succinate.

Example 2 (granules) Prescription 3 Glycyrrhizin monoammonium salt 80q Stearic acid monoglyceride 100! lactose
100kg light silicic anhydride
50■Hydroxypropylcellulose 5■Magnesium stearate 10qHydroxypropylmethylcellulose phthalate 25Production method After granulating pulverized glycyrrhizin monoammonium salt, stearic acid monoglyceride, lactose, and light silicic anhydride using an aqueous solution of hydroxypropylcellulose, Propyl methyl cell o-, x, 7 tallate F
) The film was coated using a methylene chloride-ethane-h mixture. Finally, the magnesium stearate was mixed.

Capsules with the following formulation were prepared using a similar method.

Prescription 4 Glycyrrhizin Dipotassium Salt 7511F Methionine 75 Town Glycine
1ooq stearic acid monoglyceride l
QQwy Lactose 100 towns Light silicic anhydride 50 towns Hydroxypropyl cellulose 5 gf Magnesium stearate 10 ■ Hydroxyglobil methyl cellulose phthalate 25 towns Example 3 (soft capsules) Formulation 5 Glycyrrhizin Inviturf 42 Butyl benzoate Propyl benzoate 40 Misaki 00q O , 2411g o. 16 Kizelatin 100 ~ Hydroxypropyl methylcellulose phthalate 60 Production method Glycyrrhizin monoammonium salt, Butyl benzoate,
Disperse propyl benzoate in Inviturf 42.

This dispersion was filled into soft gelatin capsules, which were then coated with an acetone-ethanol mixture of hydroxypropyl methylcellulose phthalate.

Ta.

Soft capsules having the following formulation were prepared using a similar method.

Prescription 6 Glycyrrhizin 20 Town Inviturf 42 20011P Butyl Benzoate
0.5q gelatin
100q+ Hydroxypropyl methylcellulose phthalate 5Qq [Absorption experiment] 9- -10- T, N15hihata et al. method (J, Pharm, P
harmacol.

38, 69 (1986)), the absorption of the preparation of the present invention in the gastrointestinal tract was investigated.

(Experimental Method) Glycyrrhizin monoammonium salt dispersed in Inviturf 42 was prepared and administered into the duodenum of rats under ether anesthesia. For comparison, similar experiments were conducted with the above preparation administered intragastrically and with an aqueous solution of glycyrrhizin monoammonium salt (dissolved in physiological saline) administered intraduodenally.

Blood was collected over time during a nap after administration, and the concentration of glycyrrhizin in plasma was determined by HPLC. The dose of glycyrrhizin was 20g9/Kg in all cases.

(Experimental Results) As described above, almost no glycyrrhizin was detected in the plasma of both the cases where glycyrrhizin was dispersed in Inviter and administered to the stomach, and the case where glycyrrhizin was administered as an aqueous solution. On the other hand, it was found that when glycyrrhizin was dispersed in Inviter and administered into the duodenum, much more glycyrrhizin was detected in the plasma than in the other cases.

This revealed that the formulation of the present invention exhibits excellent absorbability.

"Effects of the Invention" According to the present invention, by blending glycyrrhizin with fatty acid glyceride and preparing a preparation coated with an enteric coating, glycyrrhizin is quickly absorbed in the duodenum and small intestine and transferred into the blood even when administered orally. This shows the effect of increasing the blood concentration of .

Claims (1)

[Claims] A glycyrrhizin preparation comprising glycyrrhizin or its salts mixed with fatty acid glyceride and coated with an enteric coating.