JPH05271097A - Aculeacin solubilizing agent and medicinal composition - Google Patents

Abstract

PURPOSE:To obtain the subject medicinal composition useful as a prophylactic or therapentic medicine for Pneumocytis carini pneumonia having an antifungal action by using a solubilzing agent for Aculeacin, containing glycyrrhizin as an active ingredient and an Aculeacin. CONSTITUTION:The objective composition comprising a freeze-dried preparation which is dissolved in water on use and having antifungal activity is obtained by adding germ-free distilled water to a solubilizing agent for Aculeacin, containing glycyrrhizin such as dipotassium glycyrrhizinate as an active ingredient, and an Aculeacin such as Aculeacin Agamma, treating the solution with ultrasonic waves for 10 minutes to accelerate solubilization into a clear solution, subjecting the solution to aseptic filtration through a 0.22mum membrane filter, fractionating the filtrate into vials 1ml each and freeze-drying them. Further, when sodium salycilate or sodium benzoate is added to the composition, the solubility of the Aculeacin can be increased to give turbid-free preparations even when amino acids are further added and the mixed solution is admixed to infusion liquid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solubilizing agent for acreasins and a pharmaceutical composition.

[0002]

BACKGROUND OF THE INVENTION Acreacins are produced by microorganisms belonging to the genus Aspergillus and are known as antibiotics having antifungal activity (Japanese Patent Publication Nos. 59-20350, 59-20351, 59-59). -20
352, Japanese Patent Publication No. 59-20353). It is also expected as a prophylactic and therapeutic drug for Pneumocystis carinii pneumonia [JP-A-2-288837, Tetrahedron Letters, 414].
7-4150 (1976), Helv. Chim. Ac
ta. , 62 (4), 1252-1267 (197).
9)].

However, acreasins are extremely sparingly soluble in water, and it is difficult to uniformly disperse them in an aqueous solution and solubilize them to a completely clear state visually. For this reason, conventionally, solubilizing agents such as alcohols, polyhydric alcohols and cholic acids have been used as a solubilizing method (JP-A-2-288837). In these methods, when solubilized and then diluted with physiological saline or the like, white turbidity may occur. Therefore, addition of a nonionic surfactant such as HCO-60 or TWEEN-80 is necessary. .. On the other hand, it was difficult to solubilize the nonionic surfactant alone. Furthermore, the addition of a solubilizing agent such as the above-mentioned surfactant has a problem in terms of safety.

[0004]

As described above, in order to solubilize the acreasins, it was necessary to use alcohols, polyhydric alcohols, cholic acids, nonionic surfactants, etc., but in terms of safety. I had a problem with. Therefore, an object of the present invention is to provide a safe and stable composition of acreasins.

[0005]

[Means for Solving the Problems] In order to solve the above problems, as a result of earnest research on a solubilization method, surprisingly, by using glycyrrhizin as a solubilizing agent, safety and efficiency are high. It has become possible to obtain a composition capable of solubilizing Moreover, they have found that the composition has excellent storage stability.

[0006] That is, the present invention provides a solubilizer for acreasins containing glycyrrhizins as an active ingredient. Further, the present invention provides an aqueous composition of acreasins or a dry composition thereof, which contains acreasins and glycyrrhizins. The present inventor further investigated a solubilizing agent in order to enhance the solubilizing power of acreasins, and surprisingly, by adding sodium salicylate or sodium benzoate to the above composition, It was found that the amount of dissolution increased remarkably.

[0007] That is, the present invention provides an aqueous composition of acreasins or a dry composition thereof, which contains acreasins, glycyrrhizins and sodium salicylate or sodium benzoate. In general, the methods of administering pharmaceuticals include intravenous,
Intramuscular, intracutaneous and subcutaneous administration is considered, and when administered intravenously, one of the most frequently used methods is to administer the drug after mixing the drug with an infusion solution. Furthermore, when the administration method of the aclacins composition was examined, and the composition was mixed with an infusion solution, when the content of the solubilizer was extremely small, cloudiness was observed after mixing. As a result of various studies in order to prevent this cloudiness, it was found that cloudiness can be prevented by adding a specific amino acid, such as glutamic acid, aspartic acid or cysteine hydrochloride, to the above composition.

[0008] That is, the present invention provides an aqueous composition of acreasins or a dry composition thereof, which contains acreasins, glycyrrhizins and amino acids. The solubilization referred to in the present invention means that the acreasins are uniformly dispersed in an aqueous solvent and become a completely clear state visually. Distilled water is mentioned as a suitable example as this aqueous solvent. Further, salts, sugars, acids and the like may be added thereto as appropriate, and examples thereof include distilled water for injection, physiological saline, sugar solutions, buffer solutions and the like. Further, the above-mentioned aqueous solvent may contain a water-soluble organic solvent, for example, a small amount of ethanol etc., as long as it does not show toxicity. In the present invention, the aqueous composition means a composition in the form of a solution in which aclacins are solubilized by the above aqueous solvent, and the aqueous composition may be appropriately prepared as a dry composition by a conventional drying means.

The active ingredient of the present invention, acreasins, is represented by the general formula (1)

[0010]

[Chemical 1]

(Wherein R ₁ —O— is a long-chain saturated or unsaturated fatty acid residue or an organic acid residue which may contain a benzene ring, a pyridine ring, an oxygen atom, a sulfur atom or a nitrogen atom in the molecule. R ₂ represents a hydrogen atom, a lower alkyl group which may have a branched chain, an benzyl group or an amino-lower alkyl group in which an amino group may be substituted with a mono-lower alkyl group or a di-lower alkyl group, R ₃ represents a hydrogen atom or a —CONH ₂ group, and R ₄ represents a hydrogen atom or a hydroxyl group).

Further, in the general formula (1), examples of the group R ₁ include, for example,

[0013]

[Chemical 2]

[0014]

[Chemical 3]

[0015]

[Chemical 4]

[0016]

[Chemical 5]

[0017]

[Chemical 6]

And the like. In addition, examples of the group R ₂ include, for example, a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-Butyl, pentyl, hexyl, 3-methylbutyl, 2
-Linear or branched lower alkyl group having 1 to 6 carbon atoms such as ethylbutyl and 1-ethylbutyl, benzyl group, 2
-Amino-lower alkyl groups such as aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-aminopropyl, 2-aminobutyl, etc., where the amino group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, etc. And amino-lower alkyl groups such as 2-aminoethyl and 3-aminopropyl substituted by the mono-lower alkyl or di-lower alkyl groups of.

Group R₃As a hydrogen atom or -CON
H₂And the group R_FourAs a hydrogen atom or a hydroxyl group
Is mentioned. In the general formula (1), R₁-CO
-Is a long-chain saturated or unsaturated fatty acid residue, for example, having 1 carbon atom
4-18 (C₁₄~ C₁₈) And R₂Is a hydrogen atom, R₃
Is a hydrogen atom, R_FourIs a hydrogen atom or a hydroxyl group
Preferred is an acin derivative, and more preferred example is R.
₁-CO- is a myristic acid residue (C₁₄), R_FourIs a hydroxyl group
Acreasin Aα, R₁-CO- is palmitic
Acid residue (C₁₆), R_FourIs an acrylic acid
Aγ, R₁-CO- is myristic acid residue, R_FourIs hydrogen
Aclaresin Dα, R represented by atoms₁-CO- is pal
Mitate residue, R _FourAcreacin in which is represented by a hydrogen atom
Dγ, and R₁-CO- is stearic acid residue
Group (C₁₈), R_FourIs an Echinocande represented by a hydrogen atom
Inn C, R ₁-CO- is a linoleic acid residue (C₁₈, Double knot
2), R_FourWhere Echinocandin is represented by a hydroxyl group
B and the like are also mentioned as preferable examples.

Glycyrrhizin is known as a component extracted from natural licorice and is widely used as a cosmetic or a sweetener. The glycyrrhizins used in the present invention have the general formula (2)

[0021]

[Chemical 7]

(Where R is₁₁~ R₁₅Is a hydrogen atom or
The compound having a common basic skeleton represented by
Is a collective term for these single compounds or
It may be a mixture of compounds, specifically 18α-g
Lithyl lithitic acid [R in the above general formula (2)₁₁Is a guru
Clonyl-glucuronic acid residue, R₁₂Is a COOH group, R ₁₃
Is CH₃Group, R₁₄Is an = O group, R₁₅Is CH₃Each group
]], 18β-glycyrrhizinic acid (same as above), 18α-
Glycyrrhetinic acid (R₁₁OH group, R₁₂A COOH group,
R₁₃; CH₃Group, R₁₄; = O group, R₁₅; CH₃Group), 1
8β-glycyrrhetinic acid (same as above), 3β-glucuronyl
-18β-Glycyrrhetinic acid (R₁₁Glucuronic acid residue
Group, R₁₂COOH group, R₁₃CH3 group, R₁₄; = O
Group, R₁₅; CH₃Group), carbenoxolone (R₁₁; CO
OCH₂CH₂COOH group, R₁₂COOH group, R₁₃;
CH₃Group, R₁₄; = O group, R₁₅; CH₃Group), deoxo
Glycyrrhetinic acid (R₁₁OH group, R₁₂A COOH group,
R₁₃; CH₃Group, R₁₄; Hydrogen atom, R₁₅; CH₃Group),
3α-dehydroxyglycyrrhetinic acid (R₁₁; = O group,
R₁₂COOH group, R₁₃; CH₃Group, R₁₄; = O group, R
₁₅; CH₃Group), hederagenin (R₁₁OH group, R₁₂;
CH₃Group, R₁₃COOH group, R₁₄; Hydrogen atom, R₁₅;
CH₃Group), 11-oxohedellagenin (R₁₁OH
Group, R₁₂; CH₃Group, R₁₃COOH group, R₁₄; = O
Group, R₁₅; CH₂CH group), oleanolic acid (R₁₁; O
H group, R₁₂; CH₃Group, R₁₃COOH group, R₁₄;hydrogen
Atom, R₁₅; CH₃Group), 11-oxooleanolic acid
(R₁₁OH group, R₁₂; CH₃Group, R₁₃A COOH group,
R₁₄; = O group, R₁₅; CH₃Groups) and their non-toxicity
Salt etc. are illustrated.

Glycyrrhizinate, which has a particularly high solubility, is preferred, and nontoxic salts thereof include potassium salt, sodium salt, ammonium salt and hemisuccinate. Depending on the number of glycyrrhizinate carboxylic acids, mono,
It may be a di-, tri-salt or the like, and is usually 18β-glycyrrhizinic acid, dipotassium salt, monoammonium salt, diammonium salt, disodium salt, trisodium salt, 18β-glycyrrhetinic acid, carbenoxolone di. Sodium and the like are preferably used. The glycyrrhizins of the present invention include the above-mentioned free acids, salts or mixtures thereof.

The amount of the acreasins used as the active ingredient of the present invention is such that a medicinal effective action (antibacterial action, bioactive action) is expressed, and generally 10 per adult per day.
It is about mg to 2 g. The composition ratio of the acreasins and the glycyrrhizins differs depending on the types of the acreasins and the glycyrrhizins and the combination thereof, and the composition ratio at which the respective acreasins are solubilized may be appropriately selected. For example, normally, when using acreasin Aγ, the amount of glycyrrhizic acid dipotassium salt is about 1 to 1 part by weight.
4 parts by weight or more, and about 2 parts by weight or more of glycyrrhizic acid monoammonium salt solubilizes. Also, for example, when using acreasin Dγ, it is usually solubilized with about 1 part by weight or more of dipotassium glycyrrhizinate per 1 part by weight thereof.

The amount of acreasin dissolved can be further increased by devising the method of solubilization. For example, when solubilized by using an ultrasonic cleaner, the amount of dissolved acreasins increases in proportion to the use time, and when treated with ultrasonic waves for 60 minutes, 1 part by weight of acreasin Aγ, dipotassium glycyrrhizinate or Glycyrrhizic acid monoammonium salt is solubilized at about 0.15 parts by weight or more.

The upper limit of the amount of glycyrrhizin added is such that the glycyrrhizin itself becomes a clear solution, and the amount varies depending on the type of glycyrrhizin, but is about 85 g / 100 ml for dipotassium glycyrrhizinate.
The concentration of the solution of the composition of the present invention can be appropriately selected. For example, the concentration of acreasins is about 0.001 to 30%, and the concentration of glycyrrhizins is a concentration necessary for solubilization of acreasins. 0.001-85%,
Preferably 0.1 to 5%, more preferably 0.5 to 2
%.

In order to produce the composition of the present invention, for example, the acreasins and glycyrrhizins of the above composition are mixed, and if necessary, further known pH adjusting agents, isotonic agents, stabilizers, etc. , An extender, an antiseptic and the like may be appropriately mixed. At the time of mixing, for example, a solution of glycyrrhizins dissolved in the above-mentioned aqueous solvent is mixed with acreasins, or an aqueous solvent in which acreasins are dispersed, and a dry or solution of glycyrrhizins are mixed, or each of The dried components of the composition may be mixed directly with the aqueous solvent.

The means for solubilization is not particularly limited, but ultrasonic treatment is particularly preferable as described above,
The amount of dissolution increases depending on the length of processing time. 5-12
A treatment time of 0 minutes is preferable, but 30 is more preferable.
~ 60 minutes. When preparing a solution such as an aqueous composition, it is preferable to use a sterilized solution such as sterile distilled water. In addition, it is preferable to perform aseptic treatment with a 0.22 μm membrane filter or the like, other heat treatment, or aseptic treatment with sterilizing gas or the like.

The composition of the present invention may be either an aqueous composition or a dry composition thereof, but the dry composition is particularly preferable because the acreasins are stably stored. In order to easily obtain a dried composition, there can be mentioned, for example, a method in which a solution that has once been made into an aqueous composition is dried by various drying means. As the drying means, for example, freeze drying, spray drying, reduced pressure drying, etc. are generally used, but freeze drying is particularly preferable.

A concrete example of the above production method is as follows. After solubilizing each component having the above composition with sterile distilled water,
It may be sterile filtered through a 2 μm membrane filter and dispensed in vials, ampoules or the like, or may be prepared by freeze-drying, and if necessary, it may be dissolved in distilled water for injection to give an aqueous composition. The thus obtained aqueous or dry composition of the present invention is often used as an injection, but it can also be used as a preparation for oral or nasal administration.

The composition of the present invention is advantageous in safety by using highly safe glycyrrhizins as compared with the preparations using other solubilizers, and the stability of acreasins in the composition is further improved. Showed excellent results in storage stability especially in the dry state. In the present invention, in order to enhance the solubilizing power of acreasins, by adding sodium salicylate or sodium benzoate as a solubilizing agent to the above composition, the amount of dissolved acreasins is significantly increased.

When sodium salicylate or sodium benzoate is added, sodium salicylate is added in an amount of 0.1 part by weight or more and sodium benzoate is added in an amount of 2 parts by weight or more in a dose-dependent manner with respect to 1 part by weight of glycyrrhizins. The amount of acreasins dissolved increases. For example, when 0.2 part by weight of sodium salicylate is added to 1 part by weight of dipotassium glycyrrhizinate, the dissolution amount of acreasin Aγ is 1 part by weight of dipotassium glycyrrhizinate.
Although it is about 6.5 parts by weight with respect to parts by weight, when the amount of sodium salicylate added is 5 parts by weight, the amount of dissolved acreasin increases to about 18 parts by weight, which is about 3 times.

Similarly, when 2 parts by weight of sodium benzoate is added to 1 part by weight of dipotassium glycyrrhizinate, the amount of acreasin Aγ dissolved is about 6 parts by weight with respect to 1 part by weight of dipotassium glycyrrhizinate. When the amount of sodium benzoate added is 10 parts by weight, the amount of dissolved acreasin increases to 16 parts by weight. Aqueous composition or freeze-dried composition containing the acreasins and glycyrrhizins described above, or redissolution of the aqueous composition or a freeze-dried composition containing the acreasins and glycyrrhizins and sodium salicylate or sodium benzoate The product is clear and can be safely administered as a medicine.

When the above-mentioned acreasin composition is mixed with a known infusion solution, when the content of the solubilizer is extremely small, white turbidity is observed after mixing. In order to prevent this cloudiness, cloudiness can be prevented by adding a specific amino acid such as glutamic acid, aspartic acid, or cysteine hydrochloride. For example, it becomes cloudy when it is solubilized with 2 parts by weight or less of dipotassium glycyrrhizinate per 1 part by weight of acreasin Aγ and diluted 50 times or more with a physiological saline solution. At this time, cloudiness can be prevented by adding 0.1 parts by weight or more of amino acids such as L-aspartic acid, L-glutamic acid, and cysteine hydrochloride to 1 part by weight of dipotassium glycyrrhizinate.

The above-mentioned amino acids may be added to the composition containing acreasins and glycyrrhizins,
It may be added to a composition containing acreasins, glycyrrhizins and sodium salicylate or sodium benzoate. The amount of the amino acid added varies depending on the type of the solubilizer and the amount used, but is usually 0.1 to 0.5 parts by weight per 1 part by weight of the solubilizer or about 1 to 2% of the aqueous composition. It may be used so as to contain a certain amount. There is no limitation on the addition order of amino acids and the addition order of the above-mentioned sodium salicylate or sodium benzoate.

[0036]

The present invention will be described below with reference to examples.
The present invention is not limited to this.

[0037]

Example 1 100 mg of acreasin Aγ and 1000 mg of dipotassium glycyrrhizinate (manufactured by Maruzen Kasei Co., Ltd.) were added, 100 ml of sterile distilled water was added, and an ultrasonic cleaner (BR) was used.
ANSON Type 2200 type 45 KHz, 8
It was sonicated for 10 minutes at 0 W) to solubilize and obtain a clear solution. Then, after sterile filtration with a 0.22 μm membrane filter, 1 ml each was dispensed into a vial, freeze-dried, and nitrogen substitution, stoppering and winding were performed to obtain a freeze-dried preparation for dissolution before use (Preparation A).

Next, 100 mg of acreasin Aγ and 1000 mg of sodium deoxycholate (manufactured by Sigma) were taken and treated in the same manner as above to obtain a freeze-dried preparation (Preparation B). Store Formulation A and Formulation B at 50 ° C., 3 at each time point
Each vial was taken out, each was dissolved in 1 ml of water: acetonitrile (48:52), and the acreasin Aγ content was measured using high performance liquid chromatography (HPLC).

HPLC conditions Column: Inner diameter 4.6 × 150 mm Filler: YMC AM-302 ODS S-512
0Å (manufactured by YMC) Mobile phase: water: acetonitrile (48:52) Detection: UV220nm Flow rate: 0.8 ml / min Sample: 1 μl of mobile phase was added to the sample and 5 μl was injected after dissolution

[0040]

[Table 1]

As shown in Table 1, the acreasin Aγ content (remaining%) after storage at 50 ° C. for 2 weeks was 7 for LotA.
It was 2.6% and LotB was 30.0%, and the storage stability against heat was far better in the formulation using dipotassium glutyrrhizinate than in the formulation using sodium deoxycholate. Each sample became a clear solution by adding water or water: acetonitrile.

[0042]

Example 2 400 mg of dipotassium glycyrrhizinate was added to 100 mg of acreasin Aγ, 100 ml of sterile distilled water was added thereto, and the mixture was solubilized by stirring, and then 0.22 μ
Aseptically filter with a membrane filter of 1 ml
Each was dispensed and sealed in an ampoule to obtain an aqueous injection.

[0043]

Example 3 400 ml of sterile distilled water was added to 800 mg of monoammonium glycyrrhizinate (manufactured by Maruzen Kasei),
After adjusting the pH to 7.0 using sodium hydroxide and hydrochloric acid, sterile distilled water was added to bring the total volume to 500 ml. To this, 100 mg of acreasin Aγ was added, solubilized by an ultrasonic cleaner (10 minutes), sterile filtered with a 0.22 μm membrane filter, and then aseptically dispensed in 5 ml aliquots and melted.

[0044]

Example 4 500 mg of dipotassium glycyrrhizinate was added to 50 mg of aclacin Dγ, and sterile distilled water of 50 m was added.
1 was added and solubilized using an ultrasonic cleaner. 0.22μ
m aseptic filtration with a membrane filter, aseptically dispense 1 ml each into a vial, freeze-dry and fill with nitrogen,
The solution was capped and wound tightly to obtain a soluble preparation before use.

[0045]

Example 5 100 mg of acreasin Aγ, 600 mg of dipotassium glycyrrhizinate, and 400 mg of mannite were taken, and 100 ml of sterile distilled water was added to this to be solubilized. After aseptic filtration with a 0.22 μm membrane filter, 1 ml of each was aseptically dispensed into vials and freeze-dried to obtain a ready-to-use dissolved injection.

[0046]

[Example 6] 100 mg of acreasin Aγ, 500 mg of dipotassium glycyrrhizinate, and 500 mg of glucose were added, and 100 ml of sterile distilled water was added to the mixture to solubilize it. Dispensed into ampoules. One of them was taken, and the whole amount was sucked with a syringe and added to 500 ml of physiological saline for infusion to obtain an injectable solution for infusion.

[0047]

Example 7 40 mg of acreasin Aα and 160 mg of dipotassium glycyrrhizinate were taken, and 40 ml of sterile distilled water was used.
Was added, and the mixture was stirred to solubilize, sterile filtered with a 0.22 μm membrane filter, aseptically dispensed in 1 ml aliquots and lyophilized to obtain a ready-to-use dissolved injection.

[0048]

Example 8 40 mg of acreasin Dα and 400 mg of dipotassium glycyrrhizinate are taken and sterile distilled water 100 m
1 was added and solubilized using an ultrasonic cleaner. 0.22
After aseptic filtration with a μm membrane filter, 1 ml of each was aseptically dispensed into vials, freeze-dried, nitrogen-filled, stoppered, and tightened to obtain a dissolved injection before use.

[0049]

[Example 9] Acreasin Aγ (500 mg) and dipotassium glycyrrhizinate (200 mg) were taken, and sterile distilled water (20 m) was used.
1 was added and solubilized using an ultrasonic cleaner (60 minutes). After aseptic filtration with a 0.22 μm membrane filter, 0.5 ml of each was aseptically dispensed into vials and freeze-dried to obtain a dissolved injection for use.

[0050]

Example 10 1500 mg of acreasin Aγ, 100 mg of dipotassium glycyrrhizinate and 500 mg of sodium salicylate were taken, 10 ml of sterile distilled water was added, and the mixture was solubilized using an ultrasonic cleaner (60 minutes). 0.22μ
After aseptic filtration with a membrane filter of m, 0.5 ml of each was aseptically dispensed into vials and freeze-dried to obtain an injection for dissolution before use.

[0051]

[Example 11] To 100 mg of monoammonium glycyrrhizinate (manufactured by Maruzen Kasei Co., Ltd.), 8 ml of sterile distilled water was added, and the pH was adjusted to 6.0 using sodium hydroxide and hydrochloric acid, and then sterile distilled water was added to bring the total volume to 10 ml. did. To this, 1000 mg of acreasin Aγ was added, solubilized with an ultrasonic cleaner (60 minutes), and aseptically filtered with a 0.22 μm membrane filter, then aseptically 0.5 m.
Each one was dispensed into ampoules and melted.

[0052]

Example 12 500 mg of acreasin Aγ, 100 mg of dipotassium glycyrrhizinate and 500 mg of sodium benzoate were taken, 10 ml of sterile distilled water was added, and the mixture was solubilized using an ultrasonic cleaner (60 minutes). After aseptic filtration with a 0.22 μm membrane filter, 0.5 ml of each was aseptically dispensed into vials and freeze-dried to obtain a dissolved injection for use.

[0053]

Example 13 Acreasin Aγ 250 mg, dipotassium glycyrrhizinate 100 mg and aspartic acid 10
10 mg of sterile distilled water was added and solubilized using an ultrasonic cleaner (60 minutes). Aseptically filter 1 vial after aseptic filtration with 0.22 μm membrane filter.
It was dispensed by ml and freeze-dried to obtain an injectable solution for injection before use. This vial was taken, dissolved in 1 ml of sterile distilled water, and mixed with 50 ml of physiological saline to obtain a clear infusion preparation.

[0054]

Example 14 Acreasin Aγ 230 mg, dipotassium glycyrrhizinate 100 mg and glutamic acid 10 m
g was taken, 10 ml of sterile distilled water was added, and the mixture was solubilized using an ultrasonic cleaner (60 minutes). Aseptically filter 1 vial after aseptic filtration with 0.22 μm membrane filter.
It was dispensed by ml and freeze-dried to obtain an injectable solution for injection before use. This vial was taken, dissolved in 1 ml of sterile distilled water, and mixed with 50 ml of physiological saline to obtain a clear infusion preparation.

[0055]

Example 15 220 mg of acreasin Aγ, 100 mg of dipotassium glycyrrhizinate and cysteine hydrochloride 1
0 mg was taken, 10 ml of sterile distilled water was added, and the mixture was solubilized using an ultrasonic cleaner (60 minutes). After sterile filtration with a 0.22 μm membrane filter, 1 ml of each was aseptically dispensed into a vial and freeze-dried to obtain an injection for dissolution before use. This vial was taken, dissolved in 1 ml of sterile distilled water, and mixed with 50 ml of physiological saline to obtain a clear infusion preparation.

[0056]

EFFECTS OF THE INVENTION By using glycyrrhizin as a solubilizer for acrysin which is poorly soluble in water, it is possible to provide a highly safe solubilized aqueous composition or a dried composition thereof. It was Furthermore, the composition of the present invention is excellent in storage stability of acreasins. Further, by adding sodium salicylate or sodium benzoate to the above composition, it became possible to increase the amount of dissolved acreasins. further,
By adding amino acids, it became possible to obtain a formulation that does not become cloudy even when mixed infusion with an infusion solution.

Front page continuation (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 47/26 G 7433-4C // C07K 7/56 7306-4H C07K 99:00

Claims (4)

[Claims] 1. A solubilizing agent for acreacins containing glycyrrhizin as an active ingredient. 2. An aqueous composition of acreasins or a dry composition thereof, which contains acreasins and glycyrrhizins. 3. An aqueous composition of acreasins or a dry composition thereof, which contains acreasins, glycyrrhizins and sodium salicylate or sodium benzoate. 4. An aqueous composition of acreasins or a dry composition thereof, which contains acreasins, glycyrrhizins and amino acids.