JP6950966B2 - Sugamadex or its pharmacologically acceptable salt-containing liquid and its production method - Google Patents

Description

The present invention relates to Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, and a method for producing the same.

The efficacy and effect of sodium sugammadex is recovery from muscle relaxant state due to rocuronium bromide or vecuronium bromide (Non-Patent Document 1). Shading is essential as a storage method (Non-Patent Document 1).

Bridion® IV 200 mg, Bridion® 500 mg IV, package insert, revised October 2015 (7th edition)

An object of the present invention is to provide Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, which has improved photostability and does not necessarily require light-shielding storage.

As a result of intensive studies to solve the above problems, the present inventors have performed high-pressure steam sterilization, which is usually performed for sterilization, in the production of Sugamadex or its pharmacologically acceptable salt-containing liquid preparation. Based on this finding, it was found that Sugamadex or its pharmacologically acceptable salt-containing liquids improved photostability and did not necessarily require light-shielded storage by performing only filtration sterilization without performing the procedure. Research has progressed and the present invention has been completed.

That is, the present invention relates to the following invention.
[1] A method for producing Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, which comprises performing filtration sterilization without performing high-pressure steam sterilization in the sterilization step.
[2] Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, which is not sterilized by autoclaving but is sterilized by filtration.
[3] Using a D65 lamp, the amount of substance other than Sugamadex or its pharmacologically acceptable salt after irradiation with a total illuminance of 1.2 million lux · hr is 10% by mass or less based on the entire preparation. Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof.
[4] Sugamadex produced by the method of the above [1] or a pharmacologically acceptable salt-containing liquid agent thereof.

The present invention can provide Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, which has improved photostability and does not necessarily require light-shielding storage.
With respect to the degree of improvement in photostability, the degree of photodegradation is preferably less than one-tenth that of conventional products, namely Sugamadex or its pharmacologically acceptable salt-containing liquids that are vapor sterilized. Can reach up to.

Production Method The present disclosure comprises a method for producing Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof (hereinafter, the production method of the present invention), which comprises performing filtration sterilization in a sterilization step without performing high-pressure steam sterilization. Also called.).
Here, as the pharmacologically acceptable salt of Sugamadex, for example, a salt with a monovalent alkali metal such as a sodium salt or a potassium salt, or a divalent alkaline earth metal such as a magnesium salt or a calcium salt. And the like, preferably a salt with a monovalent alkali metal such as a sodium salt or a potassium salt. Sugamadex or a pharmacologically acceptable salt thereof can be obtained, for example, by the synthetic method described in Example 4 of Japanese Patent No. 3880041 or a method equivalent thereto.

The production method of the present invention is characterized in that high pressure steam sterilization is not performed. High-pressure steam sterilization is usually synonymous with autoclave sterilization. As used herein, the term high pressure steam sterilization typically uses a high pressure steam sterilizer (autoclave), eg, 115-118 ° C for 30 minutes, 121-124 ° C for 15-20 minutes, or 126-129 ° C. It is carried out under the condition of 10 minutes, and is carried out until the object reaches a sterile state. The production method of the present invention is not excluded when insufficient high-pressure steam sterilization that does not satisfy the above conditions is performed.

In the production method of the present invention, filtration sterilization is performed in the sterilization step. Filtration sterilization has been well established in the past and may be followed in the present invention. That is, the filtration sterilization method is not particularly limited as long as it does not interfere with the effect of the present invention, and a known method or a method known per se may be followed. The maximum pore size of the membrane filter used for filtration sterilization is preferably about 0.1 to 0.5 μm. The material of the membrane filter used for filtration sterilization is preferably PVDF (polyvinylidene fluoride), PES (polyether sulfone), PTFE (polytetrafluoroethylene), MCE (cellulose mixed ester) and the like.
In the production method of the present invention, other sterilization (γ-ray sterilization, dry heat sterilization, etc.) may be performed in the sterilization step as long as the effects of the present invention are not impaired.

In the present disclosure, "about" and "degree" are terms used with the intention of including even a slight deviation, for example. These terms are, for example, within ± 5%, within ± 2%, within ± 1%, within ± 0.5%, within ± 0.2%, within ± 0.1% or within ± 0.05%. May point. Such ranges also include cases within experimental error that are specific to the standard methods used to measure and / or quantify a given value or range.

The production method of the present invention preferably mixes a medicinal ingredient other than sugammadex or a pharmacologically acceptable salt and solvent thereof, and optionally an additive or sugammadex or a pharmacologically acceptable salt thereof. Has a mixing step.
The filtration sterilization step may be performed before the mixing step, during the mixing step, or after the mixing step, but it is preferably performed at least after the mixing step.

The production method of the present invention preferably further includes a filling step of filling the container with the obtained liquid agent after the mixing step and the sterilization step, or after the mixing step and before the sterilization step. The container is not particularly limited as long as it does not interfere with the effect of the present invention, and may be made of glass, plastic, transparent, colored, or the like.

Liquid agent The liquid agent produced by the production method of the present invention is hereinafter referred to as the liquid agent of the present invention. The feature of the liquid agent of the present invention is that it does not have a history of high-pressure steam sterilization but has a history of filtration sterilization. The concentration of sugammadex or a pharmacologically acceptable salt thereof in the liquid preparation of the present invention is preferably about 1 to 250 mg / mL, more preferably about 10 to 250 mg / mL, and particularly preferably about 10 to 200 mg / mL. Is.

The solvent used for producing the liquid preparation of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, and is, for example, water (water for injection, purified water, distilled water, etc.), glycerin, ethanol, propylene glycol, polyethylene glycol. , Macrogol, edible oil (sesame oil, corn oil, olive oil, etc.) or a mixture thereof, and water (water for injection, purified water, distilled water, etc.) is preferable.
The content of the solvent is not particularly limited as long as it does not interfere with the effect of the present invention, but is usually about 75 to 99.9% by mass, preferably about 75 to 99% by mass, particularly about 75 to 99% by mass, based on the entire liquid preparation. It is preferably about 80 to 99% by mass.

If necessary, the liquid preparation of the present invention may contain additives in addition to Sugamadex or a pharmacologically acceptable salt and solvent thereof. Examples of the additive include a pH adjuster, a solubilizing agent, an tonicity agent, an antioxidant (antioxidant), a preservative, a stabilizer, a suspending agent, a buffering agent and the like. If necessary, other known additives commonly used in the pharmaceutical field or pharmacologically acceptable additives can also be used. These additives can be used alone or in combination of two or more, depending on the form of the target liquid. These additives may be produced by a known method, or commercially available products may be used. When additives are contained, their content is preferably about 0.001 to 5% by mass, more preferably about 0.001 to 3% by mass, and about 0.01 to 3% by mass with respect to the entire liquid preparation. % Is particularly preferable. As long as the content is within the above range, the effects of these components can usually be sufficiently exerted, and the effects of the present invention are not lost.

Examples of the pH adjuster include organic acids (eg, acetic acid, carbonic acid, trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartrate acid, D-tartrate acid, citric acid, DL-apple acid, lactic acid. , Shuic acid, benzoic acid, besilic acid, ascorbic acid, adipic acid, gluconic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, edetonic acid, etc.), inorganic acids (eg, hydrochloric acid, phosphoric acid, etc.) Acids such as boric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid, etc., salts thereof (with organic or inorganic bases) or hydrates thereof; or ammonia, monoethanolamine, diethanolamine, diisopropanol Examples thereof include organic or inorganic bases such as amine, triisopropanolamine, tromethamole, triethylamine, meglumin, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, or hydrates thereof.
Examples of the solubilizing agent include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, D-mannitol, glycerin and the like, and sodium chloride is preferable. The content of the tonicity agent such as sodium chloride can be determined by a well-known calculation method for the amount to be isotonic with respect to the entire liquid preparation.
Examples of the antioxidant (antioxidant) include t-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, L-cysteine hydrochloride, sodium bisulfite, α-tocopherol, polyphenol, ascorbic acid or derivatives thereof. Be done.
Examples of the preservative include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
Examples of the stabilizer include casein, casein sodium salt and the like.

The liquid preparation of the present invention may contain other medicinal ingredients, or may be used in combination with other medicinal ingredients. Such other medicinal ingredients are not particularly limited as long as they do not interfere with the effects of the present invention, but for example, recovery from a muscle relaxant state due to rocuronium bromide or vecuronium bromide; rocuronium bromide or vecuronium bromide, etc. A drug having; or a drug having an effect and effect different from such an effect and effect; and the like may be used.

The pH of the liquid preparation of the present invention is preferably, for example, about 6 to 8. When the pH is significantly lower than 6, precipitates are likely to be formed, and when the pH is significantly higher than 8, the pH is likely to decrease. Moreover, when it is within this range, the irritation to the subject can be reduced. The pH can be adjusted, for example, by including the above pH adjusting agent in the liquid preparation.
The osmotic pressure of the liquid agent of the present invention is not particularly limited, and may be, for example, about 250 to 1000 mOsmol / kg, or 260 to 600 mOsmol / kg. Within this range, irritation to the subject can be reduced.

The pharmaceutical form of the liquid agent of the present invention may be, for example, an aqueous solution, a suspension, an emulsion, or the like, but is preferably an aqueous solution.

Examples of preferred embodiments of the liquid preparation of the present invention are shown below.
(1) A liquid preparation consisting of Sugamadex or a pharmacologically acceptable salt and water thereof.
(2) A liquid preparation consisting of Sugamadex or a pharmacologically acceptable salt, water and a pH adjuster thereof.
(3) A liquid preparation which is substantially composed of Sugamadex or a pharmacologically acceptable salt and water thereof, is not sterilized by high pressure steam, and is sterilized by filtration.
(4) Substantially composed of sugammadex or its pharmacologically acceptable salt and water, using a D65 lamp, sugammadex or its pharmacologically acceptable after irradiation with a total illuminance of 1.2 million lux · hr. A liquid preparation characterized in that the amount of substance other than salt is 10% by mass or less based on the total amount of the preparation.
(5) Consistently composed of Sugamadex or its pharmacologically acceptable salt and water, not autoclaved, filtered and sterilized, and using a D65 lamp, the total illuminance is 1.2 million lux. -A liquid preparation characterized in that the amount of substance other than sugammadex or a pharmacologically acceptable salt thereof after irradiation with light of hr is 10% by mass or less based on the total amount of the preparation.
(6) A liquid agent comprising substantially Sugamadex or a pharmacologically acceptable salt, water and a pH adjuster thereof, which are not sterilized by high pressure steam but are sterilized by filtration.
(7) Substantially composed of Sugamadex or a pharmacologically acceptable salt, water and a pH adjuster thereof, Sugamadex or its pharmacology after irradiation with a total illuminance of 1.2 million lux · hr using a D65 lamp. A liquid preparation, wherein the amount of substance other than the salt allowed in the preparation is 10% by mass or less based on the total amount of the preparation.
(8) Substantially composed of Sugamadex or its pharmacologically acceptable salt, water and pH adjuster, not autoclaved but filtered and sterilized, and total illuminance using a D65 lamp. A liquid preparation, wherein the amount of substance other than sugammadex or a pharmacologically acceptable salt thereof after irradiation with light of 1.2 million lux · hr is 10% by mass or less based on the total amount of the preparation.
(9) A liquid agent containing Sugamadex or a pharmacologically acceptable salt and water thereof, which is not sterilized by high pressure steam but is sterilized by filtration.
(10) Other than Sugamadex or its pharmacologically acceptable salt after irradiation with a total illuminance of 1.2 million lux · hr using a D65 lamp containing sugammadex or its pharmacologically acceptable salt and water. A liquid preparation, characterized in that the amount of substance of the above is 10% by mass or less based on the total amount of the preparation.
(11) It contains Sugamadex or its pharmacologically acceptable salt and water, is not autoclaved, is not sterilized by filtration, and uses a D65 lamp, and has a total illuminance of 1.2 million lux · hr. A liquid preparation, wherein the amount of substance other than sugammadex or a pharmacologically acceptable salt thereof after irradiation with light is 10% by mass or less based on the total amount of the preparation.
(12) A liquid agent containing Sugamadex or a pharmacologically acceptable salt, water and a pH adjuster thereof, which is not sterilized by high pressure steam but is sterilized by filtration.
(13) Sugammadex or its pharmacologically acceptable salt, water and a pH adjuster, using a D65 lamp, and sugammadex or its pharmacologically acceptable after irradiation with a total illuminance of 1.2 million lux · hr. A liquid preparation characterized in that the amount of substance other than the salt to be produced is 10% by mass or less based on the total amount of the preparation.
(14) It contains Sugamadex or its pharmacologically acceptable salt, water and pH adjuster, is not autoclaved and is filter sterilized, and uses a D65 lamp as a total illuminance of 120. A liquid preparation characterized in that the amount of a substance other than sugammadex or a pharmacologically acceptable salt thereof after irradiation with light of 10,000 lux · hr is 10% by mass or less based on the total amount of the preparation.
(15) Other than Sugamadex or its pharmacologically acceptable salt after irradiation with a total illuminance of 1.2 million lux · hr using a D65 lamp and not being sterilized by high-pressure steam and sterilized by filtration. Sugamadex or a pharmacologically acceptable salt-containing liquid preparation thereof, wherein the amount of substance of Sugamadex is 10% by mass or less based on the total amount of the preparation.

Method of Use The liquid preparation of the present invention can be used, for example, for humans and other mammals (eg, rats, mice, guinea pigs, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.).
Since the liquid preparation of the present invention is safe and has low toxicity, it can be administered in a sufficient amount to, for example, humans and other mammals.

The liquid preparation of the present invention is preferably an injection liquid preparation, an eye drop, an oral administration agent, or the like, and particularly preferably an injection liquid preparation. A sterilization step is indispensable in the manufacturing process of the liquid for injection, but in the present invention, sugammadex in the liquid or pharmacologically thereof by high-pressure steam sterilization (and by subsequent light irradiation). While the total amount of related substances allowed in the salt increases, if filtration sterilization is performed instead of high-pressure steam sterilization for sterilization, even if it is subsequently irradiated with light, sugammadex in the liquid or its pharmacology A particularly excellent feature of the present invention is that it has been clarified that the increase in the total amount of related substances of the allowable salt is significantly reduced.

The dose varies depending on the administration target, target organ, symptom, administration method, etc., but for example, in the case of an injectable solution, when a human body weight is about 60 kg, it is about 0.01 to 1000 mg per day in terms of sugammadex. It is convenient to administer about 50 to 1000 mg, preferably about 50 to 1000 mg by a known administration method. The total daily dose may be a single dose or a divided dose.

In addition, the solution of the present invention is administered systemically or locally through transmucosa such as transdermal, subcutaneous, intradermal, intramuscular, near nerve, intradental, intraspinal, epidural space, intravenous, or instillation. You may. The dose may be varied to obtain and / or maximize the therapeutic effect of the solution, according to the common sense of those skilled in the art.

The usage and dosage of the liquid preparation of the present invention may be the same as that of the conventionally known Sugamadex or a pharmacologically acceptable salt-containing liquid preparation thereof. Of course, it may be determined by the condition and symptoms of the patient by the doctor.

How to confirm that the problem has been solved The fact that the photostability of the liquid agent has been improved and that light-shielding storage is not always necessary is that, for example, a light tester (manufactured by Nagano Science Co., Ltd.) is used and a D65 lamp is used as a light source. The amount of substance other than Sugamadex or its pharmacologically acceptable salt after irradiation with a total illuminance of 1.2 million lux · hr is 10% by mass or less (preferably 5% by mass or less, more preferably 5% by mass or less) with respect to the entire preparation. Is 3% by mass or less, more preferably 2.5% by mass or less). The "after" in "after irradiation with a total illuminance of 1.2 million lux · hr" may be any time point immediately after the irradiation and one month after the irradiation. A substance other than Sugamadex or a pharmacologically acceptable salt thereof means, for example, a solute other than Sugamadex or a pharmacologically acceptable salt thereof in a liquid preparation, and Sugamadex or a pharmacologically acceptable salt thereof. Examples of salt relatives (eg, sugammadex or its pharmacologically acceptable salt intermediates, degradation products, etc.). A method of irradiating a total illuminance of 1.2 million lux · hr using a D65 lamp and a method of measuring the amount of a substance other than Sugamadex or a pharmacologically acceptable salt thereof with respect to the entire preparation are known methods or methods known per se. In more detail, the examples described later can be referred to.

With respect to the degree of improvement in photostability, preferably, the degree of photodegradation confirmed by the above method is 10 of the conventional product, that is, Sugamadex sterilized by high pressure vapor or a pharmacologically acceptable salt-containing liquid agent thereof. It can reach less than a fraction.

Since the photostability of the liquid agent of the present invention is improved, it is usually not necessary to store the liquid agent of the present invention in the dark. When the liquid agent of the present invention is not stored in a light-shielded manner, the options for the storage method of the liquid agent are increased, the storage and management of the liquid agent is facilitated, and the burden on the medical staff and the patient is reduced. Further, even if the liquid agent of the present invention is stored in the light-shielded state, the improvement of the light stability which is the effect of the present invention is not hindered. Therefore, the liquid agent of the present invention may be stored in the light-shielded state.

The present invention includes various combinations of the above configurations within the technical scope of the present invention as long as the effects of the present invention are exhibited.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples, and many modifications are made in the art within the technical idea of the present invention. It is possible by a person with ordinary knowledge.

In the following experimental example, high-pressure steam sterilization was performed using an autoclave (trade name SM200; manufactured by Yamato Scientific Co., Ltd.) at 121 ° C. for 20 minutes. Filtration sterilization was performed by filtering using a PVDF membrane filter having a maximum pore size of 0.22 μm. For 1.2 million lux · hr, a D65 lamp, which is a standard light source defined by the International Commission on Illumination (CIE), is used. For example, the illuminance per hour is 4,200 to 3,800 lux, and the total illuminance is 1.2 million lux · hr. It shows that it was irradiated with the light of. The total amount of related substances was determined by using high performance liquid chromatography (detector: ultraviolet absorptiometer, column: octadecylsilylated silica gel, column temperature: 40 ° C., mobile phase: phosphate buffer / acetonitrile, flow rate sample: 20 μL). It was calculated by the area percentage method.

(Manufacturing of Sugamadex sodium)
Sodium sugammadex is obtained by the synthetic method described in Example 4 of Japanese Patent No. 3880041. Sugamadex sodium, that is, the method for producing 6-per-deoxy-6-per- (2-carboxyethyl) thio-γ-cyclodextrin, sodium salt in Example 4 of Japanese Patent No. 3880041. Paragraph 0046 of the book states as follows.
3-mercaptopropionic acid (1.22 ml, 14.0 mmol) was dissolved under _{N 2} at room temperature in dry DMF (45 ml). Sodium hydride (1.23 g, 30.8 mmol; 60%) was added to this solution in 3 portions and the mixture was stirred for an additional 30 minutes. A 45 ml dry DMF solution of 6-per-deoxy-6-per-iodo-γ-cyclodextrin (3.12 g, 1.40 mmol) was added dropwise to this mixture. After the addition, the reaction mixture was heated at 70 ° C. for 12 hours. After cooling, water (10 ml) was added to the mixture, the volume was reduced to 40 ml by reduced pressure, and ethanol (250 ml) was added thereto to precipitate. The solid precipitate was collected by filtration and dialyzed for 36 hours. This volume was then reduced to 20 ml by reduced pressure. Ethanol is added to this, and the precipitate is collected by filtration and dried to obtain the title compound (6-per-deoxy-6-per- (2-carboxyethyl) thio-γ-cyclodextrin, sodium salt) as a white solid (sodium salt). Obtained as 1.3 g, 43%). _{^{1 H-NMR (D 2 O}} ) δ2.47~2.51 (m, 16H); 2.84~2.88 (m, 16H); 3.00~3.02 (t, 8H); 3. 11 to 3.14 (t, 8H); 3.62 to 3.68 (m, 16H); 3.92 to 3.97 (m, 8H); 4.04 to 4.06 (m, 8H); 5.19 (m, 8H) ppm. MS FIA + ions at 2024.9 m / z

[Experimental Example 1]
Sodium sugammadex was dissolved in Japanese Pharmacopoeia water for injection to prepare a 100 mg / mL aqueous solution. The pH is not adjusted. The storage conditions for each sample are as shown in the table below.
The results are shown in Table 1 below.

In the above table, "after 1.2 million lux · hr", "1.2 million lux · hr after high pressure steam sterilization", "1.2 million lux · hr after filtration sterilization" and "after sterilization and light irradiation" Means after an arbitrary fixed time (for example, one day) has elapsed within two days.

From the above results, it was confirmed that in Example 1, the total amount of related substances could be suppressed to a low concentration by filtration sterilization even by subsequent light irradiation (Reference Example 1, Reference Example 5 and Example 1). .. Moreover, from the comparison of Reference Examples 1 and 5, it was confirmed that the filtration sterilization itself does not affect the increase in the total amount of related substances. On the other hand, in Comparative Example 1, it was confirmed that by high-pressure steam sterilization, the total amount of related substances was remarkably increased by the subsequent light irradiation, the photostability was low, and light-shielded storage was necessary (Reference Example 1, Reference example 2 and comparative example 1). Further, from the comparison between Reference Examples 1 and 2 and the comparison between Reference Examples 3 and 4, it was confirmed that the high-pressure steam sterilization itself affects the increase in the total amount of related substances.

[Experimental Example 2]
Sodium sugammadex was dissolved in Japanese Pharmacopoeia water for injection, and an appropriate amount of 1 mol / L hydrochloric acid or sodium hydroxide was added to adjust the pH to prepare a 100 mg / mL aqueous solution.
The results are shown in Table 2 below.

In the above table, "1.2 million lux · hr after high-pressure steam sterilization" and "after" in "after sterilization and light irradiation" mean after an arbitrary fixed time (for example, 1 day) within 2 days.

From the above results, it was confirmed that by high-pressure steam sterilization regardless of the pH of the sodium sugammadex sodium-containing liquid, the total amount of related substances was significantly increased by subsequent light irradiation, the light stability was low, and light-shielded storage was necessary. (Comparative Examples 2 to 8).

[Experimental Example 3]
Sodium sugammadex was dissolved in Japanese Pharmacopoeia water for injection, and an appropriate amount of 1 mol / L hydrochloric acid or sodium hydroxide was added to adjust the pH to prepare a 100 mg / mL aqueous solution.
The results are shown in Table 3 below.

In the above table, "after 1.2 million lux · hr after filtration sterilization" and "after sterilization and light irradiation" means after an arbitrary fixed time (for example, 1 day) within 2 days.

From the above results, it was confirmed that the total amount of related substances can be suppressed to a low concentration by filtration sterilization regardless of the pH of the sodium sugammadex sodium-containing liquid, even by subsequent light irradiation (Examples 2 to 8).

INDUSTRIAL APPLICABILITY The present invention is useful for producing Sugamadex or a pharmacologically acceptable salt-containing liquid preparation thereof. In particular, it is useful for the production of Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof, which has improved photostability and does not necessarily require light-shielding storage.

Claims (2)

In the sterilization step, and carrying out filtration sterilization only, Sugamadekusu or a pharmacologically acceptable method for producing a salt-containing solution. The liquid agent uses a D65 lamp, and the amount of substance other than Sugamadex or its pharmacologically acceptable salt after irradiation with a total illuminance of 1.2 million lux · hr is 5 % by mass or less with respect to the entire preparation. , The method for producing Sugamadex or a pharmacologically acceptable salt-containing liquid agent thereof according to claim 1.