WO2021161876A1

WO2021161876A1 - Bendamustine liquid preparation

Info

Publication number: WO2021161876A1
Application number: PCT/JP2021/003981
Authority: WO
Inventors: 橋本　真一
Original assignee: 富士フイルム株式会社
Priority date: 2020-02-10
Filing date: 2021-02-03
Publication date: 2021-08-19
Also published as: JPWO2021161876A1

Abstract

A bendamustine liquid preparation comprising a liquid composition and a container in which the liquid composition is enclosed, in which the liquid composition comprises bendamustine or a salt thereof, polyethylene glycol, and at least one component selected from the group consisting of ascorbic acid, an ascorbic acid derivative and a salt of ascorbic acid or the ascorbic acid derivative in which the total content of propylene glycol and glycerin is less than 1% by mass relative to the whole mass of the liquid composition, and the oxygen concentration in a gas in the container is 10% by volume or less or the ratio of the number of molecules of oxygen to the number of molecules of bendamustine or a salt thereof in the bendamustine liquid preparation is 0.10 or less.

Description

Bendamustine solution

This disclosure relates to bendamustine solution.

Bendamustine is a compound having the following structure used for the treatment of cancers such as malignant lymphoma (for example, low-grade B-cell non-Hodgkin's lymphoma, mantle cell lymphoma) and chronic lymphocytic leukemia.

Conventionally, in a liquid preparation containing bendamustine, propylene glycol or glycerin has been used for the purpose of assisting the dissolution of bendamustine in addition to polyethylene glycol which is the main solvent of bendamustine.
Further, it is known that various bendamustine analogs are produced over time in a liquid preparation containing bendamustine. In order to improve the stability of the preparation, a bendamustine-containing liquid preparation containing an antioxidant is being studied.

For example, Japanese Patent Application Laid-Open No. 2019-99557 discloses bendamustine or a pharmaceutically acceptable salt thereof, and a bendamustine-containing solution preparation containing polyethylene glycol and glycerin. Specifically, a bentamustine-containing solution preparation containing a solvent in which polyethylene glycol and concentrated glycerin are mixed in a volume ratio of 95: 5 to 80:20 and, if desired, an antioxidant such as α-thioglycerol and ascorbic acid is disclosed. Has been done.

Japanese Patent Application Laid-Open No. 2015-506989 discloses a mixture of polyethylene glycol and propylene glycol, and a bendamustine-containing composition containing an antioxidant. Specifically, a bendamustine-containing composition in which thioglycerol is mixed as an antioxidant in a solvent obtained by mixing polyethylene glycol and propylene glycol in a volume ratio of 90:10 is disclosed.

Japanese Patent Application Laid-Open No. 2016-20365 describes bendamustine or a pharmaceutically acceptable salt thereof, one of the group consisting of polyethylene glycol, propylene glycol, and a mixture thereof, and antioxidants such as thioglycerol and lipoic acid. Bendamustine-containing compositions containing, are disclosed.

U.S. Patent Application Publication No. 2016/0310598 describes that an antioxidant such as ascorbic acid or sodium sulfite may be used in a bendamustine preparation using N-methylpyrrolidone as a solvent.

U.S. Pat. May be added. Further, as a specific formulation, a formulation using a solvent containing polyethylene glycol and glycerin is disclosed.

There are various analogs of bendamustine, and one of them is a bendamustine analog that appears at a relative retention time (hereinafter, also referred to as RRT) of 0.43 on a high performance liquid chromatograph (HPLC). However, in previous studies on bendamustine solutions, there was room for improvement in suppressing the formation of analogs appearing in RRT 0.43. Furthermore, from the viewpoint of ensuring storage stability suitable for clinical use, it is also desired to suppress the production amount of other analogs, particularly the maximum production amount, in addition to the analogs appearing in RRT0.43.

On the other hand, glycerin or propylene in polyethylene glycol described in JP-A-2019-99557, JP-A-2015-5061989, JP-A-2016-20365, and US Patent Application Publication No. 2019/0151234. With a bendamstin solution using a solvent containing a certain amount of glycol (for example, 5% by volume or more), it was difficult to sufficiently suppress the formation of analogs. In addition, Japanese Patent Application Laid-Open No. 2019-99557, Japanese Patent Application Laid-Open No. 2015-506989, Japanese Patent Application Laid-Open No. 2016-20365, US Patent Application Publication No. 2016/0310598, and US Patent Application Publication No. 2019/0151234. Although it has been proposed that an antioxidant may be added to the bendamustine solution, it has not been verified which formulation of the antioxidant can effectively suppress the amount of relatives produced.

In addition, in the bendamustine solution, coloring may progress over time during storage. Since coloring of the liquid agent is not desirable in practice, it is desirable to suppress the progress of coloring during storage as much as possible.

In view of such circumstances, the present disclosure can suppress the amount of bentamustine analogs produced at a relative retention time of 0.43 on a high performance liquid chromatograph and the maximum amount of other bentamustine analogs produced, and the progress of coloring. The present invention relates to providing a bendamustine solution capable of suppressing.

Specific means for solving the above problems include the following embodiments.
<1> Bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof are contained, and the total content of propylene glycol and glycerin is the liquid composition. A liquid composition that is less than 1% by mass based on the total mass of the product,
A container for enclosing the liquid composition and
Bendamustine solution, wherein the oxygen concentration in the gas in the container is 10% by volume or less.
<2> The bendamustine solution according to <1>, wherein the oxygen concentration in the gas in the container is 5% by volume or less.
<3> Bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof are contained, and the total content of propylene glycol and glycerin is the liquid composition. A liquid composition that is less than 1% by mass based on the total mass of the product,
A container for enclosing the liquid composition and
Bendamustine solution, wherein the ratio of the number of oxygen molecules to the number of molecules of bendamustine or a salt thereof in the bendamustine solution is 0.10 or less.
<4> The bendamustine solution according to <3>, wherein the ratio of the number of oxygen molecules to the number of molecules of bendamustine or a salt thereof in the bendamustine solution is 0.05 or less.
<5> The content of at least one selected from the group consisting of ascorbic acid, ascorbic acid derivatives, and salts thereof in the liquid composition is 0.001% by mass to 1.50% by mass in terms of ascorbic acid. The bendamustine solution according to any one of <1> to <4>.
<6> The content of at least one selected from the group consisting of ascorbic acid, ascorbic acid derivatives, and salts thereof in the liquid composition is 0.003% by mass to 0.25% by mass in terms of ascorbic acid. The bendamustine solution according to any one of <1> to <5>.
<7> The bendamustine solution according to any one of <1> to <6>, wherein at least one selected from the group consisting of ascorbic acid, an ascorbic acid derivative, and a salt thereof is ascorbic acid.
<8> The bendamustine solution according to any one of <1> to <7>, wherein the total content of propylene glycol and glycerin is 0.5% by mass or less based on the total mass of the liquid composition.
<9> The bendamustine solution according to any one of <1> to <8>, wherein the polyethylene glycol contains at least one selected from the group consisting of polyethylene glycol 300 and polyethylene glycol 400.
<10> The bendamustine solution according to any one of <1> to <9>, wherein the polyethylene glycol contains polyethylene glycol 300.

According to the present disclosure, it is possible to suppress the amount of bentamustine analogs produced and the maximum amount of other bentamustine analogs produced at a relative retention time of 0.43 on a high performance liquid chromatograph, and it is possible to suppress the progress of coloring. Bendamustine solution is provided.

Hereinafter, embodiments of the present disclosure will be described. The following description is an example of the embodiments of the present disclosure and does not limit the scope of the invention.

The numerical range indicated by using "-" in the present disclosure means a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.
In the present disclosure, in the numerical range described stepwise, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the upper limit value or the lower limit value of another numerical range described stepwise. Further, in the numerical range described in the present disclosure, the upper limit value or the lower limit value of a certain numerical range may be replaced with the values shown in the examples.
In the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.
When referring to the amount of each component in the composition in the present disclosure, if a plurality of substances corresponding to each component are present in the composition, unless otherwise specified, the plurality of substances present in the composition are present. Means the total amount of.
In the present disclosure, the term "process" is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even if it cannot be clearly distinguished from other processes. ..

In the present disclosure, the relative retention time measured by HPLC means the relative retention time when measured under the following conditions.
Detector: Ultraviolet-visible spectrophotometer (measurement wavelength: 254 nm)
Column: Agilent Technologies Zorbox Bonus-RP (particle size 5 μm, inner diameter 4.6 mm, length 150 mm)
Column temperature: Constant temperature around 30 ° C Cleaning solution: Water / methanol mixed solution (volume ratio 1: 1)
Mobile phase A: Water / acetonitrile mixed solution (volume ratio 9: 1), containing 0.1% trifluoroacetic acid Mobile phase B: Water / acetonitrile mixed solution (volume ratio 1: 9), containing 0.1% trifluoroacetic acid Mobile phase Liquid delivery: Concentration gradient control is performed by setting the mixing ratio of mobile phase A and mobile phase B as the mixing ratio shown in Table 1 described later.
Flow rate: 1.0 mL / min Area measurement range: 4 to 30 minutes after injection of test solution

It should be noted that those skilled in the art will understand that the relative retention time may change when the HPLC conditions are different. For example, RRT 0.43 measured under the above conditions may have a relative retention time greater than or less than 0.43 when HPLC analysis is performed under different conditions. In any case, the embodiments of the present disclosure are not limited by the relative retention time of the bendamustine analogs measured by HPLC.

≪Bendamustine solution≫
The Bendamstin liquid preparation (hereinafter, also referred to as “liquid preparation (1)”) according to the first embodiment of the present disclosure is a group consisting of bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and salts thereof. A liquid composition containing at least one selected from the above, wherein the total content of propylene glycol and glycerin is less than 1% by mass based on the total mass of the liquid composition, and a container for enclosing the liquid composition. The oxygen concentration in the gas in the container is 10% by volume or less.

The Bendamstin liquid agent (hereinafter, also referred to as “liquid agent (2)”) according to the second embodiment of the present disclosure is a group consisting of Bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and salts thereof. A liquid composition containing at least one selected from the above, wherein the total content of propylene glycol and glycerin is less than 1% by mass based on the total mass of the liquid composition, and a container for enclosing the liquid composition. The ratio of the number of oxygen molecules to the number of molecules of bendamstin or a salt thereof in the bendamstin solution is 0.10 or less.

One of the various bendamustine analogs, the bendamustine analog that appears at RRT0.43 on HPLC, is an oxide of bendamustine in which one of the chloroethyl groups in the bis (2-chloroethyl) amino group of bendamustine is replaced by a hydrogen atom. It is presumed to have the above-mentioned structure.
In addition, as another main bendamstin analog, an ester obtained by esterifying the carboxy group of bendamstin with a solvent (for example, a PEG ester formed by reacting polyethylene glycol with the carboxy group of bendamstin (RRT1.1 by HPLC). An ester that appears in ~ 1.2), an ester formed by reacting the carboxy group of bendamstin with another solvent, etc.), and water substitution in which one or both of the two chlorine atoms of bendamstin are replaced with hydroxyl groups due to the presence of water. The body, etc. can be mentioned.

The inventor has found that in the liquid preparation (1) and the liquid preparation (2), the maximum production amount of the bendamustine analog appearing in RRT0.43 and other bendamustine is suppressed, and the progress of coloring is suppressed. The reason for this is not always clear, but in the liquid preparation (1) and the liquid preparation (2), in addition to having a low oxygen concentration or a small number of oxygen molecules in the liquid composition, polyethylene glycol is contained and propylene glycol and glycerin are contained. It is considered that ascorbic acid exerts a good antioxidant ability in the composition in which the content is suppressed, so that the generation of oxidants can be suppressed. Further, according to the liquid agent (1) and the liquid agent (2), since the content of propylene glycol and glycerin in the liquid composition is suppressed, the decomposition of bendamustine caused by the hydroxyl group in the propylene glycol and glycerin is suppressed. It is thought that it can be done. Further, according to the liquid preparation (1) and the liquid preparation (2) containing ascorbic acid in the liquid composition containing polyethylene glycol and suppressing the content of propylene glycol and glycerin, the liquid composition is colored over time. It was found that progression could also be suppressed. Therefore, the liquid preparation (1) and the liquid preparation (2) have high storage stability and are considered to be particularly useful for use as an injection liquid preparation or the like.

<Liquid composition>
The liquid preparations (1) and liquid preparations (2) of the present disclosure contain bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof. A liquid composition having a total content of propylene glycol and glycerin of less than 1% by mass based on the total mass of the liquid composition is provided. Hereinafter, each component of the liquid composition in the liquid preparation (1) and the liquid preparation (2) will be described in detail.

[Bendamustine or its salt]
Bendamustine is a compound represented by the structural formula shown below (4- [5- {bis (2-chloroethyl) amino} -1-methyl-2-benzimidazolyl] butanoic acid).

The salt of bendamstin may be any pharmaceutically acceptable salt, and examples thereof include salts of inorganic acids and salts of organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of the organic acid include acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, lactic acid, methylsulfonic acid, p-toluenesulfonic acid and the like.
As the salt of bendamustine, an acid salt prepared from hydrochloric acid, hydrobromic acid, or hydrobromic acid is preferable.
Among them, as the salt of bendamustine, bendamustine hydrochloride is preferable from the viewpoint of actual use.

The content of bendamstin or a salt thereof is 0.01% by mass to 5% by mass with respect to the total mass of the liquid composition in terms of bendamstin from the viewpoint of solubility and medicinal effect of bendamstin in the liquid composition. Preferably, 0.05% by mass to 3% by mass is more preferable, 0.1% by mass to 3% by mass is further preferable, and 1% by mass to 3% by mass is particularly preferable. In the present disclosure, the content of bendamustine or a salt thereof means the content in terms of bendamustine.

When bendamstin hydrochloride is used as bendamstin or a salt thereof, the concentration of bendamstin hydrochloride in the liquid composition is 0.13 mg / mL to 66 mg / from the viewpoint of solubility and medicinal effect of bendamstin hydrochloride in the liquid composition. mL is preferable, 0.66 mg / mL to 40 mg / mL is more preferable, 1.3 mg / mL to 40 mg / mL is further preferable, 13.2 mg / mL to 40 mg / mL is particularly preferable, and 25 mg / mL is most preferable.

[Polyethylene glycol]
Polyethylene glycol is an ethylene glycol polymer (specifically, an addition polymer of ethylene oxide and water), and its molecular formula is represented by HO (C ₂ H ₄ O) _n H (n is an integer). From the viewpoint of application to a liquid agent, those in a liquid state at room temperature (for example, temperature 20 ° C.) or higher are preferable.
As the polyethylene glycol, polyethylene glycol (so-called macrogol) satisfying the standards listed in the Japanese Pharmacopoeia or the pharmaceutical additive standard is preferable.
One type of polyethylene glycol may be used alone, or two or more types may be used in combination.

The polyethylene glycol includes polyethylene glycol 200, polyethylene glycol 300 (hereinafter, also referred to as PEG300), polyethylene glycol 400 (hereinafter, also referred to as PEG400), polyethylene glycol 600, and polyethylene glycol 1000 from the viewpoint of solubility of bendamstin or a salt thereof. Of these, at least one selected from the group consisting of polyethylene glycol 300 and polyethylene glycol 400 is preferable from the viewpoint of actual use, and for example, polyethylene glycol 300 and polyethylene glycol 400 may be used in combination. good.
Polyethylene glycol 300 (PEG300) is a polyethylene glycol having a molecular weight distribution, which is mainly composed of n = 6 and n = 7 molecules in the above molecular formula, has an average molecular weight of 300, and is colorless and transparent at room temperature. It is a viscous liquid. Polyethylene glycol 400 (PEG400) is a polyethylene glycol having a molecular weight distribution, which is mainly composed of n = 8 and n = 9 molecules in the above molecular formula, has an average molecular weight of 400, and is colorless and transparent at room temperature. It is a viscous liquid.

Among them, polyethylene glycol has excellent solubility of bendamstin or a salt thereof, and has a melting point of -10 ° C or less so that the liquid does not freeze even in refrigerated storage, which makes it easy to handle, and further, viscosity. Polyethylene glycol 300 (PEG300) is particularly preferable from the viewpoint that the amount is relatively low and it is easy to extract the required amount of the liquid at the time of administration.

The content of polyethylene glycol is preferably 86.0% by mass to 99.9% by mass and 90.0% by mass to the total mass of the liquid composition from the viewpoint of solubility and medicinal effect of bendamstin or a salt thereof. 99.0% by mass is more preferable, 95.0% by mass to 99.0% by mass is further preferable, and 95.0% by mass to 98.0% by mass is particularly preferable.

The liquid composition may or may not contain other solvents in addition to polyethylene glycol. Examples of the solvent other than polyethylene glycol include propylene glycol and glycerin, which will be described later. The ratio of polyethylene glycol to the total mass of the solvent is preferably 90.0% by mass or more, more preferably 95.0% by mass or more, further preferably 97.5% by mass or more, and 99. It is particularly preferable that the content is 0.0% by mass or more. Here, the solvent refers to a liquid medium having a solubility of bendamustine of 1.0 mg / mL or more at 25 ° C.

[Ascorbic acid, ascorbic acid derivatives, and salts thereof]
The liquid preparation (1) or the liquid composition according to the liquid preparation (2) contains at least one selected from the group consisting of ascorbic acid, ascorbic acid derivatives, and salts thereof. Hereinafter, "at least one selected from the group consisting of ascorbic acid, ascorbic acid derivatives, and salts thereof" is also collectively referred to as "ascorbic acid group". The ascorbic acid group may be used alone or in combination of two or more.

Ascorbic acid may be a commercially available product. Examples of commercially available products include "ascorbic acid" (trade name) manufactured by Kyowa Pharma Chemical Co., Ltd. and "ascorbic acid bulk powder" Takeda "(trade name) manufactured by Takeda Pharmaceutical Company Limited.

The ascorbic acid derivative is not particularly limited as long as it is a pharmaceutically acceptable ascorbic acid derivative, and examples thereof include ascorbic acid fatty acid ester, ascorbic acid phosphate ester, ascorbic acid glucoside, and ascorbic acid alkyl ether.
More specifically, ascorbic acid derivatives include ascorbic acid such as ascorbic acid monostearate, ascorbyl monopalmitate, ascorbyl monoisopalmitate, ascorbic monooleate, ascorbyl distearate, ascorbyl dipalmitate, and ascorbyl monopalmitate. Fatty acid ester; ascorbic acid phosphate such as ascorbic acid monophosphate ester, ascorbic acid diphosphate ester, ascorbic acid triphosphate ester; ascorbic acid ether such as ethyl ascorbic acid ether, ascorbic acid methyl ether, ascorbic acid glyceryl; ascorbic acid mono Examples thereof include ascorbic acid glucoside such as glucoside and ascorbic acid diglucoside. These ascorbic acid derivatives have a structure in which at least one of the hydroxyl groups at the 6, 2, 3, and 5 positions of ascorbic acid is substituted.

Among them, as the ascorbic acid derivative, at least one selected from the group consisting of ascorbic acid fatty acid ester, ascorbic acid phosphate ester, ascorbic acid glucoside, and ascorbic acid alkyl ether is preferable, and ascorbic acid fatty acid ester and ascorbic acid phosphorus are preferable. At least one selected from the group consisting of acid ester and ascorbic acid glucoside is more preferable, and at least one selected from the group consisting of ascorbic acid fatty acid ester and ascorbic acid glucoside is further preferable.

As the ascorbic acid derivative, a commercially available product may be used. Commercially available products include glyceryl ascorbic acid (trade name: Glyceryl Ascorbate) manufactured by Fujifilm Shonan Wako Co., Ltd. and ascorbic monopalmitate (trade name: L-ascorbyl palmitate); 2-glucoside ascorbic acid manufactured by Hayashihara Co., Ltd. (Product name: Ascofresh); and ascorbic magnesium phosphate (trade name: PM ascorbic acid) manufactured by Showa Denko Co., Ltd., ascorbic sodium phosphate (trade name: PS ascorbic acid), and the like can be mentioned.

The salt of ascorbic acid or the ascorbic acid derivative may be any pharmaceutically acceptable salt, and is a salt of ascorbic acid or the ascorbic acid derivative and an alkali metal (for example, sodium, potassium, etc.), ascorbic acid or the ascorbic acid derivative. Salts with alkaline earth metals (eg calcium, magnesium, etc.), ascorbic acid or ascorbic acid derivatives and transition metals (eg zinc, iron, cobalt, copper, etc.), ascorbic acid or ascorbic acid derivatives and bases Examples include salts with sex ammonium, salts with ascorbic acid or ascorbic acid derivatives and triethanolamine, salts with ascorbic acid or ascorbic acid derivatives and amino acids (eg, L-histidine, L-arginine, L-lysine, etc.). Be done.
Among them, as the salt of ascorbic acid or ascorbic acid derivative, sodium ascorbic acid, potassium ascorbic acid, magnesium ascorbic acid, calcium ascorbic acid, sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate and the like are preferable.

Among the ascorbic acid group, ascorbic acid is preferable from the viewpoint of solubility in polyethylene glycol.

The content of the ascorbic acid group in the liquid composition (when a plurality of types of the ascorbic acid group are used in combination, the total content of the plurality of types) is not particularly limited, and the decomposition of bendamstin is well suppressed and the coloring is good. From the viewpoint of suppressing the amount of ascorbic acid, it is preferably 0.001% by mass to 1.500% by mass, and 0.003% by mass to 0.250% by mass, based on the total mass of the liquid composition. More preferably, it is more preferably 0.005% by mass to 0.150% by mass, and particularly preferably 0.005% by mass to 0.020% by mass.

In the present disclosure, "ascorbic acid equivalent" adopts its own mass for ascorbic acid, and for ascorbic acid derivatives, ascorbic acid salts, and ascorbic acid derivative salts, ascorbic acid contained in the derivatives and salts. It means to calculate by adopting the mass of the derived partial structure.

[Propylene glycol and glycerin]
In the liquid composition according to the liquid preparation (1) and the liquid preparation (2), the total content of propylene glycol and glycerin is less than 1% by mass with respect to the total mass of the liquid composition. In other words, the liquid composition contains neither propylene glycol nor glycerin, or at least one selected from the group consisting of propylene glycol and glycerin is more than 0% by mass and 1% by mass with respect to the total mass of the liquid composition. It is contained in a total content of less than%. For example, when the liquid composition contains both propylene glycol and glycerin, the total content of propylene glycol and glycerin is less than 1% by mass based on the total mass of the liquid composition, and the liquid composition is propylene glycol. When the content of propylene glycol is less than 1% by mass based on the total mass of the liquid composition when the liquid composition contains glycerin and does not contain glycerin, and when the liquid composition contains glycerin and does not contain propylene glycol, The content of glycerin is less than 1% by mass based on the total mass of the liquid composition.
When the total content of propylene glycol and glycerin in the liquid composition is less than 1% by mass, the amount of propylene glycol and glycerin that does not substantially affect the formation of bendamustine analogs, especially esters, and the progress of coloring. It is thought that it is suppressed to. Therefore, it is considered that by suppressing the total content of propylene glycol and glycerin in the liquid composition to less than 1% by mass, the formation of bendamustine analogs and the progress of coloring can be suitably suppressed.

The total content of propylene glycol and glycerin is preferably 0.5% by mass or less, more preferably 0.2% by mass or less, based on the total mass of the liquid composition. It is more preferable that it does not contain glycerin (that is, the total content of propylene glycol and glycerin is 0% by mass).

When the liquid composition contains propylene glycol and does not contain glycerin, the content of propylene glycol is less than 1% by mass, preferably 0.5% by mass or less, based on the total mass of the liquid composition. , 0.2% by mass or less, more preferably.

When the liquid composition contains glycerin and does not contain propylene glycol, the content of glycerin is less than 1% by mass, preferably 0.5% by mass or less, based on the total mass of the liquid composition. It is more preferably 0.2% by mass or less.

In the present disclosure, the liquid composition "does not contain propylene glycol and glycerin", "does not contain propylene glycol", or "does not contain glycerin" means that the amount of each component is a measurement limit value in gas chromatography. Means less than. Gas chromatography is performed under the following conditions.
Diluting solvent: Methanol detector: Flame ionization detector Column: Inner surface of a fused silica tube with an inner diameter of 0.32 mm and a length of 30 m, 14% cyanopropylphenyl-86% dimethyl silicone polymer for gas chromatography at a thickness of 1 μm Cover.
Column temperature: Inject at a constant temperature around 100 ° C., raise the temperature to 220 ° C. at 7.5 ° C. per minute, and maintain at a constant temperature around 220 ° C.
Injection port temperature: Constant temperature around 220 ° C Detector temperature: Constant temperature around 250 ° C Carrier gas: Helium Flow rate: Approximately 38 cm / sec Split ratio: 1:20

[PH regulator]
The liquid composition may or may not contain a pH adjuster. The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable. Specific examples of the pH adjuster include hydrochloric acid, sodium hydroxide, sodium hydroxide aqueous solution, potassium hydroxide, potassium hydroxide aqueous solution, magnesium hydroxide, calcium hydroxide, phosphoric acid or a salt thereof, citric acid or a salt thereof. , Tartrate acid or its salt, acetic acid or its salt, succinic acid or its salt, lactic acid or its salt, gluconic acid or its salt, adipic acid or its salt, fumaric acid or its salt, boric acid or its salt, maleic acid or its salt From salt, methanesulfonic acid or a salt thereof, malic acid or a salt thereof, triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, tromethamole (trishydroxymethylaminomethane), glycine, meglumine, and disodium edetate. At least one selected from the above group is preferable: hydrochloric acid, sodium hydroxide, sodium hydroxide aqueous solution, potassium hydroxide, potassium hydroxide aqueous solution, phosphoric acid or a salt thereof, citric acid or a salt thereof, triethanolamine, tromethamole (Tris). At least one selected from the group consisting of hydroxymethylaminomethane) and disodium edetate is more preferable, and from the viewpoint of satisfactorily adjusting the pH, it is selected from the group consisting of an aqueous solution of sodium hydroxide and an aqueous solution of potassium hydroxide. At least one is more preferable, and an aqueous sodium hydroxide solution is particularly preferable. The pH adjuster may be used alone or in combination of two or more.

The content of the pH adjuster is not particularly limited, and may be appropriately set according to the type of the pH adjuster and the like. For example, when a predetermined sodium hydroxide aqueous solution is used as the pH adjuster, the content of the sodium hydroxide aqueous solution is 0.01% by mass to 1.0% by mass with respect to the total mass of the liquid composition. It is more preferable, and it is more preferably 0.05% by mass to 0.50% by mass, and further preferably 0.05% by mass to 0.30% by mass, particularly from the viewpoint of satisfactorily suppressing coloring. ..

When a 1-specified sodium hydroxide aqueous solution is used as the pH adjuster, the mass ratio of the 1-specified sodium hydroxide aqueous solution to the ascorbic acid group (sodium hydroxide aqueous solution / ascorbic acid group) is preferably 0.01. By adjusting in the range of ~ 200, more preferably 0.1 to 150, further preferably 5.0 to 150, and particularly preferably 9.0 to 20.0, while preferably suppressing the decomposition of bendamstin analogs. , The progress of coloring also tends to be suppressed satisfactorily. In one aspect, it is also preferable that the liquid composition does not contain a pH adjuster such as an aqueous sodium hydroxide solution.

[Antioxidants other than ascorbic acid group]
The liquid composition may contain an antioxidant other than the ascorbic acid group. Among the antioxidants other than the ascorbic acid group, examples of the antioxidants that can be suitably used in the liquid composition of the present disclosure include antioxidants having a thiol group.

Antioxidants having a thiol group include cysteine and its salt, thioglycerol, thioglycolic acid and its salt, N-acetylcysteine and its salt, dithioerythol, and 2-mercaptoethane from the viewpoint of antioxidant ability against bendamstin. Preferred are examples of at least one compound selected from the group consisting of sulfonic acid and salts thereof, and thiolinic acid and salts thereof.

The salts of cysteine, thioglycolic acid, N-acetylcysteine, 2-mercaptoethanesulfonic acid, and thioapple acid may be any pharmaceutically acceptable salt, and may be a salt with an alkali metal; with an alkaline earth metal. Salts; salts with transition metals; salts with basic ammonium; and the like.
Specific examples of the salts of cysteine, thioglycolic acid, N-acetylcysteine, 2-mercaptoethanesulfonic acid, and thioannic acid include alkali metal salts with sodium, potassium, and the like; alkaline earth with calcium, magnesium, and the like. Metal salt; Transition metal salt with zinc, iron, cobalt, copper, etc .; Basic ammonium salt with ammonium, triethanolamine, L-histidine, L-arginine, L-lysine, etc .; Hydrochloride, formate, acetate , Maleate, fumarate, tartrate and the like.

Among them, as the antioxidant having a thiol group, thioglycerol, cysteine, cysteine hydrochloride, N-acetylcysteine, thioglycolic acid, and sodium thioglycolate are preferable from the viewpoint of developing antioxidant ability against bendamstin, and polyethylene is preferable. From the viewpoint of solubility in glycol, thioglycerol, cysteine, N-acetylcysteine, and thioglycolic acid are more preferable.

Among antioxidants having a thiol group, thioglycerol is particularly preferable from the viewpoint of developing antioxidant ability for bendamustine and having high solubility in the liquid composition in the liquid preparation.

When the liquid composition contains an antioxidant having a thiol group (preferably thioglycerol), the content of the antioxidant having a thiol group (preferably thioglycerol) is determined from the viewpoint of the expression of antioxidant ability and. From the viewpoint of suppressing the formation of bendamstin analogs, 0.05% by mass to 1.5% by mass is preferable, 0.1% by mass to 1.0% by mass is more preferable, and 0 by mass, based on the total mass of the liquid composition. .1% by mass to 0.8% by mass is more preferable, and 0.1% by mass to 0.5% by mass is particularly preferable.

On the other hand, in the liquid composition according to the liquid agent (1) and the liquid agent (2) of the present disclosure, by using the ascorbic acid group as the antioxidant, RRT0 is performed by HPLC without using other antioxidants in combination. It has been found that the amount of bentamustine analogs produced in .43 and the maximum amount of other bentamustine analogs produced can be satisfactorily suppressed, and the progress of coloring can be suppressed. The total mass of the antioxidant in the liquid composition (for example, when the ascorbic acid group and the antioxidant having a thiol group are used in combination as the antioxidant, the ascorbic acid group and the antioxidant having a thiol group are used in combination. The amount of the ascorbic acid group with respect to the total mass) is preferably 50% by mass or more, more preferably 80% by mass or more, further preferably 90% by mass or more, and 100% by mass (that is, antioxidant). It is particularly preferable to use only the ascorbic acid group as the oxidizing agent).

[Other ingredients]
The liquid composition may optionally contain other pharmaceutically acceptable ingredients.
Other ingredients include tonics, stabilizers, solubilizers, surfactants, sustainers, defoamers, colorants, emulsifiers, dispersants, preservatives, preservatives, solubilizers, solvents. Etc., but are not limited to these. The content of other components can be appropriately set according to the desired purpose.

[PH of liquid composition]
The pH of the liquid composition is preferably 3.3 to 4.0, more preferably 3.3 to 3.8, from the viewpoint of suppressing the decomposition of bendamustine. Is more preferable.
In the present disclosure, the pH is measured by diluting the liquid composition with uncarbonated water and a saturated aqueous potassium chloride solution, and setting the temperature of the diluted liquid to 25 ° C. Specifically, for example, a mixed solution of 100 mg of a liquid agent, 2 mL of uncarbonated water, and 6 μL of a saturated potassium chloride aqueous solution is prepared, and the mixed solution is measured at a temperature of 25 ° C.
The pH measuring method is not particularly limited, and a method generally used as a pH measuring method can be used. For example, the pH can be measured with a pH meter (for example, device model number: F-73, manufactured by HORIBA, Ltd., pH electrode: MicroToup pH electrode 9618-10D).

<Container>
The bentamustine liquid preparation of the present disclosure is a liquid preparation in a container provided with a container for enclosing the above-mentioned liquid composition.
Examples of the container for enclosing the liquid composition include vials, ampoules, syringes (for example, prefilled syringes) and the like. Among them, a vial is preferable as a container for enclosing the liquid composition from the viewpoint of handleability in the medical field.
Further, as the container for enclosing the liquid composition, a container in which the amount of silicon eluted into water when filled with water and heat-treated at 121 ° C. for 60 minutes is preferably 1.0 ppm or less, preferably 0.5 ppm or less. Is more preferred.

Commercially available products can be used as the container for enclosing the liquid composition. For example, Daikyo Seiko Co., Ltd.'s Resin CZ, Fuji Glass Co., Ltd.'s 3010, 3010 Siricoat, FY-5, FY-5 Siricoat, etc. FY-5 Sulfer Treatment, CS-10, CS-10 Siricoat, CS-20 Siricoat, CS-30 Siricoat, CS-40 Siricoat, Daiwa Special Glass Co., Ltd. 23 x 43LA, 23 x 43VIST, Nipro Co., Ltd. VIALEX Etc. can be used.

Further, by using an oxygen-blocking film as the packaging of the container for enclosing the liquid composition, the storage stability of bendamustine or a salt thereof contained in the liquid composition can be improved.
As the material of the film, alumina coated PET (polyethylene terephthalate), silica coated PET, nanocomposite coated PET, PET, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polyvinylidene chloride, vinylidene chloride-methyl acrylate. Copolymers, taxylylene adipamide 6 nylon, biaxially stretched nylon, non-stretched nylon, biaxially stretched polypropylene, high-density polyethylene, non-stretched polypropylene, polyvinylidene, polystyrene, low-density polyethylene and the like can be used.

Oxygen gas permeability of the film, from the viewpoint of storage ^stability, it is preferred that ^{100cm 3 / m 2 · 24h ·} atm or ^less, more preferably ^{10cm 3 / m 2 · 24h ·} atm or less, 2 cm ³ even more preferably less / ^m 2 · 24h · atm.
The container for enclosing the liquid composition may be single-packed using an oxygen-blocking film, or may be multiple-packed using a plurality of oxygen-blocking films.

In the presently disclosed bendamustine solution, from the viewpoint of improving the storage stability of bendamustine or a salt thereof, the oxygen scavenger may be loaded in any of the spaces between the container and the outermost space where the container is packaged.
As oxygen scavengers, iron-based self-reactive oxygen scavengers (manufactured by Mitsubishi Gas Chemicals Co., Ltd., Ageless ZP, Ageless ZJ-PT, Ageless ZJ-PK, Ageless S), iron-based moisture-dependent oxygen scavengers (Mitsubishi Gas) Chemical Co., Ltd., Ageless FX), non-iron self-reacting oxygen scavenger (Mitsubishi Gas Chemicals Co., Ltd., Ageless GLS, Ageless GL-M, Ageless GT) and the like can be used.

[Oxygen concentration in gas in container]
In the liquid agent (1) of the present disclosure, the oxygen concentration in the gas in the container in which the liquid composition is sealed is 10% by volume or less. In the liquid agent (1), the oxygen concentration in the gas in the container containing the liquid composition is 10% by volume, so that the decomposition of bendamustine during storage (particularly, it is represented by RRT 0.43 due to the decomposition of bendamustine). The formation of bendamustine analogs) can be satisfactorily suppressed.

In the liquid agent (1) of the present disclosure, the oxygen concentration in the gas in the container containing the liquid composition is preferably 7% by volume or less, preferably 5% by volume, from the viewpoint of further suppressing the decomposition of bendamstin during storage. % Or less is more preferable, 4% by volume or less, 3% by volume or less, 2% by volume or less, or 1% by volume or less.

In the present disclosure, the oxygen concentration in the gas in the container refers to the oxygen concentration in the gas sealed in the container during the production of the bendamstin solution, the oxygen concentration in the gas in the container immediately after the production of the bendamstin solution, or the bendamstin solution. It refers to the concentration of oxygen in the gas in the container at any one time point within the usable period (for example, within the expiration date for the desired use of the Bendamstin solution).

The gas in the container that encloses the liquid composition is preferably replaced with an inert gas. Nitrogen is preferable as the inert gas. According to the inert gas (particularly nitrogen), the oxygen concentration in the gas in the container containing the liquid composition can be easily adjusted.

The oxygen concentration in the gas in the container is measured by an oxygen concentration meter based on the fluorescence time disappearance type. As the measuring device, for example, a non-destructive needle type oxygen concentration meter (for example, product name: Microx TX3, PreSens, measuring method: fluorescence time disappearance type) is used.
When it is necessary to measure the oxygen concentration in the gas in the container non-destructively (for example, when the container is an ampoule), the following method can be used. For example, as a method of measuring the oxygen concentration in the gas in the ampoule, for example, a method of nondestructively measuring the oxygen concentration in the head space in the container by using the absorption of near-infrared laser light by oxygen. You may. As a method for non-destructively measuring the oxygen concentration in the head space in the container, for example, a head space oxygen analyzer FMS-760 manufactured by Lighthouse Co., Ltd. can be used.

Specific examples of the method for measuring the oxygen concentration in the gas in the container include the following two methods.
(1) The sampler needle portion of the oxygen concentration meter is pierced into the container of the Bendamstin solution, the gas in the head space in the container is sucked, and the oxygen concentration in the gas is measured (minimum resolution: 0.01%).
(2) When it is necessary to measure the oxygen concentration in the gas in the container non-destructively The oxygen concentration in the head space in the container (for example, ampoule) of the bendamstin solution is non-destructively measured.
In the case of the method (1), it is preferable to perform the measurement in a nitrogen atmosphere (gas oxygen concentration less than 0.1 v / v%) in order to prevent oxygen from being mixed outside the container during the measurement.

[Dissolved oxygen concentration in the liquid composition]
The liquid agent (1) of the present disclosure has a dissolved oxygen concentration in the liquid composition from the viewpoint of suppressing the decomposition of bendamustine during storage (particularly, the formation of a bendamustine analog represented by RRT0.43 due to the decomposition of bendamustine). Is preferably 9 ppm or less, more preferably 7 ppm or less, further preferably 3 ppm or less, particularly preferably 0.5 ppm or less, and most preferably 0.1 ppm or less.

The dissolved oxygen concentration in the liquid composition is measured using an oxygen concentration measuring device. Examples of the oxygen concentration measuring device include a product name: organic solvent compatible DO meter B-506S (Iijima Denshi Kogyo Co., Ltd.).

As a specific example of the method of measuring the dissolved oxygen concentration in the liquid composition, the electrode of the oxygen concentration measuring device is applied to the liquid composition in a nitrogen atmosphere (oxygen concentration is 0.1% by volume or less) in a glove box. Is a method of measuring the dissolved oxygen concentration in the liquid composition by contacting the liquid, or the sampler needle part of the oxygen concentration measuring device is pierced into the container of the liquid agent, and the liquid composition in the container is sucked to obtain the liquid. Examples thereof include a method of measuring the dissolved oxygen concentration in the composition.

[Ratio of the number of oxygen molecules to the number of molecules of bendamustine or its salt in the bendamustine solution]
In the liquid preparation (2) of the present disclosure, the ratio of the number of oxygen molecules to the number of molecules of bendamstin or a salt thereof in the liquid preparation (that is, the number of oxygen molecules / the number of molecules of bendamstin or a salt thereof; hereinafter, "the number of oxygen molecules / the number of bendamstin molecules". ”) Is 0.10 or less.
When the number of oxygen molecules / the number of bendamustine molecules in the liquid preparation is 0.10 or less, decomposition of bendamustine during storage (particularly, formation of a bendamustine analog appearing at RRT 0.43 by HPLC by decomposition of bendamustine) is preferably performed. It can be suppressed.

In the liquid preparation (2) of the present disclosure, the number of oxygen molecules / the number of bendamstin molecules in the liquid preparation is preferably 0.08 or less, preferably 0.06 or less, from the viewpoint of further suppressing the decomposition of bendamstin during storage. More preferably, it is more preferably 0.05 or less, and particularly preferably 0.04 or less.

Here, the number of oxygen molecules / the number of bendamstin molecules in the liquid preparation is determined by the oxygen concentration in the gas in the container and the dissolved oxygen concentration in the liquid composition, respectively, when the liquid composition is sealed in the container. It is calculated based on the total number of oxygen molecules calculated by multiplying the volume of. The number of oxygen molecules / number of bendamstin molecules in the liquid preparation is determined when the liquid composition is not sealed in a container or when the liquid composition is sealed in a container and no gas is present (for example, a prefilled syringe). , Calculated based on the dissolved oxygen concentration in the liquid composition.

In the present disclosure, the number of oxygen molecules / the number of bendamustine molecules is arbitrary at the time of manufacturing the bendamustine solution, immediately after the production of the bendamustine solution, or within the usable period of the bendamustine solution (for example, within the expiration date for the desired use of the bendamustine solution). It is a value calculated based on the measured value at one time point of.

In the present disclosure, the number of bendamustine molecules in the bendamustine solution and the number of oxygen molecules in the bendamustine solution are calculated according to the following methods, respectively.

Formula 1: Number of bendamstin molecules (mol) in the bendamstin solution = concentration of bendamstin in the liquid composition (mol / L) x volume of the liquid composition (L)
Formula 2: Number of oxygen molecules in Bendamstin solution (mol) = Number of oxygen molecules in gas in container (mol) + Number of oxygen molecules in liquid composition (mol)
Equation 3: Number of oxygen molecules in the gas in the container (mol) = Oxygen concentration in the gas in the container (volume%) ÷ 100 × Volume of gas in the container (L) ÷ (0.082 × (273.15 +) Temperature (℃))
Formula 4: Number of oxygen molecules in the liquid composition (mol) = Dissolved oxygen concentration in the liquid composition (mg / L) ÷ 32 ÷ 1000 × Volume of the liquid composition (L)

The temperature in Equation 3 is when the method of measuring the oxygen concentration in the gas in the container prepares a liquid agent while controlling the injection amount of nitrogen and oxygen so as to reach the target oxygen concentration in the glove box. In the case of the method of reading the display value of the oxygen monitor with a built-in sensor in the glove box, it means the temperature when sealed.
On the other hand, the method of measuring the oxygen concentration in the gas in the liquid agent is to pierce the sampler needle part of the oxygen concentration measuring device into the liquid agent container, suck the gas in the head space in the liquid agent container, and the oxygen concentration in the gas. In the case of the method of measuring, the temperature in the formula 3 means the temperature at the time of measurement.

<Manufacturing method of bendamustine solution>
The method for producing the liquid agent (1) or the liquid agent (2) is not particularly limited. In one embodiment, the method for producing the liquid agent (1) or the liquid agent (2) is
It contains bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof, and the total content of propylene glycol and glycerin is the total content of the liquid composition. Preparing a liquid composition having a weight of less than 1% by mass (hereinafter, also referred to as “liquid composition preparation step”), and
Filling a container with an inert gas atmosphere (hereinafter, also referred to as “filling step”), or filling the container with the liquid composition and then replacing the gas in the container with an inert gas. (Hereinafter, also referred to as "replacement process")
It may be a method including.
The method for producing the liquid agent (1) or the liquid agent (2) may include other steps, if necessary.
Hereinafter, one aspect of the method for producing the liquid agent (1) or the liquid agent (2) will be described. However, the matters common to the above-mentioned bendamustine liquid agent, for example, the components contained in the liquid composition, the amount thereof, the container and the like will be described. The explanation is omitted.

(Liquid composition preparation process)
In the liquid composition preparation step, a liquid composition is prepared using each component contained in the liquid composition.
The method for preparing the liquid composition is not particularly limited, and examples thereof include the following methods.
First, a solvent containing polyethylene glycol and other solvents as needed was prepared, and the obtained solvent was composed of bendamstin or a salt thereof, ascorbic acid, an ascorbic acid derivative, and salts thereof. A method of gradually adding at least one selected and is mentioned.

The temperature conditions for dissolving bendamustine or a salt thereof in a solvent are not particularly limited, and can be appropriately set according to the composition (that is, type and content) of the solvent.
The temperature of the solvent is set to 25 ° C. to 80 ° C., and at least one selected from the group consisting of bendamustine or a salt thereof, ascorbic acid, ascorbic acid derivatives, and salts thereof, and optionally pH. The regulator, other components, etc. may be dissolved.

(Filling process)
In the filling step, the liquid composition is filled in a container in an atmosphere of an inert gas.
In the filling step, the method of filling the container with the liquid composition under the atmosphere of an inert gas is not particularly limited, and a known method can be adopted.
Nitrogen is preferable as the inert gas.

In the filling step, the liquid agent (1) can be obtained by setting the oxygen concentration in the gas in the container containing the liquid composition to 10% by volume or less and filling the container with the liquid composition in an inert gas atmosphere. can.
Further, in the filling step, the liquid preparation (2) can be obtained by setting the number of oxygen molecules / bendamstin molecules in the liquid preparation to 0.10 or less and filling the container with the liquid composition in an inert gas atmosphere.

(Replacement process)
In the replacement step, after the liquid composition is filled in the container, the gas in the container is replaced with the inert gas.
In the replacement step, the method of substituting the gas in the container filled with the liquid composition with the inert gas is not particularly limited, and a known method can be adopted.
As the inert gas, nitrogen or argon is preferable.

In the replacement step, the oxygen concentration in the gas in the container containing the liquid composition is set to 10% by volume or less, the liquid composition is filled in the container, and then the gas in the container is replaced with an inert gas to prepare the liquid. (1) can be obtained.
Further, in the replacement step, the number of oxygen molecules / bendamstin molecules in the liquid preparation is set to 0.10 or less, the liquid composition is filled in the container, and then the gas in the container is replaced with an inert gas to replace the liquid preparation (2). ) Can be obtained.

The device used in the replacement step is not particularly limited, and is, for example, a glove box, a tapping machine having a function of tapping under an inert gas stream, a vacuum tapping machine, or a sealed state. A chamber having the function of plugging can be used.
For example, as a replacement method, specifically, a vial and a rubber stopper filled with a liquid composition are placed in a glove box, an inert gas is blown into the glove box to obtain a desired oxygen concentration, and then the glove. An example is a method of replacing the gas in the container with an inert gas by sealing the box with a rubber stopper. As a replacement method, the vial filled with the liquid composition is covered with a chamber part to shut off the vial from the outside air, and vacuuming and blowing an inert gas are repeated to eliminate the gas in the container. A method of substituting with an active gas can be mentioned. In addition, a semi-plugged vial is installed in a chamber that has a function of tapping in a sealed state, an inert gas is blown into the chamber so that the desired oxygen concentration is obtained, and the vial is sealed in the chamber to seal the inside of the container. A method of replacing the gas in the chamber with an inert gas can be mentioned.

(Other processes)
If necessary, the production method of the present disclosure may include steps other than the above-mentioned liquid composition preparation step, filling step, and substitution step.
Other steps include, for example, a pH adjusting step of adjusting the pH of the liquid composition obtained in the liquid composition preparing step.
The method for adjusting the pH of the liquid composition is not particularly limited, and for example, it can be adjusted by using the above-mentioned pH adjuster or the like.

For a general method for producing a liquid preparation, for example, the description in Japanese Patent Publication No. 2003-521518 can be referred to.

Hereinafter, the embodiments of the present disclosure will be described in more detail by way of examples, but the following examples do not limit the embodiments of the present disclosure.

Details of each component used in this example are shown below.

[Bendamustine or its salt]
-Bendamustine hydrochloride [Product name: Bendamustine Hydrochloride, manufactured by Cool Pharm Ltd]

[Polyethylene glycol]
PEG400: Polyethylene Glycol 400 [Product Name: Macrogol 400 (Polyethylene Glycol 400) EMPROVE® ESMENTIAL Ph, Eur, JP, manufactured by Merck Millipore]
PEG300: Polyethylene Glycol 300 [Product Name: Macrogol 300 (Polyethylene Glycol 300) EMPROVE® ESSENTIAL Ph, Eur, manufactured by Merck Millipore]

[Ascorbic acid group]
・ Ascorbic acid [Product name: Ascorbic acid 100M, manufactured by Kyowa Pharma Chemical Co., Ltd.]
・ Glyceryl ascorbic acid [Product name: Glyceryl Ascorbate, manufactured by FUJIFILM Shonan Wako Co., Ltd.]
・ Ascorbyl palmitate [Product name: L-ascorbyl palmitate, manufactured by FUJIFILM Shonan Wako Co., Ltd.]

[Other antioxidants]
・ Thioglycerol [Product name: 1-thioglycerol 98%, manufactured by Asahi Kagaku Kogyo Co., Ltd.]

[Propylene glycol and glycerin]
-PG: Propylene glycol [Product name: Propylene glycol (1,2-propanediol) EMPROVE (registered trademark) ESMENTIAL Ph, Eur, BP, USP, manufactured by Merck Millipore]
・ Glycerin [Product name: Japanese Pharmacopoeia concentrated glycerin, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.]

[PH regulator]
1N NaOH: 1 mol / L sodium hydroxide aqueous solution [trade name: 1 mol / L sodium hydroxide solution for volumetric analysis, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.]

<Example 1: Preparation of bendamustine solution (C-1)>
In a clean 50 mL vial containing a stirrer, 27.35 g of polyethylene glycol 300, 50.0 mg of a 1 mol / L sodium hydroxide aqueous solution, and 1.0 mg of ascorbic acid are weighed and mixed, and stirred for 30 minutes to prepare a uniform solution. After obtaining the solution, 625.3 mg of bendamstin hydrochloride was weighed, mixed, and stirred for 1 hour to obtain a liquid composition.
The obtained liquid composition was placed in a glove box and stirred at room temperature for 30 minutes in a nitrogen atmosphere to replace the gas in the liquid composition with nitrogen, and the dissolved oxygen concentration of the liquid composition was set to 0 ppm. Then, under a nitrogen atmosphere (oxygen concentration: 5.0% by volume, temperature: 25 ° C.), 2.0 mL was filled in a vial (Fuji Glass Co., Ltd., Vial Bottle CS-2). The volume of gas in the container at this time was 2.3 mL.
Seal with a laminated coated rubber stopper (Daikyo Seiko, Ltd.), cover the vial and the mouth of the rubber stopper with an aluminum seal (Nichiden Rika Co., Ltd., Aluminum Seal B (middle) (trade name)), and then cover the top. The desired Bendamstin solution (C-1) was obtained by tightening with a clipper.

<Examples 2 to 18: Preparation of bendamustine solutions (C-2) to (C-18)>
The target bentamustine solutions (C-2) to (C-18) were obtained in the same manner as in Example 1 except that the composition of the liquid composition was changed as shown in Table 2A below.

<Comparative Examples 1 to 8: Preparation of Bendamustine Liquids (R-1) to (R-8)>
The target bendamustine solutions (R-1) to (R-8) were obtained in the same manner as in Example 1 except that the composition of the liquid composition was changed as shown in Table 2B below.

<Measurement>
[Measurement of oxygen concentration in gas in container]
The oxygen concentration in the gas in the container of each liquid agent was measured by the following measuring device and measuring method. Tables 2A and 2B show the values rounded to the first decimal place of the measured values.
Measuring device: Desktop oxygen monitor (Product name: OXY-1, manufactured by Ichinenjiko Co., Ltd.)
Measuring method: Diaphragm type galvanized battery type Specifically, the amount of nitrogen and air sent into the glove box is adjusted, and the oxygen concentration of the oxygen concentration measuring device when tapping with a rubber stopper is read and read oxygen. The concentration value was taken as the oxygen concentration in the gas in the container.
It should be noted that the oxygen concentration in the gas in the container of each liquid after plugging is the value shown in Tables 2A and 2B below that the method described above (specifically, the non-destructive needle type oxygen concentration). It can be confirmed by (measurement by meter).

[Ratio of oxygen molecule number to bendamustine molecule number in liquid preparation]
The ratio of the number of oxygen molecules to the number of bendamustine molecules in each solution (number of oxygen molecules / number of bendamustine molecules) was calculated by the following method. The calculated values are shown in Table 2A and Table 2B.

Formula 1: Number of molecules of bendamstin in the liquid preparation (mol) = concentration of bendamstin in the liquid composition (mol / L) × volume of the liquid composition (L)
Formula 2: Number of oxygen molecules in the liquid (mol) = Number of oxygen molecules in the gas in the container (mol) + Number of oxygen molecules in the liquid composition (mol)
Equation 3: Number of oxygen molecules in the gas in the container (mol) = Oxygen concentration in the gas in the container (volume%) ÷ 100 × Volume of gas in the container (L) ÷ (0.082 × (273.15 +) Temperature (℃))
Formula 4: Number of oxygen molecules in the liquid composition (mol) = Dissolved oxygen concentration in the liquid composition (mg / L) ÷ 32 ÷ 1000 × Volume of the liquid composition (L)

[Measurement of pH]
In a 5 mL vial, 100 mg of the liquid composition of each of the liquid preparations of Examples 1 to 18 and Comparative Examples 1 to 8, 2 mL of uncarbonated water, and 6 μL of a saturated potassium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) aqueous solution prepared in advance. The mixture was mixed to obtain a mixed solution. A pH meter (device model number: F-73, manufactured by HORIBA, Ltd.) microToup pH electrode (manufactured by HORIBA, Ltd.) was brought into contact with this mixed solution, and the pH value was measured. The results are shown in Tables 2A and 2B.

[Measurement of water content]
The water content of each of the liquids of Examples 1 to 18 and Comparative Examples 1 to 8 was measured by a coulometric titration method using a moisture measuring device CA-200 / KF-200 (manufactured by Mitsubishi Chemical Analytics Co., Ltd.). A Karl Fischer titer (Aquamicron (registered trademark) AX, manufactured by Mitsubishi Chemical Analytical Co., Ltd.) was used for the anode solution tank.
The measured values are shown in Table 2A and Table 2B.

[Evaluation of storage stability]
(Measurement of bendamustine amount and bendamustine analog amount)
First, each of the obtained liquids was stored in a constant temperature bath at 70 ° C. for 1 week.

100 mg of the liquid composition in each bendamustine solution after storage is diluted with a 0.1% trifluoroacetic acid aqueous solution / N-methylpyrrolidone mixed solution (volume ratio = 1: 1), and the volume ratio is increased to 10 mL to prepare the test solution. Obtained.
Degradation of bendamustine was quantified by high performance liquid chromatography (HPLC). As a decomposition product of bendamstin, the amount of bendamstin analogs detected alone at a relative retention time of 0.43 and a plurality of bendamstin analogs detected at a relative retention time of 1.1 to 1.2 under the following measurement conditions. Among them, the single maximum amount, and among the other multiple Bendamstin analogs detected, the single maximum amount (in the table, "RRT0.43 analog amount", "RRT1.1-1" .2 Maximum analog mass ”and“ Other maximum analog mass ”; the unit is [area%]), respectively, determined based on their respective peak areas.
In addition, the amount of bendamustine [area%] was calculated from the total amount [area%] of the analogs of bendamustine obtained under the following measurement conditions.

(HPLC measurement conditions)
Detector: Ultraviolet-visible spectrophotometer (measurement wavelength: 254 nm)
Column: Agilent Technologies Zorbox Bonus-RP (particle size 5 μm, inner diameter 4.6 mm, length 150 mm)
Column temperature: Constant temperature around 30 ° C Cleaning solution: Water / methanol mixed solution (volume ratio 1: 1)
Mobile phase A: Water / acetonitrile mixed solution (volume ratio 9: 1), 0.1% trifluoroacetic acid-containing mobile phase B: Water / acetonitrile mixed solution (volume ratio 1: 9), 0.1% trifluoroacetic acid-containing mobile phase Liquid delivery: The concentration gradient was controlled by setting the mixing ratio of mobile phase A and mobile phase B as the mixing ratio shown in Table 1 below.
Flow rate: 1.0 mL / min Area measurement range: 4 to 30 minutes after injection of test solution

Tables 2A and 2B show the amount of bendamustine, the amount of RRT0.43 analogs, the maximum amount of RRT1.1 to 1.2, and the amount of other analogs measured by the above method.

(Evaluation of coloring)
First, each of the obtained liquids was stored in a constant temperature bath at 70 ° C. for 1 week.

450 mg of the liquid composition in each bendamustine solution after storage was diluted with 4 mL of ethanol to obtain a test solution.
The absorbance of the test solution at a wavelength of 420 nm was determined by an ultraviolet-visible spectrophotometer (V-630, manufactured by JASCO Corporation), and the degree of coloring was quantitatively evaluated. The absorbances are shown in Tables 2A and 2B.

(Evaluation criteria)
According to the following evaluation criteria, the storage stability was evaluated from the viewpoints of bendamstin amount, RRT0.43 analog amount, RRT1.1-1.2 maximum analog amount, and other analog amount, and coloring. rice field.

1. 1. Bendamustine amount (unit is area%)
AA: 94.5% or more A: 90.0% or more and less than 94.5% B: 80.0% or more and less than 90.0% C: 50.0% or more and less than 80.0% D: less than 50.0%

2. RRT0.43 Analog amount (unit is area%)
AA: Less than 1.00% A: 1.00% or more and less than 1.50% B: 1.50% or more and less than 3.00% C: 3.00% or more and less than 5.00% D: 5.00% or more

3. 3. RRT 1.1-1.2 Maximum amount of analogs (unit is area%)
AA: Less than 1.00% A: 1.00% or more and less than 1.50% B: 1.50% or more and less than 3.00% C: 3.00% or more and less than 5.00% D: 5.00% or more

4. Other maximum analog mass (unit is area%)
AA: Less than 1.00% A: 1.00% or more and less than 1.50% B: 1.50% or more and less than 3.00% C: 3.00% or more and less than 5.00% D: 5.00% or more

5. Coloring AA: Less than 0.010 A: 0.010 or more and less than 0.030 B: 0.030 or more and less than 0.050 C: 0.050 or more

6. Comprehensive evaluation AA: All evaluation results of evaluations 1 to 5 are AA A: The evaluation results of evaluations 1 to 5 include A, and the others are AA B: Evaluation results of evaluations 1 to 5 include B Includes and does not include C or D C: C is included in the evaluation results of evaluations 1 to 5, and D is not included in the evaluation results of evaluations 1 to 5 D: D is included in the evaluation results of evaluations 1 to 5.

In Tables 2A and 2B, the content of bendamustine hydrochloride means the content in terms of bendamustine. The ascorbic acid content means the content in terms of ascorbic acid.

From Tables 2A and 2B, the bendamustine solutions of Examples 1 to 18 have a smaller amount of RRT0.43 analogs and a maximum of RRT1.1 to 1.2 as compared with the bendamustine solutions of Comparative Examples 1 to 8. It can be seen that the amount of analogs and the maximum amount of other analogs are small, and the degree of coloring is small.
That is, the oxygen concentration in the gas in the container is 10% by volume or less, or the number of oxygen molecules / the number of bendamstin molecules in the bendamstin solution is 0.10 or less, and bendamstin or a salt thereof, polyethylene glycol, and A liquid containing at least one selected from the group consisting of ascorbic acid, ascorbic acid derivatives, and salts thereof, and the total content of propylene glycol and glycerin is less than 1% by mass based on the total mass of the liquid composition. It can be said that the Bendamstin solution containing the composition has high storage stability.

The disclosure of Japanese Patent Application No. 2020-02621 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards described herein are to the same extent as if the individual documents, patent applications, and technical standards were specifically and individually stated to be incorporated by reference. Incorporated herein by reference.

Claims

It contains bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof, and the total content of propylene glycol and glycerin is the total content of the liquid composition. Liquid compositions that are less than 1% by weight by weight,
A container for enclosing the liquid composition and
Bendamustine solution, wherein the oxygen concentration in the gas in the container is 10% by volume or less.
The bendamustine solution according to claim 1, wherein the oxygen concentration in the gas in the container is 5% by volume or less.
It contains bendamstin or a salt thereof, polyethylene glycol, ascorbic acid, an ascorbic acid derivative, and at least one selected from the group consisting of salts thereof, and the total content of propylene glycol and glycerin is the total content of the liquid composition. Liquid compositions that are less than 1% by weight by weight,
A container for enclosing the liquid composition and
Bendamustine solution, wherein the ratio of the number of oxygen molecules to the number of molecules of bendamustine or a salt thereof in the bendamustine solution is 0.10 or less.
The bendamustine solution according to claim 3, wherein the ratio of the number of oxygen molecules to the number of molecules of bendamustine or a salt thereof in the bendamustine solution is 0.05 or less.
The content of at least one selected from the group consisting of the ascorbic acid, the ascorbic acid derivative, and a salt thereof in the liquid composition is 0.001% by mass to 1.50% by mass in terms of ascorbic acid. , The bendamustine solution according to any one of claims 1 to 4.
The content of at least one selected from the group consisting of the ascorbic acid, the ascorbic acid derivative, and a salt thereof in the liquid composition is 0.003% by mass to 0.25% by mass in terms of ascorbic acid. , The bendamustine solution according to any one of claims 1 to 5.
The bendamustine solution according to any one of claims 1 to 6, wherein at least one selected from the group consisting of ascorbic acid, an ascorbic acid derivative, and a salt thereof is ascorbic acid.
The bendamustine solution according to any one of claims 1 to 7, wherein the total content of propylene glycol and glycerin is 0.5% by mass or less based on the total mass of the liquid composition.
The bendamustine solution according to any one of claims 1 to 8, wherein the polyethylene glycol contains at least one selected from the group consisting of polyethylene glycol 300 and polyethylene glycol 400.
The bendamustine solution according to any one of claims 1 to 9, wherein the polyethylene glycol contains polyethylene glycol 300.