JP2019099557A - Solution preparation containing bendamustine - Google Patents

Abstract

To provide bendamustine preparations which can be used as it is, or can be further diluted as it is, by eliminating the need for reconstitution of the lyophilized powder, and which have better usability in medical sites and stable over a long period of time.SOLUTION: Provided is a bendamustine-containing solution preparation containing bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive containing polyethylene glycol and glycerin. Preferably, the amount of glycerin in the pharmaceutically acceptable liquid is 1% by volume to 50% by volume, and the volume ratio of polyethylene glycol to glycerin is 99: 1 to 50:50. More preferably, the concentration as bendamustine free base is 5 mg/mL to 50 mg/mL.SELECTED DRAWING: None

Description

  The present invention relates to a ready-to-use bendamustine solution formulation that eliminates the need for reconstitution.

Bendamustine is a compound represented by the structural formula (1) and is used in the form of a hydrochloride salt for the treatment of leukemia and non-Hodgkin's lymphoma. Bendamustine hydrochloride is marketed as a lyophilized formulation as Treaxin (TREAKISYM®), and is reconstituted after being reconstituted with water for injection and then administered after dilution. Patent Document 1 describes a lyophilized preparation of bendamustine hydrochloride.

Bendamustine is a chemically unstable physical property and is known to degrade rapidly in aqueous solution. In particular, since it has a very unstable aliphatic chlorine atom, hydrolysis of this part produces the corresponding hydroxy compound as a decomposition product. For example, a monohydroxy compound (HP1 (hydrolysis product 1)) is known as one of the degradation products of bendamustine.

Lyophilized formulations of bendamustine have excellent chemical stability. However, the lyophilized preparation needs reconstitution with water for injection etc. at the time of use. For this reason, it is extremely troublesome, inconvenient, and inconvenient for clinical use, and there is a concern that the active ingredient may be hydrolyzed from solution preparation to administration. Therefore, there is a need for a ready-to-use, ready-to-use bendamustine solution formulation that does not require reconstitution at the time of use.
As for bendamustine solution formulation, Patent Document 2 describes a solution formulation for injection using a polar aprotic solvent such as N, N-dimethylacetamide. Moreover, the solution formulation which added the antioxidant further is described in patent document 3 and 4 using the mixed solvent of polyethyleneglycol and propylene glycol.

JP, 2013-056901, A JP 2012-503666 Publication Japanese Patent Publication No. 2013-518130 gazette Japanese Patent Publication No. 2015-506989

  An object of the present invention is to provide a bendamustine solution formulation that is stable over a long period of time. Another object of the present invention is to provide a more convenient preparation at medical sites.

The present application relates to the inventions according to the following [1] to [6].
[1] A bendamustine-containing solution formulation comprising bendamustine or a pharmaceutically acceptable salt thereof, and polyethylene glycol and glycerin.
[2] The bendamustine-containing solution formulation according to the above [1], wherein the amount of glycerin is 1% to 50% by volume, and the volume ratio of polyethylene glycol to glycerin is 99: 1 to 50:50.
[3] The bendamustine or the pharmaceutically acceptable salt thereof is a bendamustine-containing solution formulation described in the above [1] or [2], wherein the concentration as bendamustine free base is 5 mg / mL to 50 mg / mL.
[4] The bendamustine-containing solution formulation according to any one of the above [1] to [3], which contains an antioxidant.
[5] The bendamustine-containing solution preparation is sealed in a sealable sealed container, and the oxygen concentration in the void portion of the container is 5% by volume or less, according to any one of the above [1] to [4] The bendamustine containing solution formulation as described.
[6] The bendamustine-containing solution formulation according to any one of the above [1] to [5], containing 0.5 to 2.0% by mass of water.

  The bendamustine solution preparation containing polyethylene glycol and glycerin of the present invention is a stable preparation over a long period of time, eliminates the need for reconstitution, and can be administered by simple dilution operation. That is, a stable and easy-to-use solution preparation of bendamustine can be provided.

The present invention uses bendamustine or a pharmaceutically acceptable salt thereof. Bendamustine is 4- [5- {bis (2-chloroethyl) amino} -1-methyl-2-benzimidazolyl] butyric acid.
Pharmaceutically acceptable salts of bendamustine include salts of inorganic or 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 a pharmaceutically acceptable salt of bendamustine, an acid salt prepared from hydrochloric acid, hydrobromic acid and hydroiodic acid is preferable.
In the present invention, it is particularly preferred to use bendamustine hydrochloride.

  In the solution preparation of the present invention, bendamustine or a pharmaceutically acceptable salt thereof is preferably used at a concentration of 5 mg / mL to 100 mg / mL as bendamustine free base. Particularly preferably, the concentration as bendamustine free base is 5 mg / mL to 50 mg / mL, particularly preferably 15 mg / mL to 40 mg / mL.

The present invention is characterized in that a mixed solvent of polyethylene glycol and glycerin is used as a solution preparation.
As polyethylene glycol, it is preferable to use polyethylene glycol which is an ethylene glycol polymer and exists in a liquid state at a temperature of 30 ° C. or higher. Preferably, polyethylene glycol which meets the standards listed in the Japanese Pharmacopoeia (General Bureau) or the Pharmaceutical Additives Standard (Pharmaceutical Addendum), macrogol is preferably used. Macrogol is used in pharmaceutical preparations as a stabilizer, a solubilizer, a base, a coating, a wetting agent, an emulsifying agent, a dispersing agent, a solvent, a solubilizing agent and the like. Preferably, the macro goal 300, the macro goal 400 or the macro goal 600 is used. Macrogol 300 is a clear, colorless, viscous liquid composed of molecules with an average molecular weight of 300. Macrogol 400 is a clear, colorless, viscous liquid composed of molecules with an average molecular weight of 400. Macrogol 600 is a clear, colorless, viscous liquid or white petrolatum-like solid composed of molecules of average molecular weight 600. It is more preferable to use the macro goal 300 and / or the macro goal 400. When Macrogol 300 and Macrogol 400 are mixed and used, they may be mixed and used at an arbitrary ratio, but Macrogol 300: Macrogol 400 has a ratio of 1: 0.1 to 2.0 (v / v). It is preferred to use, more preferably 1: 0.1 to 1.0 (v / v). It is preferable to use Macrogol 400 in excess, and it is particularly preferable to use Macrogol 300: Macrogol 400 at a ratio of 1: 0.1 to 0.5 (v / v).
In the solution preparation of the present invention, polyethylene glycol is preferably contained at 50% by volume to 99% by volume. More preferably, it is 80 volume%-99 volume%, More preferably, it contains by 90 volume%-99 volume%.

The present invention is characterized by using glycerin. The glycerin is not particularly limited, but is preferably concentrated glycerin. Concentrated glycerin is a liquid that is viscous at room temperature, and contains stabilizers, plasticizers, solubilizers, sweeteners, bases, flavors, binders, coatings, coatings, skins, wetting agents, wetting agents, and tonicity. It is used as an agent, thickener, thickener, excipient, dispersant, solvent, solubilizer, solubilizer, fluidizer and the like.
In the solution preparation of the present invention, it is preferable to contain glycerin at 1% by volume to 50% by volume. More preferably, it is 1 volume%-20 volume%, More preferably, it contains by 1 volume%-10 volume%.

In the bendamustine solution preparation of the present invention, an antioxidant may be used for the purpose of maintaining or improving the stability of bendamustine. Examples of antioxidants include lipoic acid, monothioglycerol and its analogues, ascorbic acid and its salts, propyl gallate, methionine, cysteine, metabisulfite, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds And one or more selected from dihydrolipoic acid. Preferably, the antioxidant is monothioglycerol, ascorbic acid or a salt thereof, or a mixture thereof.
The preferred antioxidant concentration in the solution formulation is preferably applied at 2.5 mg / mL to 40 mg / mL, more preferably 2.5 mg / mL to 20 mg / mL.

Other additives may be used in the bendamustine solution formulation of the present invention for the purpose of maintaining or improving the stability of bendamustine. As other additives, buffers, pH adjusters, equalizing agents, stabilizers, auxiliary solvents and the like used in conventional pharmaceutical preparations may be added.
As the buffer, for example, phosphate, citrate, acetate and the like can be mentioned.
Examples of pH adjusters include hydrochloric acid, sodium hydroxide, acetic acid and salts thereof, phosphoric acid and salts thereof, citric acid and salts thereof, and tartaric acid and salts thereof.
Examples of tonicity agents include sodium chloride, calcium chloride, magnesium chloride, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, refined sucrose, mannitol and the like.
As a stabilizer, for example, acetyl tryptophan, alanine, arginine, albumin, benzoic acid, inositol, histidine, fructose, sodium caldiamide, sodium carbazochrome sulfonate, sodium carbonate, xylitol, glycine, glutamic acid, creatinine, dihydrogen phosphate Sodium, chondroitin sulfate sodium, diethylenetriaminepentaacetic acid, cystine, calcium bromide, gelatin, sorbitol, sodium hydrogencarbonate, potassium thiocyanate, dextran, calcium phosphate, sodium formaldehyde sulfosylate, nicotinamide, lactic acid, lactose, urea, Propyl parahydroxybenzoate, methyl parahydroxybenzoate, glacial acetic acid, benzalkonium, benzethonium, maltose, sodium pyrophosphate, Maleic acid, phosphoric acid and its salts, meglumine, Metasuruho sodium benzoate, lysine hydrochloride, such as magnesium sulfate.
As a cosolvent, a solvent used together with polyethylene glycol and glycerin, for example, is used to further promote the dissolution of bendamustine. As a co-solvent to be used, for example, ethanol, oleic acid, sesame oil, N, N-dimethylacetamide, refined olive oil, refined oleic acid, sorbitan fatty acid ester, soybean oil, medium chain fatty acid triglyceride, propylene glycol, benzyl alcohol, poly Oxyethylene hydrogenated castor oil 60, Polysorbate 80, Macrogol 4000, lidocaine and the like can be mentioned.
In the bendamustine solution preparation of the present invention, the pH can be controlled to suppress the formation of related substances. The preferred pH is 3.0 to 4.5, more preferably pH 3.3 to 4.1, and still more preferably pH 3.4 to 3.9.
In the bendamustine solution formulation of the present invention, the formation of related substances can be suppressed by controlling the water content in the formulation low. The moisture value suitable for the solution preparation is 4.0% or less, more preferably 3.0% or less. By adjusting the water content to 2.0% or less, it is possible to suppress the formation of solvent-derived analogues such as polyethylene glycol and glycerin, which is more preferable.

  The present invention is a bendamustine solution formulation containing a mixed solvent of polyethylene glycol and glycerin. The mixed solvent of polyethylene glycol and glycerin is, for example, a mixed solvent which may contain 50% by volume of polyethylene glycol and 50% of glycerol. Alternatively, it is a mixed solvent containing 99% by volume of polyethylene glycol and 1% of glycerin. That is, the volume ratio of polyethylene glycol: glycerin in the solution preparation is preferably in the range of 99: 1 to 50:50. The amounts of polyethylene glycol and glycerin can be varied appropriately within this range. More preferably, the volume ratio of polyethylene glycol: glycerin is in the range of 99: 1 to 80:20.

In a preferred embodiment of the solution preparation of the present invention, the amount of glycerol in the solution preparation is 1% to 50% by volume, and the volume ratio of polyethylene glycol to glycerol is 99: 1 to 50: 50, including bendamustine It is a solution formulation. Under the present circumstances, it is preferable to contain the density | concentration as a bendamustine free base by the density | concentration of 18 mg / mL. Alternatively, it is preferable that the concentration as bendamustine free base is contained at a concentration of 36 mg / mL. In some cases, it is preferable to include the concentration as bendamustine free base at a concentration of 9 mg / mL. Moreover, it is preferable to contain the density | concentration as a bendamustine free base by the density | concentration of 54 mg / mL.
In another embodiment, a bendamustine-containing solution formulation wherein the amount of glycerin in the solution preparation is 1% to 20% by volume, and the volume ratio of polyethylene glycol to glycerin is 99: 1 to 80:20. It can be mentioned. Under the present circumstances, it is preferable to contain the density | concentration as a bendamustine free base by the density | concentration of 18 mg / mL. Alternatively, it is preferable that the concentration as bendamustine free base is contained at a concentration of 36 mg / mL. In some cases, it is preferable to include the concentration as bendamustine free base at a concentration of 9 mg / mL. Moreover, it is preferable to contain the density | concentration as a bendamustine free base by the density | concentration of 54 mg / mL.

  The basic method of adjusting the solution preparation containing bendamustine of the present invention is not particularly limited. For example, after preparing a mixed solvent by previously mixing polyethylene glycol and glycerin in any ratio, bendamustine or this may be added thereto. It is prepared by adding the salt and dissolving it by stirring or sonication at room temperature. Alternatively, after preparing a mixed solvent by mixing polyethylene glycol and glycerin in any ratio in advance, an additive used for the purpose of maintaining or improving the stability of bendamustine is added and stirred or sonicated at room temperature. The solution is dissolved, and after confirmation of dissolution, bendamustine or a salt thereof is added thereto, and the mixture is dissolved by stirring or sonication at room temperature.

The solution preparation of the present invention is aseptically filled in a vial and prepared as a sealed filling preparation sealed with an airtight rubber stopper.
The container to be used is not particularly limited in the form of a vial, a syringe or the like, as long as it can be sealed by a rubber stopper or the like, but a vial is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer. Moreover, the container processed by the surface can be used for the said container according to the objective, such as a stability improvement and elution suppression of a glass component. Examples of surface-treated vials include silycoat vials (manufactured by Fuji Glass Co., Ltd.), VIST vials (manufactured by Yamato Special Glass Co., Ltd.), VIALEX (manufactured by Nipro Corporation), type 1 plus (manufactured by SCHOTT Co., Ltd.) And the like.
As a material of the rubber plug, it is preferable to use one made of butyl rubber, and further a rubber plug made of butyl rubber laminated with a fluorine resin.
These sealable containers are preferably packaging materials that have been sterilized by an appropriate method for both the container and the rubber stopper.

  Bendamustine is known to produce related substances by oxidation. Therefore, in the bendamustine-containing solution formulation of the present invention, related substances are suppressed by lowering the concentration of dissolved oxygen in the solution. The dissolved oxygen concentration of the solution affects the oxygen partial pressure of the space (head space) other than the filled solution in the container. In order to reduce the concentration of dissolved oxygen, it is effective to remove oxygen in the head space, and it is preferable to be filled with an inert gas such as nitrogen or argon. Specifically, it is preferable that the oxygen concentration in the space of the container of the preparation is 10% by volume or less. More preferably, it is a solution preparation in which the oxygen concentration in the space of the container is 5.0% by volume or less, more preferably 3.0% by volume or less, and particularly preferably 1.5% by volume or less.

As a method of controlling the concentration of dissolved oxygen in the solution in the solution preparation of the present invention, an inert gas such as nitrogen or argon was directly injected into a container filled with the solution, and a fixed amount of inert gas was injected. Later, the container may be sealed with a rubber stopper or the like. By using this method, it is possible to control the inside of the container to a desired void oxygen concentration.
In addition, a container filled with the solution preparation according to the present invention is placed in a sealed space, the pressure in the space is reduced to a level not lower than the vapor pressure at any temperature of the drug solution, and then inert gas such as nitrogen or argon is After pouring until it becomes atmospheric pressure, and leaving still for several hours, you may use the method of sealing with a rubber stopper etc. By using this method, it is possible to control the void oxygen concentration in the container to a desired concentration or less.
The oxygen concentration of the voids in the solution can be measured by an oxygen concentration meter using an oxygen sensor. For example, the void oxygen concentration of the container in the sealed preparation according to the present invention can be measured by using an oximeter (Microx TX3, manufacturer: PreSens) to which a needle type oxygen sensor is connected.

  The injectable solution preparation of the present invention can be used by diluting it with water for injection or physiological saline as a medicine for a disease having bendamustine as a therapeutic agent.

Example 1
Add a solution of PEG300 (Kanto Chemical Industry Co., Ltd.): concentrated glycerin (Genuine Chemical Co., Ltd.) 9: 1 (vol%) so that the concentration as bendamustine hydrochloride is 20 mg / mL in 40.5 mg of bendamustine hydrochloride The solution formulation of Example 1 was prepared by dissolution at room temperature in sonication.

Example 2
Add a solution of PEG300 (Kanto Chemical Industry Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 8: 2 (vol%) so that the concentration as bendamustine hydrochloride is 20 mg / mL in 41.5 mg of bendamustine hydrochloride The solution formulation of Example 2 was prepared by dissolution at room temperature and sonication.

[Example 3]
Add a solution of PEG300 (Kanto Chemical Industry Co., Ltd.): concentrated glycerin (Genuine Chemical Co., Ltd.) 9: 1 (volume%) to 40.8 mg of bendamustine hydrochloride so that the concentration as bendamustine hydrochloride is 40 mg / mL. The solution formulation of Example 4 was prepared by dissolution at room temperature and sonication.

[Liquid chromatography (HPLC) analysis conditions of bendamustine and related substances derived from bendamustine]
Solution formulations of Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: AGORENT ZORBAX Bonus-RP (inner diameter 4.6 mm, length 15.0 cm)
Column temperature: 30 ° C
Mobile phase A: 0.1% (v / v) aqueous trifluoroacetic acid solution mobile phase B: 0.1% (v / v) trifluoroacetic acid acetonitrile solution delivery amount: 1.0 mL / min.
Wavelength: 254 nm
Sample preparation method: Approximately 250 mg of the solution preparation was accurately measured in a 5 mL measuring flask, and the solution was adjusted with a mobile phase A: N-methyl-2-pyrrolidone = 1: 1 solution.
Delivery of mobile phase: Delivery was performed under the conditions shown in Table 1.

Test Example 1 Storage Stability Test at 40 ° C. The injectable solution formulations of Examples 1 to 3 were stored for 1 week at 40 ° C. The content ratio of each preparation bendamustine, as well as related substances derived from bendamustine were analyzed by HPLC. Table 2 summarizes the content ratio (%) of bendamustine, the content ratio (%) of total analogues, and the content ratio (%) of monohydroxy compound (HP1) which is a hydrolyzed analogue.

The bendamustine (BM) ratio (%) described in Table 2 is a numerical value representing the bendamustine peak area as a percentage after the storage test relative to the bendamustine peak area at the start. The total related substance (%) is a numerical value representing the sum of the peak area of the related substance derived from bendamustine relative to the sum of the peak area of the related substance derived from bendamustine and bendamustine as a percentage. In addition, HP1 (%), which is a hydrolyzed analogue, is a numerical value representing the peak area derived from HP1 as a percentage relative to the sum of the peak areas of bendamustine and the analogue derived from bendamustine.
As a result of examination, regardless of the use ratio of the mixed liquid, Examples 1 to 3 using the mixed solvent of polyethylene glycol and concentrated glycerin suppress the decomposition of bendamustine and also suppress the amount of total related substances and oxidized related substances. Was confirmed. Furthermore, in Example 3 in which the bendamustine concentration is high, it can be confirmed that there is not much difference in the degradation of bendamustine, the increase in total analogues and HP1 as compared with Examples 1 and 2.

  The bendamustine solution preparation described in Patent Document 2 is known to undergo degradation reaction and the like in a storage environment of 25 ° C. or higher, and to be reduced in content, and it is recommended to store only in a cold place . According to Patent Document 3, it is said that a shelf life of 15 months to 24 months at 25 ° C. is obtained by adding a stabilizer such as an antioxidant or a chloride to a mixed solvent of polyethylene glycol and propylene glycol. It is stated that it can. The solution preparation according to the present invention is improved in stability by using a mixed solvent of polyethylene glycol and concentrated glycerin, and therefore, by adding an antioxidant or a stabilizer such as a chloride, it is possible at 25 ° C. It can be considered that a bendamustine-containing solution formulation having a stability of 24 months or more can be produced.

Example 4
Prepare a solution of PEG400 (Nippon Oil Co., Ltd.): Concentrated Glycerin (Genuine Chemical Co., Ltd.) = 95: 5 (vol%) and add ascorbic acid (Three F Corporation) to a concentration of 2.5 mg / mL. It was dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The solution was adjusted to pH 3.5 with aqueous sodium hydroxide solution and 2 mL each was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper and an aluminum cap to obtain a preparation of Example 4.
The oxygen concentration in the void portion of this preparation was 0.2% when measured using an oximeter (Microx TX3, manufactured by PreSens) connected to a needle type oxygen sensor.

[Example 5]
Prepare a solution of PEG400 (Nippon Oil Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 90:10 (vol%) and add ascorbic acid (Three F Co., Ltd.) to a concentration of 2.5 mg / mL. It was dissolved. Using this, the preparation of Example 5 was performed in the same manner as in Example 4.
The oxygen concentration in the void portion of this preparation was 0.2% when measured using an oximeter (Microx TX3, manufactured by PreSens) connected to a needle type oxygen sensor.

[Comparative example]
To 50 mL of PEG400 (NOF Corp.), 50 μL of 1N aqueous sodium hydroxide solution was added and stirred to obtain base-treated PEG400. To this solution is added propylene glycol (PG, Maruishi Pharmaceutical Co., Ltd.) to prepare a solution of PEG400: PG = 90: 10 (volume%), and it will be 5.0 mg / mL of α-thioglycerol (Tokyo Chemical Industry Co., Ltd.) Added and dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. 2 mL of this solution was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper and an aluminum cap to obtain a preparation of Comparative Example.
The pH of this preparation was 3.1, and the oxygen concentration in the void portion was 0.2% when measured using an oximeter (Microx TX3, manufactured by PreSens) having a needle type oxygen sensor connected.

[Test Example 2]
The injectable solution formulations of Examples 4 and 5 and Comparative Example were stored at 40 ° C. for 4 weeks. The content ratio of each preparation bendamustine, as well as related substances derived from bendamustine were analyzed by HPLC. Table 3 summarizes the content ratios (%) of total analogues, analogues derived from PEG and analogues derived from glycerol (Gly) or propylene glycol (PG).

  Comparing Examples 4 and 5 with Comparative Example, it is possible to suppress the analogue derived from the solvent in the example using glycerin as the mixed solvent, and to suppress the esterification of bendamustine and PEG.

[Example 6]
PEG 300 (Nippon Oil Co., Ltd.): PEG 400 (Nippon Oil Co., Ltd.): Concentrated glycerin (Gen Chemical Co., Ltd.) = 60: 35: 5 (volume%) solution is prepared, ascorbic acid (Three F Corporation) 2 .5 mg / mL was added and dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The solution was adjusted to pH 3.5 with an aqueous solution of sodium hydroxide, and 1 mL each was filled into a glass vial. The vial was blown with nitrogen and air and sealed with a rubber stopper and an aluminum cap to obtain a preparation of Example 6.
The oxygen concentration in the void portion of this preparation was measured using an oximeter (Microx TX3, manufactured by PreSens) connected with a needle type oxygen sensor and found to be 5.3%.

[Example 7]
A bendamustine solution was prepared by the same procedure as in Example 6, and filled in a glass vial. The vial was blown with nitrogen and air and sealed with a rubber stopper and an aluminum cap to obtain a preparation of Example 7.
The measured oxygen concentration in the void portion of this preparation was 2.9%.

[Example 8]
A bendamustine solution was prepared by the same procedure as in Example 6, and filled in a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper / aluminum cap to obtain a preparation of Example 8.
It was 0.2% when the oxygen concentration of the void part of this formulation was measured.

[Test Example 3]
The injectable solution formulations of Examples 6 to 8 were stored at 40 ° C. for 4 weeks. The related substances derived from bendamustine of each preparation were analyzed by HPLC. The contents (%) of total analogues, oxidized analogues, PEG analogues and glycerin (Gly) analogues are summarized in Table 4.

  As the concentration of oxygen in the preparation increased, there was a tendency for total related substances to increase. It was suggested that the void oxygen concentration was greatly reduced in the examples having many similar substances, and that the amount of oxygen in the void was involved in the formation of the similar substances. In order to prevent decomposition by oxidation, it is useful to reduce the oxygen concentration by nitrogen substitution, and it is useful to be 10% or less, preferably 5% or less, more preferably 3% or less, still more preferably 1.5% or less Met.

[Example 9]
Prepare a solution of PEG 300 (Nippon Oil Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 90:10 (vol%), and use 2.5 mg of α-thioglycerol (monothioglycerol, Tokyo Chemical Industry Co., Ltd.) It was added and dissolved so as to be mL. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The solution was adjusted to pH 3.7 with an aqueous solution of sodium hydroxide, and 1 mL each was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper / aluminum cap to obtain a preparation of Example 9.
It was 0.2% when the oxygen concentration of the void part of this formulation was measured.

[Example 10]
Prepare a solution of PEG300 (Nippon Oil Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 90:10 (vol%) and add ascorbic acid (Three F Co., Ltd.) to 2.5 mg / mL. It was dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The solution was adjusted to pH 3.6 with an aqueous solution of sodium hydroxide and 1 mL each was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper / aluminum cap to obtain a preparation of Example 10.
It was 0.2% when the oxygen concentration of the void part of this formulation was measured.

[Test Example 4]
The injectable solution formulations of Examples 9 and 10 were stored at 40 ° C. for 4 weeks. The related substances derived from bendamustine of each preparation were analyzed by HPLC. The content ratios (%) of total related substances, oxidized related substances, and HP1 are summarized in Table 5.

  When monothioglycerol or ascorbic acid was used as the antioxidant, it was confirmed that the formation of the oxidation related substance was predominantly suppressed. As an antioxidant to be used, monothioglycerol or ascorbic acid is preferable.

[Example 11]
Prepare a solution of PEG300 (Nippon Oil Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 90:10 (vol%) to give 5.0 mg / mL of α-thioglycerol (Tokyo Chemical Industry Co., Ltd.) And dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The pH of this solution was adjusted to 3.2 with an aqueous solution of sodium hydroxide, and after adding a suitable amount of water for injection, 1 mL each was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper / aluminum cap to obtain a preparation of Example 11.
The water content of this preparation was measured by the Karl Fischer method, and it was 1.8% (w / w), and the oxygen concentration in the void portion was 0.2%.

[Example 12]
Prepare a solution of PEG300 (Nippon Oil Co., Ltd.): concentrated glycerin (Gen Chemical Co., Ltd.) = 90:10 (vol%) to give 5.0 mg / mL of α-thioglycerol (Tokyo Chemical Industry Co., Ltd.) And dissolved. Bendamustine hydrochloride was added to this solution to a concentration of 25 mg / mL and dissolved. The pH of this solution was adjusted to 3.2 with an aqueous solution of sodium hydroxide, and after adding a suitable amount of water for injection, 1 mL each was filled into a glass vial. The vial was blown with nitrogen and sealed with a rubber stopper / aluminum cap to obtain a preparation of Example 12.
The water content of this preparation was measured by the Karl Fischer method, and it was 2.1% (w / w), and the oxygen concentration in the void portion was 0.3%.

[Test Example 5]
The injectable solution formulations of Examples 11 and 12 were stored at 40 ° C. for 2 weeks. The related substances derived from bendamustine of each preparation were analyzed by HPLC. The content ratios (%) of the total analogues, HP1, and the solvent analogues (the sum of the PEG-derived analogues and the glycerol-derived analogues) are summarized in Table 6.

From the results in Table 6, it became clear that controlling the water content in the preparation suppresses the hydrolyzate upon storage. In addition, by controlling the water content to 2.0% (w / w), it was possible to suppress the formation of solvent analogues (PEG ester and / or glycerin ester).

Claims (6)

  A bendamustine-containing solution formulation comprising bendamustine or a pharmaceutically acceptable salt thereof, and polyethylene glycol and glycerin.   The bendamustine-containing solution formulation according to claim 1, wherein the amount of glycerin is 1% to 50% by volume, and the volume ratio of polyethylene glycol to glycerin is 99: 1 to 50:50.   The bendamustine-containing solution formulation according to claim 1 or 2, wherein bendamustine or a pharmaceutically acceptable salt thereof has a concentration of 5 mg / mL to 50 mg / mL as bendamustine free base.   The bendamustine containing solution formulation as described in any one of Claims 1-3 containing an antioxidant.   The bendamustine-containing solution preparation according to any one of claims 1 to 4, wherein the bendamustine-containing solution preparation is sealed in a sealable sealed container, and the oxygen concentration in the void portion of the container is 5% by volume or less. . The bendamustine containing solution formulation as described in any one of Claims 1-5 which contains water at 0.5-2.0 mass%.