JP2019001733A - Injectable solution preparation containing pemetrexed - Google Patents

Abstract

To provide an injectable solution preparation containing pemetrexed in which the production of analogous is inhibited and the formation of insoluble foreign matters is also inhibited in storing for a long period of time by using cysteine having an effect of inhibiting the production of analogous of pemetrexed, since, in a medical site, RTU (Ready-to-use) formulation in a solution form with high convenience, for example, because it has no need for complicated dissolving step compared with a freeze-dried formulation and is ready to administration.SOLUTION: Provided is an injectable solution preparation containing additives selected from the group consisting of pemetrexed or a pharmaceutically acceptable salt thereof, cysteine, and a salt thereof, the concentration of cysteine being 0.3 mg/mL to 2 mg/mL, pH being 9.0 or more, and being free of organic solvent.SELECTED DRAWING: None

Description

  The present invention relates to an injectable solution formulation that retains the stability of pemetrexed.

  Pemetrexed has the chemical name N- [4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] L- It is an antimetabolite antineoplastic agent containing glutamic acid disodium salt as an active ingredient, and is used as a therapeutic agent for malignant pleural mesothelioma and unresectable advanced / recurrent non-small cell lung cancer. As a pharmaceutical preparation of pemetrexed, a lyophilized powder preparation containing pemetrexed hydrate as an active ingredient and D-mannitol as an additive is provided as a pemetrexed injectable preparation (ALIMTA (registered trademark)). The preparation is sufficiently dissolved by adding physiological saline at the time of administration, and a necessary amount of the dissolved solution is taken out and mixed with physiological saline to be used as 100 mL.

  In general, lyophilized preparations are excellent in storage stability, but require a dissolution step at the time of use, and a sufficient mixing operation is required for complete dissolution. Accordingly, there is a need in the medical field for RTU (Ready-to-use) formulations in the form of solutions that do not require complicated dissolution steps and can be administered immediately after dilution.

Pemetrexed is known to have low solution stability, and its decomposition mainly involves an oxidation reaction in an aqueous solution. Then, the aqueous solution formulation which suppressed decomposition | disassembly in aqueous solution as an RTU formulation of pemetrexed has been reported. For example, Patent Document 1 discloses a pemetrexed disodium solution formulation having an oxygen partial pressure of 0.2% or less. By vacuum degassing, distillation degassing, nitrogen bubbling, membrane degassing, catalyst resin degassing methods, and the like, A solution formulation with controlled oxygen partial pressure is described.
On the other hand, aqueous solution formulations in which the stability of pemetrexed is improved using various antioxidant additives have been reported. Patent Document 2 discloses a pemetrexed aqueous solution formulation using monothioglycerol, cysteine or thioglycolic acid as an antioxidant. Patent Document 3 discloses a pemetrexed solution containing an antioxidant selected from lipoic acid, dihydrolipoic acid, methionine or a mixture thereof, and a chelating agent selected from lactobionic acid, tribasic sodium citrate or a mixture thereof. The formulation is described. Patent Document 4 describes a pemetrexed solution formulation containing an antioxidant selected from citric acid and cysteine. Patent Document 5 describes a pemetrexed solution formulation containing cysteine, arginine and propylene glycol. Patent Document 6 describes a pemetrexed solution preparation containing cysteine and thioglycerin. Patent Document 7 describes a pemetrexed solution formulation containing acetylcysteine and sodium citrate.

International Publication WO2012 / 121523 Special table 2003-521518 gazette Special table 2013-540104 gazette JP 2014-237607 A International Publication No. WO2015 / 193517 International Publication No. WO2015 / 145911 JP-T-2006-518404

  The problem to be solved by the present invention is to use cysteine, which has an inhibitory effect on the production of an analogous substance of pemetrexed, and for injection containing pemetrexed that inhibits the production of an analogue and suppresses the production of insoluble foreign matter even during long-term storage. It is to provide a solution formulation. In particular, it is an object of the present invention to provide a pemetrexed solution solution having a simple composition that does not require the use of an insoluble related substance solubilizing agent such as an organic solvent, as an RTU formulation in the form of a solution using cysteine of pemetrexed.

The present invention relates to an injectable solution preparation comprising pemetrexed active ingredient, by using cysteine or a salt thereof at 0.3 mg / mL to 2 mg / mL, and adjusting the pH to 9.0 or more, without using an organic solvent. Is based on the finding that it is possible to suppress the decomposition of pemetrexed, which is an active ingredient, and to suppress the formation of insoluble foreign matter. The gist of the present invention is the following [1] to [4].
[1] An injectable solution preparation containing pemetrexed or a pharmaceutically acceptable salt thereof, cysteine or a salt thereof, wherein the cysteine concentration is 0.3 mg / mL to 2 mg / mL, and the pH is 9.0. An injectable solution preparation containing pemetrexed that does not contain an organic solvent.
[2] The injectable solution preparation according to [1], which is sealed in a closed container and has a void oxygen concentration in the container of 1% or less.
[3] The injectable solution formulation according to [1] or [2] above, wherein the concentration of pemetrexed is 5 to 50 mg / mL [4] The above [1] to [3] wherein the pH is 9.0 to 12.0 ] Solution preparation for injection according to any one of

  The solution preparation for injection containing pemetrexed of the present invention can suppress the formation of related substances that are degradation products of pemetrexed under storage conditions, and can suppress insoluble foreign substances, and has excellent storage stability. Pemetrexed RTU formulations can be provided. In particular, it can be a pharmaceutical formulation that does not use an organic solvent such as propylene glycol, can maintain the efficacy and safety of pemetrexed over a long period of time, is excellent in safety, and easy to prepare an administration solution Can be provided.

  The present invention relates to an injectable solution preparation containing pemetrexed as an active ingredient, which does not contain an organic solvent, uses cysteine or a salt thereof at 0.3 to 2 mg / mL, and has a pH of 9.0 to 11.0. An injectable solution formulation containing pemetrexed. The details will be described below.

  In the present invention, pemetrexed is used as an active ingredient of an antimetabolite antitumor agent and has a chemical name of N- [4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo]. [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] L-glutamic acid, a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, ammonium salt, trimethylammonium salt, triethylammonium salt, monoethanolammonium salt, triethanolammonium salt, pyridinium salt, substituted Examples include pharmaceutically acceptable alkali metal salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts such as pyridinium salts. A sodium salt is preferably used, and a disodium salt is preferable. That is, in the present invention, it is preferable to use pemetrexed disodium salt. The pemetrexed or pharmaceutically acceptable salt thereof may be an anhydride, hydrate or solvate. As the hydrate, 2.5 hydrate and 7 hydrate are known and can be used without any particular limitation.

  In the present invention, cysteine or a cysteine salt is used. The cysteine salt can be used as a pharmaceutically acceptable salt such as sodium salt, potassium salt, lithium salt, ammonium salt, amine salt, pyridinium salt and the like. In order to prepare the solution preparation of the present invention, it is preferable to use cysteine or cysteine hydrochloride. However, since the solution preparation according to the present invention has a pH of 9.0 or more, it can be said that the solution preparation is in a salt form with a pH adjuster for adjusting to the set pH.

  The cysteine concentration is preferably 0.3 mg / mL or more, and the upper limit is preferably 3 mg / mL or less. The cysteine concentration refers to a mass concentration in terms of cysteine based on the amount of cysteine or a salt thereof added. When the cysteine concentration is less than 0.3 mg / mL, there is a possibility that a sufficient effect of inhibiting the formation of related substances during the storage period cannot be obtained. On the other hand, when the cysteine concentration is higher than 3 mg / mL, there is a possibility that insoluble foreign matter may be generated during the storage period. Preferably, the concentration in terms of cysteine is 0.3 mg / mL or more and 2 mg / mL or less. More preferably, the concentration is 0.5 mg / mL or more and 2.0 mg / mL or less.

It is widely known that cysteine or a salt thereof is used as an antioxidant for inhibiting related substances in pemetrexed solution for injection. However, in the study by the present inventors, it was found that an oxidant in which cysteine or a salt thereof is insoluble in water is generated during long-term storage of the solution preparation, and this appears as an insoluble foreign matter. Examples of conventional preparations include preparation examples in which other antioxidants such as ascorbic acid and thioglycerin are used in combination when cysteine or a salt thereof is used as an antioxidant, chelating agents such as EDTA as an antioxidant synergist, Examples of preparations in which organic acids such as citric acid and tartaric acid coexist, and solution preparations to which an organic solvent such as propylene glycol is further added. That is, when cysteine or a salt thereof is used as an antioxidant, it is used in combination with other additives in order to limit the amount of cysteine or a salt thereof used. There was a need to do.
However, even a pharmaceutical additive may exhibit undesirable side effects on the human body. For example, EDTA, which is a chelating agent, is known to have side effects such as inflammatory effects and allergic effects caused by intravenous administration. Therefore, it is desirable to refrain from using multiple types of additives such as organic solvents and chelating agents. As a solution preparation for injection, it can be said that it is desirable to provide a solution preparation having a simple preparation formulation, assuming that there are as few additives as possible other than water as an active ingredient and its solvent.

The present invention is a solution preparation containing pemetrexed and cysteine or a salt thereof, and by controlling the pH to 9.0 or more, the formation of related substances derived from pemetrexed is suppressed, and an insoluble foreign substance considered to be derived from cysteine Generation can be suppressed. Therefore, the present inventors have found an injectable solution formulation that maintains stability during a long storage period without using an organic solvent such as a solubilizing agent, a chelating agent, or the like.
The pH of the injectable solution preparation of the present invention is 9.0 or more, preferably the injectable solution preparation having a pH of 9.0 or more and 12.0 or less. More preferably, it is a solution preparation for injection having a pH of 9.0 or more and 11.0 or less. More preferably, it is a solution preparation for injection having a pH of 10.0 or more and 11.0 or less.
The injectable solution preparation is prepared by using pemetrexed or a pharmaceutically acceptable salt thereof, cysteine or cysteine hydrochloride, and any other additive in an organic solvent-free solvent mainly containing water, It can be prepared by adjusting the pH to 9.0 or higher using a pH adjusting agent or a buffering agent.
Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, acetic acid and its salt, phosphoric acid and its salt, citric acid and its salt, tartaric acid and its salt, and the like. As the buffer, a combination of an acid and a base of the pH adjusting agent may be used, and examples thereof include phosphoric acid and its salt, citric acid and its salt, acetic acid and its salt, and the like.

  The injectable solution preparation of the present invention does not contain an organic solvent that is acceptable as a pharmaceutical additive. Examples of the organic solvent acceptable as a pharmaceutical additive include ethanol, benzyl alcohol, dibutylhydroxytoluene, sorbitan fatty acid ester, sorbitan sesquioleate, propylene glycol, benzyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 20, Polysorbate 80, macrogols, monoethanolamine and the like can be mentioned. That is, the injectable solution preparation of the present invention is an aqueous solution preparation containing water as a sole solvent.

In the injectable solution preparation of the present invention, additives other than cysteine or cysteine salts may be used within the range that maintains the stability of pemetrexed. As such other additives, antioxidants, isotonic agents, chelating agents, stabilizers and the like used in usual pharmaceutical preparations may be added.
Examples of the antioxidant include ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite, citric acid, sodium thioglycolate, α-thioglycerin, sodium edetate, methionine, acetylcysteine, and the like.
Examples of the chelating agent include sodium edetate (EDTA).
Examples of tonicity agents include sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, purified sucrose, mannitol and the like.
Examples of stabilizers include acetyltryptophan, alanine, arginine and salts thereof, albumin, benzoic acid and salts thereof, inositol, histidine and salts thereof, fructose, sodium cardiamide, sodium carbazochrome sulfonate, sodium carbonate, xylitol, and glycine. Glutamate and its salts, creatinine, sodium dihydrogen phosphate, sodium chondroitin sulfate, diethylenetriaminepentaacetic acid, cystine, calcium bromide, gelatin, sorbitol, sodium hydrogen carbonate, potassium thiocyanate, dextran, calcium saccharide, sodium formaldehyde sulfosi Rate, nicotinamide, lactic acid, lactose, urea, propyl paraoxybenzoate, methyl paraoxybenzoate, glacial acetic acid, benzalkonium, benzethonium, ma Toast, sodium pyrophosphate, maleic acid, phosphoric acid and its salts, meglumine, sodium metasulfobenzoate, lysine hydrochloride, such as magnesium sulfate.
However, these additives are optional components that are not essential. More preferably, the solution preparation of the present invention is a preparation not containing sodium edetate (EDTA) which is a chelating agent. Furthermore, the solution formulation of the present invention preferably uses cysteine as the only antioxidant without containing other antioxidants.

  The concentration of pemetrexed in the injectable solution preparation of the present invention is preferably set to 5 mg / mL or more and 50 mg / mL or less. More preferably, the pemetrexed concentration is 10 mg / mL or more and 40 mg / mL or less.

The injectable solution preparation of the present invention is prepared as a hermetically filled preparation that is aseptically filled in a vial container and sealed with an airtight rubber stopper.
The container to be used is not particularly limited in the shape of a vial, a syringe or the like as long as it can be sealed with a rubber stopper or the like, but a vial shape is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer. Moreover, the said container can use the container surface-treated according to the objectives, such as a stability improvement and elution suppression of a glass component. Examples of surface-treated vials include siricoat vials (Fuji Glass Co., Ltd.), VIST vials (Yamato Special Glass Co., Ltd.), VIALEX (Nipro Co., Ltd.), type 1 plus (SCHOTT Co., Ltd.) ) And the like.
A highly deoxygenated solution solution for injection can be prepared by performing deoxygenation treatment by the method of the present invention using this container and sealing with an airtight rubber stopper. As the material of the rubber plug, it is preferable to use a butyl rubber rubber plug and a butyl rubber rubber plug laminated with a fluororesin.
These sealable containers are preferably packaging materials that have been sterilized by an appropriate method for both the container and the rubber stopper.

Pemetrexed is known to produce related substances mainly by oxidation. Therefore, the solution preparation for injection of the present invention preferably controls the concentration of dissolved oxygen in the solution. For this reason, the oxygen concentration in the voids of the container of the preparation is preferably 1% or less. By controlling the oxygen concentration in the void in the container, the dissolved oxygen in the solution can be reduced and controlled. More preferably, it is a solution preparation for injection whose oxygen concentration in the voids of the container is 0.5% or less.
The dissolved oxygen concentration in the solution can be measured by an oxygen concentration measuring device using an oxygen sensor. For example, by using an oxygen concentration meter (MicroxTX3, manufacturer: PreSens) connected with a needle type oxygen sensor, the oxygen sensor of the oxygen concentration meter is brought into contact with the solution of the solution for injection, and the sealed state according to the present invention The dissolved oxygen concentration in each vial preparation can be measured.
In the injectable preparation of the present invention, it is preferable that a space (head space) other than the solution filled in the vial is filled with an inert gas such as nitrogen or argon. The dissolved oxygen concentration affects the oxygen partial pressure in the headspace. In order to reduce the dissolved oxygen concentration, it is effective to remove oxygen in the head space, and it is preferable to fill with an inert gas such as nitrogen or argon.

As a method for controlling the concentration of dissolved oxygen in the solution of the injectable solution preparation of the present invention, an inert gas such as nitrogen or argon is directly injected into a container filled with the solution, and a certain amount of inert gas is injected. After the injection, a method of sealing the container with a rubber stopper or the like can be mentioned. By using this method, the oxygen concentration in the void of the container of the preparation can be made 1% or less, and the oxygen concentration in the injection solution can be controlled to 1.0 ppm or less.
In addition, a container filled with an injection solution according to the present invention is placed in a sealed space, and the space is depressurized to a level not lower than the vapor pressure at an arbitrary temperature of the chemical solution, and then an inert gas such as nitrogen or argon is removed. A method of injecting to atmospheric pressure, allowing to stand for several hours, and then sealing with a rubber stopper or the like may be used. By using this method, the oxygen concentration in the void of the container of the preparation can be made 1% or less, and the oxygen concentration in the solution can be controlled to 1.0 ppm or less.

  The solution preparation for injection of the present invention is stored at room temperature, preferably in a cold place. In addition, it is preferable to store under light shielding.

  The injectable solution preparation of the present invention can be used as a pharmaceutical agent for diseases using pemetrexed as a therapeutic agent.

In the following, the present invention will be further illustrated by examples. However, the present invention is not limited to these examples.
[Example 1]
10.9 mg of cysteine hydrochloride hydrate (7.5 mg in terms of cysteine) and 755 mg of pemetrexed disodium salt 2.5 hydrate (625 mg in terms of pemetrexed) are dissolved in an appropriate amount of water for injection, and an appropriate amount of hydrochloric acid solution The pH was adjusted to 9.0 with an appropriate amount of sodium hydroxide solution, and water for injection was added to make a total volume of 25 mL.
This solution was subjected to aseptic filtration using a membrane filter having a pore diameter of 0.22 μm, and 4 mL of the filtered solution was filled into the vial, nitrogen was injected into the void portion of the vial, and the solution was stoppered with a rubber stopper. Then, it wound up with the aluminum cap and prepared the solution formulation for injection of Example 1.

[Example 2]
An injectable solution preparation of Example 2 was prepared by performing the same operation as in Example 1 except that the pH was 10.0 in the operation described in Example 1.

[Example 3]
In the operation described in Example 1, the same operation as in Example 1 was performed except that the addition amount of cysteine hydrochloride hydrate was 18.1 mg (12.5 mg in terms of cysteine). An injectable solution formulation was prepared.

[Example 4]
In the operation described in Example 1, the same amount as in Example 1 except that the addition amount of cysteine hydrochloride hydrate was 18.1 mg (12.5 mg in terms of cysteine) and the pH was 10.0. The procedure was carried out to prepare the injection solution formulation of Example 4.

[Example 5]
In the operation described in Example 1, the same operation as in Example 1 was performed except that the addition amount of cysteine hydrochloride hydrate was changed to 32.6 mg (22.5 mg in terms of cysteine). An injectable solution formulation was prepared.

[Example 6]
In the operation described in Example 1, the same amount as in Example 1 except that the addition amount of cysteine hydrochloride hydrate was 32.6 mg (22.5 mg in terms of cysteine) and the pH was 10.0. The operation was carried out to prepare a solution preparation for injection of Example 6.

[Example 7]
In the operation described in Example 1, the same operation as in Example 1 was performed except that the addition amount of cysteine hydrochloride hydrate was 72.5 mg (50.0 mg in terms of cysteine). An injectable solution formulation was prepared.

[Example 8]
In the operation described in Example 1, the same amount as in Example 1 except that the addition amount of cysteine hydrochloride hydrate was 72.5 mg (50.0 mg in terms of cysteine) and the pH was 10.0. The procedure was carried out to prepare the injectable solution preparation of Example 8.

[Comparative Example 1]
Dissolve 755 mg of pemetrexed disodium salt 2.5 hydrate (625 mg in terms of pemetrexed) in an appropriate amount of water for injection, adjust to pH 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and add water for injection. The total volume was 25 mL.
This solution was subjected to aseptic filtration using a membrane filter having a pore diameter of 0.22 μm, and 4 mL of the filtered solution was filled into the vial, nitrogen was injected into the void portion of the vial, and the solution was stoppered with a rubber stopper. Then, it wound up with the aluminum cap and prepared the solution preparation for injection of comparative example 1.

[Comparative Example 2]
Dissolve 7.3 mg of cysteine hydrochloride hydrate (5.0 mg in terms of cysteine) and 1,510 mg of pemetrexed disodium salt 2.5 hydrate (1,250 mg in terms of pemetrexed) in an appropriate amount of water for injection, The pH was adjusted to 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make a total volume of 50 mL.
This solution was subjected to aseptic filtration using a membrane filter having a pore diameter of 0.22 μm, and 4 mL of the filtered solution was filled into the vial, nitrogen was injected into the void portion of the vial, and the solution was stoppered with a rubber stopper. Then, it wound up with the aluminum cap and prepared the solution preparation for injection of comparative example 1.

[Comparative Example 3]
An injectable solution preparation of Comparative Example 3 was prepared by performing the same operation as in Example 1 except that the pH was 8.5 in the operation described in Example 1.

[Comparative Example 4]
In the operation described in Example 1, the same amount as in Example 1 except that the addition amount of cysteine hydrochloride hydrate was 18.1 mg (12.5 mg in terms of cysteine) and the pH was 8.5. The operation was performed to prepare a solution preparation for injection of Comparative Example 4.

[Comparative Example 5]
In the operation described in Example 1, the same amount as in Example 1 except that the addition amount of cysteine hydrochloride hydrate was 32.6 mg (22.5 mg in terms of cysteine) and the pH was 8.5. The operation was carried out to prepare a solution preparation for injection of Comparative Example 5.

[Comparative Example 6]
Cysteine hydrochloride hydrate 72.5 mg (50.0 mg converted to cysteine), propylene glycol 1,250 mg, and pemetrexed disodium salt 2.5 hydrate 755 mg (converted to pemetrexed 625 mg) in an appropriate amount of water for injection And adjusted to pH 9.0 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make a total volume of 25 mL. Subsequent operations were performed in the same manner as in Example 1 to prepare a solution preparation for injection of Comparative Example 6.

[Analysis conditions for pemetrexed-related substances]
The related substances derived from pemetrexed decomposition in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: Inertsil ODS-3 (inner diameter 4.6 mm, length 25 cm) manufactured by GL Sciences Inc.
Column temperature: 40 ° C
Mobile phase A: phosphate buffer (pH 6.8) / acetonitrile mixture (47: 3)
Mobile phase B: acetonitrile feed rate: 1.0 mL / min.
Wavelength: 225nm
Liquid feeding of mobile phase: Liquid feeding was carried out under the conditions shown in Table 1.

[Table 1]

[Measurement of dissolved oxygen]
An oxygen concentration meter (MicroxTX3, manufacturer: PreSens) connected with a needle type oxygen sensor was used. There is a fiber coated with a fluorescent dye (oxygen sensor) that is sensitive to oxygen at the tip of the needle, and the needle type oxygen sensor is inserted into the rubber stopper of the injectable solution preparation of the example and comparative example, and the void portion in the vial Oxygen was measured.

[Test Example 1] 60 ° C. Storage Stability Test The injectable solution formulations of Examples 1 to 8 and Comparative Examples 1 to 6 were stored at 60 ° C. for a maximum of 4 weeks. For each preparation, properties (coloring), pH, and pemetrexed-related substances were evaluated. Further, the dissolved oxygen in the solution at the start of the preparation storage test was measured with an oxygen concentration meter. The evaluation results are shown in Tables 2 and 3.

[Test Example 2] Evaluation of insoluble foreign matter during storage at 25 ° C. The solution preparations for injection of Examples 1 to 8 and Comparative Examples 1 to 6 were stored for 2 months under the condition of 25 ° C. The presence or absence of insoluble foreign matter was evaluated visually. The evaluation results are shown in Tables 2 and 3.

[Table 2]

[Table 3]

From the results of the storage stability test of the solution preparations of the examples shown in Table 2, by adding 0.3 mg / mL or more of cysteine as a concentration and setting the pH to 9.0 or more, generation of insoluble foreign substances and related substances It was confirmed that the stability was improved.
On the other hand, as shown in Table 3, in Comparative Example 1 in which no additive was used, the related substances increased and coloring was also observed. Moreover, the inhibitory effect of the related substance was not recognized about the thing which added 0.1 mg / mL as a density | concentration of cysteine in the comparative example 2. In Comparative Examples 3, 4, and 5, the cysteine concentration was 0.3 mg / mL or more and an inhibitory effect on related substances was observed, but insoluble foreign matter was confirmed after 2 months at 25 ° C. This insoluble foreign matter is thought to be due to the product of cysteine oxidation. In the examples, no insoluble foreign matter was confirmed, and it is considered that this insoluble foreign matter does not appear when the pH is 9.0 or more.
In Comparative Example 6, propylene glycol as an organic solvent is added. The total amount of the related substances was increased as compared with that of Example 7 in which propylene glycol was not added. Therefore, it is thought that the amount of related substances increases by adding an organic solvent.
Based on the above results, a formulation containing 0.3 mg / mL or more of cysteine without containing an organic solvent and having a pH of 9.0 or more suppresses the formation of insoluble foreign matter and suppresses pemetrexed-related substances to the maximum extent. Became clear.

ADVANTAGE OF THE INVENTION According to this invention, the solution formulation for injection containing the pemetrexed which is excellent in the storage stability which suppressed the production | generation of the related substance accompanying decomposition | disassembly of pemetrexed can be provided. The additive used in the injectable solution preparation of the present invention has a record of use for humans and is an amount less than the record of use. Therefore, it is possible to provide a solution formulation for pemetrexed injection that is pharmaceutically safe and easy to prepare at the time of administration.

Claims (4)

An injectable solution preparation containing pemetrexed or a pharmaceutically acceptable salt thereof, cysteine or a salt thereof, wherein the cysteine concentration is 0.3 mg / mL to 2 mg / mL, and the pH is 9.0 or more An injectable solution formulation containing pemetrexed without organic solvent. The injectable solution preparation according to claim 1, which is enclosed in a closed container and has a void oxygen concentration in the container of 1% or less. The injectable solution preparation according to claim 1 or 2, wherein the concentration of pemetrexed is 5 to 50 mg / mL. The solution preparation for injection according to any one of claims 1 to 3, which has a pH of 9.0 to 12.0.