TW202000204A - Pemetrexed sodium injection solution formulation and manufacturing method therefor - Google Patents

Abstract

In medical sites, there is a demand for a ready-to-use (RTU) formulation having a solution form that is more convenient than a freeze-dried formulation since, for example, a troublesome dissolution step is unnecessary and administration is possible immediately after dilution. The present invention addresses the problem of providing an injection solution formulation which contains pemetrexed and in which generation of analogue substances is suppressed and solution coloring is suppressed in a preservation period. The present invention provides a manufacturing method for an injection solution formulation that contains pemetrexed disodium as an active ingredient, the manufacturing method including: (1) a step for preparing an injection solution by using a pemetrexed disodium-containing raw material; and (2) a step for loading the injection solution into a formulation container and then tightly stopping the container with a rubber stopper in an atmosphere in which the oxygen concentration in a gap part of the rubber stopper is 1 vol% or less, wherein the raw material contains 0.10% or less of a component having a relative retention time period (RRT) of 0.41 ± 0.03 which uses, as an index, a retention time period (RT) of pemetrexed in a HPLC analysis.

Description

Pemetrexed sodium injection solution preparation and manufacturing method thereof

The present invention relates to an injectable solution preparation containing pemetrexed, whose coloration is suppressed during storage, a method for producing the same, and a raw material containing pemetrexed disodium used for preparing an injectable solution preparation.

Pemetrexed (chemical name: N-[4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl )Ethyl]benzyl]L-glutamic acid disodium) is a therapeutic agent for malignant pleural mesothelioma and unresectable progressive, recurrent non-small cell lung cancer, and is registered with pemetrexed (ALIMTA) Trademarks) are commercially available as freeze-dried preparations. The preparation is added with physiological saline to dissolve it during administration, and the required amount of solution is withdrawn, diluted with physiological saline as appropriate, and administered intravenously.

Generally speaking, although freeze-dried preparations are excellent in storage stability, they require complicated dissolution steps during use. Therefore, in the medical field, a solution preparation that can be administered immediately after dilution without complicated dissolution steps is required. Therefore, pemetrexed formulations also have an urgent need for solution formulations for injection with high convenience. However, it is known that the solution of pemetrexed is less stable, oxidative decomposition will occur in the aqueous solution, and the coloring of the solution will gradually be seen during storage. In order to prepare a solution formulation of pemetrexed for which stability is ensured, it has previously been reported that the oxygen concentration and dissolved oxygen in the vial are strictly controlled, and a method of preparing a composition added with an antioxidant is also made.

For example, Patent Document 1 discloses a pemetrexed solution preparation with an oxygen partial pressure of 0.2% or less, and describes the use of reduced-pressure degassing, distillation degassing, nitrogen gas introduction, membrane degassing, or catalyst resin degassing methods. . In addition, formulations using antioxidants are also known, and Patent Document 2 describes a pemetrexed aqueous solution preparation using monothioglycerin, cysteine, or thioglycolic acid as an antioxidant. Patent Document 3 describes a pemetrexed solution preparation containing an antioxidant selected from lipoic acid, dihydrolipoic acid, methionine, or a mixture thereof; and selected from lactobionic acid, tribasic citric acid Chelating agent for sodium or its mixture. Patent Document 4 describes a pemetrexed solution preparation containing an antioxidant selected from citric acid and cysteine. Patent Document 5 describes a pemetrexed solution preparation containing cysteine, arginine, and propylene glycol. Patent Document 6 describes a pemetrexed solution preparation containing cysteine and thioglycerol. Patent Document 7 describes a pemetrexed solution preparation containing acetylcysteine and sodium citrate. It is described that these injection solution preparations using pemetrexed as an active ingredient aim to suppress the formation of similar substances during storage, and can also suppress the coloring of the solution. [Prior Technical Literature] [Patent Literature]

[Patent Literature 1] International Publication No. 2012/121523 [Patent Document 2] Japanese Patent Special Publication No. 2003-521518 [Patent Document 3] Japanese Patent Special Publication No. 2013-540104 [Patent Document 4] Japanese Patent Laid-Open No. 2014-237607 [Patent Literature 5] International Publication No. 2015/193517 [Patent Literature 6] International Publication No. 2015/145911 [Patent Document 7] Japanese Patent Special Publication No. 2016-518404

[Problems to be solved by the invention]

Regarding the solution preparation of pemetrexed for injection, it is known that similar substances are gradually increased during storage, and the color of the solution is also found. In particular, sometimes the coloring of the solution can be recognized visually, and the coloring preparation is regarded as a defective product in the medical field. Prior to this, as a pemetrexed solution preparation with guaranteed storage stability, the situation of strict management of the oxygen concentration in the solution preparation containing dissolved oxygen and/or the use of additives such as antioxidants was studied. These are the methods whose main goal is to suppress the decomposition of pemetrexed and inhibit the formation of similar substances. However, there is no relevant information on the relationship between the amount of similar substances and coloring. Even reducing similar substances cannot suppress coloring. The relationship between the amount of similar substances and coloring is not clear. An object of the present invention is to provide an injection solution preparation containing pemetrexed disodium as an active ingredient with suppressed coloration during storage. [Technical means to solve the problem]

The present invention is based on the discovery that the composition and content of similar substances contained in the raw material containing pemetrexed disodium used in the preparation of pemetrexed solution solutions for injection will preserve the solution of the solution formulation The impact of the color. That is, by using pemetrexed disodium whose content of a specific similar substance is controlled as a raw material drug for preparation, a solution solution for injection of pemetrexed that suppresses coloration and has excellent storage stability is provided.

The invention of the present application is the first invention of the method for producing the pemetrexed injectable solution preparation described in the following [1] to [7]. [1] A method for manufacturing an injectable solution preparation, which is a method for manufacturing an injectable solution preparation containing pemetrexed disodium as an active ingredient, the method comprising: (1) The steps of preparing a solution for injection using raw materials containing pemetrexed disodium, and (2) The step of filling the above-mentioned injection solution into a container for a preparation, and tightening it with a rubber stopper in an atmosphere in which the oxygen concentration of the void is 1% by volume or less, The above raw material contains 0.10% or less of HPLC (High Performance Liquid Chromatography, high performance liquid chromatography) analysis with pemetrexed retention time (RT) as the index of the relative retention time (RRT) of 0.41 ± 0.03 components, The above HPLC analysis conditions are the analysis conditions shown below; [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B. Flow rate: 1.0 mL/min Area measurement range: 32 minutes after sample solution injection

That is, when preparing an injectable solution formulation of pemetrexed, by using a raw material containing pemetrexed disodium whose RRT is 0.41±0.03 and controlled to 0.10% or less, the coloration can be suppressed Solution preparation for injection.

[2] The production method described in [1], wherein the raw material containing pemetrexed disodium contains 0.05% or less. In HPLC analysis, the relative retention time (RRT) of pemetrexed retention time as an index is 0.34 The composition of ±0.03. Furthermore, it is also focused on the detection of a similar substance with an RRT of 0.34±0.03, and it is preferable to use a raw material containing pemetrexed disodium whose content is controlled to 0.05% or less.

[3] The production method described in [1] or [2], wherein the HPLC purity of the raw material containing pemetrexed disodium is 98.50% or more. The raw material containing pemetrexed disodium is preferably low in content of other similar substances and is of extremely high purity.

Pemetrexed will react sharply in the presence of oxygen, causing the solution to color. It was found that especially in the preparation of the solution formulation of pemetrexed, the rubber stopper as a sealing material in the vial of the injection preparation also has oxygen permeability, and the penetrating oxygen will color or similar to pemetrexed in solution Substance formation causes adverse effects. That is, in the preparation of pemetrexed solution preparations, it is important to select a rubber stopper as a sealing material. By using a rubber stopper with a low temperature dependence of oxygen permeability, coloring of the solution and/or the like can be suppressed generate.

[4] The production method as described in any one of [1] to [3], wherein the amount of oxygen which penetrates into the container during storage for 2 weeks under the temperature condition of 60°C is 0.0013 mmol or less Tighten the rubber plug. [5] The production method according to any one of [1] to [4], wherein the volume of the void portion of the container obtained by removing the volume of the injection solution from the volume of the container for the preparation is relative to the volume of the container Below 60%.

By using a specific sealing material, it can provide a solution solution of pemetrexed for injection under the storage conditions in a wide temperature range of 5°C to room temperature, the coloring is suppressed, and the production of similar substances is suppressed . Furthermore, it is preferable to reduce the amount of oxygen in the preparation by reducing the gap.

The pemetrexed solution preparation prepared in the present invention is characterized in that the content of similar substances is small even during storage, and the coloring of the solution is suppressed. That is, the following similar substance profiles of [6] and [7] are characteristic.

[6] The production method as described in any one of [1] to [5], wherein an injection solution preparation containing pemetrexed disodium as an active ingredient contains less than 0.05% of pemetrexed in HPLC analysis The retention time (RT) as an index is a component whose relative retention time (RRT) is 1.07±0.03. [7] The production method as described in any one of [1] to [6], wherein the injection solution preparation containing pemetrexed disodium as an active ingredient contains 0.05% or less of the compound represented by formula (IX) Or its salt.

Furthermore, the compound represented by formula (IX) is a compound known as one of pemetrexed analogs (also known as Keto-Amine (ketoamine) body), and RRT was detected by HPLC analysis It is a component of 0.94±0.03. [Chemical 1]

The present invention also includes a pemetrexed solution preparation whose coloration is suppressed during storage. That is, a solution preparation having an overview of similar substances described in [8] and [9] below.

[8] A solution preparation for injection, which contains pemetrexed disodium as the active ingredient and contains less than 0.05% of the relative retention time (RRT) using pemetrexed retention time (RT) as an indicator in HPLC analysis For a component of 1.07±0.03, the above HPLC analysis conditions are the analysis conditions shown below. [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B. Flow rate: 1.0 mL/min Area measurement range: 32 minutes after sample solution injection

[9] The solution preparation for injection as described in [8], which contains 0.05% or less of the compound represented by formula (IX). The compound represented by the formula (IX) is a component whose RRT is 0.94±0.03 by HPLC analysis. [Chem 2]

The present invention also includes a raw material containing pemetrexed disodium, which is a raw material for manufacturing a pemetrexed solution preparation whose coloration is suppressed during storage. That is, a raw material containing pemetrexed disodium having the profile of similar substances described in [10] and [11] below.

[10] A raw material containing pemetrexed disodium for injection solution preparations, which is used for the manufacture of pharmaceutical injection solution preparations, and contains 0.10% or less of the retention time of pemetrexed in HPLC analysis (RT) As an index, the relative retention time (RRT) is 0.41±0.03, and the conditions of the above-mentioned HPLC analysis are the analysis conditions shown below. [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B. Flow rate: 1.0 mL/min Area measurement range: 32 minutes after sample solution injection

The above invention [10] is also the invention that is the use of a raw material containing pemetrexed disodium containing specific similar substances, which is used to manufacture an injection solution preparation containing pemetrexed disodium as an active ingredient, The specific similar substance contains a component with a relative retention time (RRT) of 0.41±0.03 using the retention time (RT) of pemetrexed as an index in HPLC analysis of 0.10% or less.

[11] The raw material containing pemetrexed disodium for injection solution preparation as described in [10], which contains the relative retention time (RRT) with the retention time of pemetrexed as an index in the HPLC analysis of 0.05% or less ) Is 0.34±0.03.

The above invention [11] is also the invention that is the use of a raw material containing pemetrexed disodium containing specific similar substances, which is used to manufacture an injection solution preparation containing pemetrexed disodium as an active ingredient, Specific similar substances contain components with a relative retention time (RRT) of 0.41±0.03 with retention time (RT) of pemetrexed as an indicator in HPLC analysis of 0.10% or less, and components with RRT of 0.34±0.03 below 0.05% . [Effect of invention]

By focusing on the composition and content of similar substances contained in the raw material containing pemetrexed disodium used for the preparation of the injection solution preparation of pemetrexed, the present invention can provide a method for the preservation of the solution preparation A method that can suppress the coloring of the solution. In particular, it can provide an injectable solution preparation containing pemetrexed under the storage conditions in a wide temperature range of 5°C to above room temperature, the coloring of the solution is suppressed.

The present invention provides the use of pemetrexed disodium-containing raw materials whose content of specific similar substances is controlled as a raw material drug for the preparation of solution preparations, thereby providing a pemetrexed-containing composition that suppresses coloration and has excellent storage stability Solution preparation for injection. The details will be described below.

[Raw material containing pemetrexed disodium used in solution preparation for injection] The chemical name of pemetrexed disodium in the present invention is N-[4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d ]Pyrimidin-5-yl)ethyl]benzyl]L-glutamic acid disodium, which is known as an active ingredient of antimetabolite antitumor agent, if it is of suitable quality as a raw material for pharmaceuticals Otherwise, there is no special problem to use. The pemetrexed disodium may be anhydrous, hydrate or any solvate. As the hydrate, 2.5 hydrate or 7 hydrate is known and can be used without particular limitation.

Regarding the manufacturing method of pemetrexed disodium, there are a large number of prior art documents, for example, the preparation method of pemetrexed disodium 7 hydrate is described in Japanese Patent Publication No. 2003-530321. The manufacturing method of pemetrexed disodium of the present invention is not particularly limited. According to a known method and a purification step is suitably applied to this method, pemetrexed disodium having a similar composition and content can be manufactured . Preferably, pemetrexed disodium can be obtained according to the method based on steps 1 to 4 below.

[Step 1] Amidation reaction In this step, the compound represented by formula (II) and diethyl glutamate are subjected to a condensation reaction to synthesize the diethyl ether of pemetrexed represented by formula (III). [Chemical 3]

[Step 2] Hydrolysis reaction This step hydrolyzes the diethyl ether (III) of pemetrexed to produce pemetrexed diacid (IV). [Chemical 4]

[Step 3] Purification step This step is to recrystallize pemetrexed diacid (IV) from dimethyl sulfoxide and ethanol to obtain DMSO (Dimethyl Sulfoxide, dimethyl) of pemetrexed diacid (IV) Sublime) compound. [Chem 5]

[Step 4] Sodium salt preparation step This step is to obtain pemetrexed disodium (I) by dissolving the DMSO compound of pemetrexed diacid (IV) in a sodium hydroxide solution. Metrexide disodium. [化6]

In this manufacturing step, as the preferred conditions for obtaining pemetrexed disodium with the content of specific similar substances suppressed, it is preferable to perform all operations of the manufacturing step under a nitrogen gas flow and control the oxygen content to implement; and /Or maintain low temperature conditions when processing under alkaline conditions. That is, in the entire manufacturing step, it is preferable to operate in an oxygen atmosphere of 5 v/v% or less, more preferably 2 v/v%. In addition, in each step, when the treatment is performed under alkaline conditions, it is preferably controlled to 15° C. or lower, and more preferably controlled to 10° C. or lower.

It is known that the physical properties of pemetrexed disodium are slightly insufficient in stability, and it is known that similar substances are mainly produced through oxidation reaction in the state of solutions such as aqueous solutions. That is, in the process of manufacturing raw materials containing pemetrexed disodium (also known as pemetrexed disodium raw material), the generation of these similar substances is unavoidable, even after a purification step, by a high-efficiency liquid layer Analysis method (HPLC) will also detect a plurality of similar substances.

As the main similar substances contained in the raw material containing pemetrexed disodium, the components whose relative retention time (RRT) is 0.34±0.03 using the retention time (RT) of pemetrexed as an index in HPLC analysis can be cited , RRT is 0.41±0.03, RRT is 0.55±0.03 (Formula V, also known as α-Hydroxy Lactone (α-hydroxylactone) body); RRT is 0.69±0.03 and RRT is 0.70±0.03 (Formula VI, also known as Keto-Pemetrexd (keto-pemetrexed)); RRT composition of 0.83±0.03 (Formula VII, also known as N-Me body); RRT composition of 0.91±0.03 (Formula VIII, Also known as Oxidateve Dimer (oxidized dimer); RRT is 0.94±0.03 component (formula IX, also known as Keto-Amine (ketoamine) body); RRT is 1.07±0.03 component, RRT is 1.12±0.03 Ingredients, RRT is 1.14±0.03 (Formula X, also known as Keto-Formamide (keto-formamide) body); RRT is 1.17±0.03, etc. The main similar substances and their RRT values obtained by HPLC analysis are summarized in Table 1. One or more of these similar substances coexist in the raw material containing pemetrexed disodium as a manufacturing grade of pharmaceutical products.

[Table 1]

[化7]

The HPLC analysis conditions for the analysis of the purity of pemetrexed disodium and similar substances in the present invention are as follows. [HPLC analysis conditions] Detector: UV absorbance photometer (measurement wavelength: 228 nm) Column: Zorbax SB-C8, 150×4.6 mm, 3.5 μm (manufactured by Agilent) Column temperature: fixed temperature near 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Liquid feeding of mobile phase: Change the mixing of mobile phases A and B as shown in Table 2 to control the concentration gradient. Flow rate: 1.0 mL/min Area measurement range: 32 minutes after sample solution injection Determination of similar substances: Percentage of peak area of chromatograms other than the blank peak until the dissolution time is 0 to 32 minutes

[Table 2]

In order to prepare the injectable solution formulation of pemetrexed with suppressed coloration of the solution of the present invention, in the raw material containing pemetrexed disodium, focus on the retention time (RT) of pemetrexed as an indicator in HPLC analysis The relative retention time (RRT) is 0.41±0.03, and pemetrexed disodium whose content is 0.1% or less is used. That is, the solution coloring of the solution preparation for injection contains the component having the above RRT of 0.41±0.03, and by controlling the content of the component, the coloring of the solution during storage can be suppressed. The content of the component having an RRT of 0.41±0.03 is preferably 0.075% or less, and more preferably 0.05% or less.

A better aspect of the present invention uses the following pemetrexed disodium, which is contained in the raw material containing pemetrexed disodium with a relative retention time (RRT) of 0.41±0.03 and the content of the component is 0.10% or less, and The content of the component with RRT of 0.34±0.03 is 0.05% or less. The component having an RRT of 0.34±0.03 preferably contains 0.03% or less, and more preferably 0.02% or less. In addition, the structure of the component with RRT 0.41±0.03 and the component with RRT 0.34±0.03 was not identified. These components are assumed to be physical properties that gradually disappear during storage of the solution solution for injection, and therefore are assumed to be precursors of coloring components.

The component with RRT of 0.41±0.03 was detected by analysis by high-performance liquid chromatography-mass spectrometry (LC-MS) with m/z=478 ([M+H] ⁺ ). In addition, the component with RRT of 0.34±0.03 was also detected by the same LC-MS analysis with m/z=478 ([M+H] ⁺ ). The LC-MS measurement conditions for detecting a component with an RRT of 0.41±0.03 and a component with an RRT of 0.34±0.03 are performed using, for example, the following analysis conditions. [LC-MS analysis] Mobile phase flow rate: 0.2 mL/min Mobile phase A: 0.1% formic acid solution Mobile phase B: 0.1% formic acid acetonitrile solution Mobile phase delivery: Mix the mobile phases A and B as shown in Table 3 Generally change to control the concentration gradient.

[table 3]

Column: Zorbax SB-C8, 150×4.6 mm, 3.5 μm (manufactured by Agilent) Ionization mode: ESI(+/-) Scanning range: m/z 350-900

In the present invention, the focus is on controlling the content of the ingredients containing pemetrexed disodium with an RRT of 0.41±0.03, and an RRT with a value of 0.34±0.03, but it is more preferable to use less content of other similar substances. That is, as the content based on the area percentage in the above-mentioned HPLC analysis, it is preferable to use a raw material containing pemetrexed disodium at 98.50% or more in terms of pemetrexed. More preferably, the purity of pemetrexed is above 99.00%, and even more preferably, the purity is above 99.50%. That is, it is preferable that all raw materials containing pemetrexed disodium have a content of similar substances of less than 1.50%, more preferably less than 1.00%, and even more preferably less than 0.50%.

The raw material containing pemetrexed disodium of the present invention sometimes further contains a component (formula IX, ketone) whose relative retention time (RRT) is 0.94±0.03 using the retention time (RT) of pemetrexed as an indicator in HPLC analysis Amine body), and/or a component with an RRT of 1.14±0.03 (formula X, ketone formamide body) may be characterized by its content. It is preferable that the component with the RRT of 0.94±0.03 (formula IX, ketamine body) is 0.10% or less, and/or the component with the RRT of 1.14±0.03 (formula X, ketamine body) is 0.10% or less. More preferably, the component having an RRT of 0.94±0.03 (formula IX, ketamine body) is 0.05% or less, and/or the component having an RRT of 1.14±0.03 (formula X, ketamine body) is 0.05% or less.

Furthermore, as further other similar substances, it may contain a component with an RRT of 0.69±0.03 and an RRT of 0.70±0.03 (Formula VI, ketopemetrexed) and/or a component with an RRT of 0.91±0.03 (Formula VIII, oxidation Dimer). Preferably, the content of the RRT is 0.69±0.03 and the RRT is 0.70±0.03 (formula VI, ketopemetrexed) is less than 0.10%, and/or the RRT is 0.91±0.03 (formula VIII, oxidized dimerization) Body) content is 0.10% or less. More preferably, the content of the RRT is 0.69±0.03 and the RRT is 0.70±0.03 (formula VI, ketopemetrexed) is 0.01% or more and 0.075% or less, and/or the RRT is 0.91±0.03 (formula VIII, The content of oxidized dimer) is 0.01% or more and 0.075% or less.

As other similar substances, a component with an RRT of 0.55±0.03 (formula V, α-hydroxylactone body) and a component with an RRT of 0.83±0.03 (formula VII, N-Me body) are sometimes contained. The content of the component having the RRT of 0.55±0.03 (formula V, α-hydroxylactone body) is 0.10% or less, more preferably 0.05% or less. The content of the component (formula VII, N-Me body) whose RRT is 0.83±0.03 is 0.10% or less, more preferably 0.05% or less.

[Injectable solution preparation with pemetrexed disodium as active ingredient] Regarding the injectable solution preparation of pemetrexed of the present invention, the first step is to prepare the pemetrexed disodium-containing raw material using the raw material containing pemetrexed disodium satisfying the above-mentioned similar substance profile as the raw material medicine Raw material solution. As a solvent used for preparing this solution, if it is permitted as a solvent for parenteral administration, it can be used without particular limitation. For example, water, ethanol, polysorbate 80, polyethylene glycols, glycerin, polyoxyethylene hydrogenated castor oil, etc. may be mentioned, these may be used alone, or may be a mixed solvent of two or more kinds. The solvent is preferably a quality that can be administered orally. As a particularly preferred solvent, it is an aqueous solvent with water as the main component. It may be in the form of using only water as a solvent.

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

In addition, the temperature for preparing the solution is not particularly limited, and it is preferably prepared at 60° C. or lower in consideration of the stability of pemetrexed.

The solution preparation of the present invention may also contain additives which are allowed as pharmaceutical products. As an additive, if it can be administered orally, it can be used without particular limitation. As the type of additives, antioxidants, buffers, pH adjusting agents, isotonic agents, chelating agents, and stabilizers may also be contained.

The so-called antioxidants refer to additives used to inhibit the decomposition of active ingredients due to oxidation. For example, ascorbic acid, cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, α-thioglycerol, citric acid, sodium thioglycolate, sodium ethylenediaminetetraacetate, methionine, tocopherol, Butylhydroxymethoxybenzene, dibutylhydroxytoluene, etc. The so-called buffering agent refers to an additive used to maintain a fixed pH value. For example, citrate, phosphate, acetate, etc. are used.

The so-called pH adjusting agent refers to an additive used to make the pH value within the range of the set pH value. For example, hydrochloric acid, sodium hydroxide, acetic acid or its salt, phosphoric acid or its salt, citric acid or its salt, tartaric acid or its salt, etc. are used. The so-called isotonic agent refers to an additive used to approximate the osmotic pressure of serum. For example, sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, refined white sugar, mannitol, polyethylene glycol, etc. may be mentioned. The chelating agent refers to an additive that indirectly inhibits decomposition caused by the presence of metal ions by forming a complex with metal ions. For example, ethylenediaminetetraacetic acid disodium tetraacetic acid, citric acid or its salt, tartaric acid or its salt, gluconic acid or its salt, etc. are mentioned.

Stabilizers are used for various purposes such as suppression of decomposition of active ingredients and stabilization of particles. Examples include: acetyl serotonin, alanine, arginine or its salt, albumin, benzoic acid or its salt, inositol, ethanol, histidine or its salt, fructose, and caldiamide sodium (Caldiamide sodium), Carbazochrome sulfonate sodium, sodium carbonate, xylitol, glycine, glutamic acid or its salts, creatinine, sodium dihydrogen phosphate, sodium chondroitin sulfate, diethanolamine, diethanolamine Ethylenetriaminepentaacetic acid, cystine, dibutylhydroxytoluene, calcium bromide, refined gelatin, refined soybean lecithin, gelatin, sorbitan fatty acid ester, sorbitan trioleate, sorbitol , Sodium bicarbonate, potassium thiocyanate, dextran, calcium saccharate, triethanolamine, tromethamine, sodium formaldehyde sulfoxylate, nicotinamide, lactic acid, lactose, urea, propyl paraben , Methyl paraben, glacial acetic acid, butyl hydroxymethoxybenzene, propylene glycol, benzalkonium, benzyl alcohol, benzalkonium sulfonate, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polysorbate 20. Polysorbate 80, polyethylene glycols, maltose, sodium pyrophosphate, maleic acid, phosphoric acid or its salts, meglumine, metasulfobenzoate sodium, monoethanolamine, lysine Hydrochloride, magnesium sulfate, etc. Since the solution preparation of the present invention uses active ingredients that are susceptible to oxidation, it preferably contains an antioxidant.

The solution preparation for injection of the present invention includes the following steps: after preparing a solution containing the raw material of pemetrexed disodium, the above solution is filled into a preparation container, and the oxygen concentration in the void portion is 1% by volume or less The atmosphere was sealed with rubber plugs. Since the present invention is a solution preparation for injection, by aseptically filling into a preparation container, it is controlled to an atmosphere with an oxygen concentration of 1% by volume or less, and is sealed with a rubber plug with high air tightness, and filled with a seal Preparation in the form of a preparation.

As the container used, if it can be sealed with a rubber stopper or the like, the shape of the vial-like shape or the shape of the syringe is not particularly limited, but the shape of the vial-like shape is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer.

In terms of forming a complex with a divalent metal ion and forming insoluble fine particles, pemetrexed is preferably a vial in which the elution of glass components is suppressed. In particular, regarding a vial filled with water and sealed, it is preferable to perform a high-pressure steam sterilization treatment at 121° C. for 1 hour, and then dissolve the silicon in the water to 1 ppm or less. As such a glass vial in which the elution of silicon is suppressed, it is preferable to use a container that has been surface-treated for the purpose of inhibiting elution of glass components and the like.

Examples of vials in which the elution of glass components is suppressed include VIST vials (manufactured by Daiwa Special Glass), VIALEX (manufactured by NIPRO), type 1 plus (manufactured by SCHOTT), and the like. Particularly preferred is a borosilicate glass vial with silicon oxide on the inner surface. As an example of a vial whose inner surface is treated with silicon oxide, a SILICORT vial (manufactured by Fuji Glass Co., Ltd.) can be cited.

Using these containers, the method of the present invention is used for deoxygenation treatment and sealed with an airtight rubber stopper, whereby a highly deoxygenated solution preparation for injection can be prepared. As the material of the rubber plug, a rubber plug made of butyl rubber and a rubber plug made of butyl rubber laminated with a fluororesin are preferably used. These sealable containers are preferably packaging materials that have been sterilized by suitable methods on both the container and the rubber stopper.

It is known that pemetrexed mainly produces similar substances due to oxidation. Therefore, the solution preparation for injection of the present invention needs to control the concentration of dissolved oxygen in the solution. The oxygen concentration in the gap of the container of the preparation is below 1%. Preferably, it is an injectable solution preparation having an oxygen concentration of 0.5% or less in the gap of the container, and more preferably an oxygen concentration of 0.3% by volume or less.

The oxygen concentration in the gap of the container can be measured by an oxygen concentration measuring device using an oxygen sensor. For example, an oxygen concentration meter (MicroxTX3, manufactured by PreSens Co., Ltd.) connected with a needle-type oxygen sensor is used, and the solution of the injectable solution preparation is brought into contact with the oxygen sensor of the oxygen concentration meter to determine the value The oxygen concentration in the sealed vial formulation of the invention.

Furthermore, the void portion (head space) in the vial of the injection preparation of the present invention is preferably filled with an inert gas such as nitrogen or argon. The oxygen partial pressure in the headspace is related to the dissolved oxygen concentration in the preparation solution. Therefore, by removing the oxygen in the head space, the dissolved oxygen concentration of the pemetrexed solution can be reduced, and the storage stability can be effectively ensured.

As a method for controlling the oxygen concentration in the void portion of the solution preparation for injection of the present invention, the following method may be mentioned: inject an inert gas such as nitrogen or argon directly into the container filled with the solution, inject a certain amount of inert gas, and use A rubber stopper etc. seals the container. By using this method, it becomes possible to control the concentration of void oxygen in the container to 1.0% by volume or less.

In addition, the following method can also be used: a container filled with the injection solution of the present invention is provided in a closed space, and the pressure in the space is reduced until it is not lower than the vapor pressure at any temperature of the chemical liquid, and thereafter, Inject an inert gas such as nitrogen or argon until the atmospheric pressure is reached, and after standing for several hours, use a rubber stopper or the like to close tightly. By using this method, it becomes possible to control the concentration of void oxygen in the container to 1.0% by volume or less.

The volume of the space in the container other than the filled solution (head space) will also affect the stability of pemetrexed. The larger the ratio of the volume of the head space part to the filled volume, the more the amount of oxygen in the container becomes, and the easier the oxidative decomposition of pemetrexed proceeds. Therefore, it is preferable that the volume of the head space in the container is small. Specifically, the ratio of the volume of the head space to the volume of the container is preferably 70% or less, and more preferably 60% or less.

Pemetrexed also reacts sharply due to the inflow of a small amount of oxygen, resulting in coloration of the solution. The present inventors found that when preparing a solution formulation of pemetrexed, the rubber stopper used as the sealing material for the vial of the injection preparation also has oxygen permeability, and the penetrating oxygen will affect pemetrexed in solution. The formation of coloring or similar substances causes adverse effects. That is, in the preparation of pemetrexed solution preparations, it is important to select a rubber stopper as a sealing material. By using a rubber stopper with a low temperature dependence of oxygen permeability, coloring of the solution and/or the like can be suppressed generate. Therefore, the rubber stopper used in the solution preparation for injection needs to be highly suppressed for the penetration of oxygen. It is particularly preferred that the oxygen permeability does not change due to temperature. Specifically, it is necessary to use a rubber stopper with an amount of oxygen of 0.0013 mmol or less that penetrates into the space of the container through the rubber stopper during storage at 60°C for 2 weeks. More preferably, a rubber stopper having an oxygen permeability of 0.0010 mmol or less under the same conditions, and further preferably a rubber stopper having an oxygen permeability of 0.0008 mmol or less.

In this specification, the oxygen permeability of the rubber plug is calculated according to the following method. Oxygen permeability (mmol) = Increased amount of oxygen (volume %) ÷ 100 × void volume in the container (mL) ÷ (0.082 × (273 + temperature (℃))) Oxygen increase (volume %) = void oxygen concentration (vol%) after storage at 60°C for 2 weeks-void oxygen concentration (vol%) immediately after manufacturing

As the material of the rubber plug, if the oxygen permeability is less than the above-mentioned oxygen permeability, any material can be selected, preferably a rubber plug made of butyl rubber and a rubber plug made of butyl rubber laminated with a fluororesin. More specifically, rubber plugs made of fluororesin laminated materials of D713 and D777 made by Daikyo Seiko Co., Ltd. are preferable. As the thickness of the rubber plug, generally speaking, if the thickness is the same material, the thicker the thickness, the lower the oxygen permeability. As a preferable thickness of the rubber stopper, the minimum thickness of the wetted part is 1.5 mm or more, more preferably 2 mm or more.

Also, the smaller the area of the rubber plug's wetted part, the lower the oxygen permeability. The area of the wetted part of the rubber stopper depends on the inner diameter of the container. Therefore, the smaller the inner diameter of the container, the smaller the area of the wetted part of the rubber stopper and the lower the oxygen permeability. Therefore, the inner diameter of the mouth of the container is preferably 20 mm or less, and more preferably 15 mm or less. These sealable containers are preferably packaging materials that have been sterilized by appropriate methods on both the container and the rubber stopper.

In the present invention, it is clear that the rubber stopper has extremely small oxygen permeability. Therefore, with regard to the solution preparation for injection, by reducing the oxygen concentration in the periphery of the container, the oxygen penetrating into the preparation container can be suppressed and stability can be ensured. In particular, the solution preparation for injection can be reliably stored in an atmosphere with an oxygen concentration of 1% by volume or less. As a specific method for disposing the solution preparation for injection in an atmosphere having an oxygen concentration of 1% by volume or less, a container may be placed in an oxygen-barrier bag, and the inside of the bag may be filled with an inert gas such as nitrogen or argon. Seal etc. At this time, the oxygen concentration inside the bag is preferably 1% by volume or less, and more preferably 0.5% by volume or less. In addition, a deoxidizing agent is inserted into the space between the container for the solution solution for injection and the oxygen-barrier bag and sealed, so that the oxygen inside the bag can be absorbed, thereby improving the stability. Furthermore, regarding the oxygen concentration inside the oxygen-proof bag, the oxygen concentration inside the bag can be adjusted to 1 by applying a deoxidizer corresponding to the oxygen adsorption capacity relative to the oxygen content equivalent to the internal volume of the bag The volume% or less is preferably adjusted to 0.5 volume% or less.

The oxygen permeability of the oxygen barrier bag is preferably 1 mL/m ² ·24 hr·atm or less, more preferably 0.5 mL/m ² ·24 hr·atm or less, and further preferably 0.2 mL/m ² ·24 Below hr・atm. As the material of the oxygen-barrier film used in the oxygen-barrier bag, aluminum foil, nylon, polyvinylidene chloride, ethylene-vinyl alcohol copolymer, inorganic vapor-deposited film (for example, aluminum oxide vapor-deposited poly (Ethylene terephthalate, silicon oxide vapor-deposited polyethylene terephthalate, etc.).

Examples of the deoxidizer include MAGERANS S, SP, ZP, Z-PKC, ZJ-PT manufactured by Mitsubishi Gas Chemical Co., Ltd., which is an iron-based self-reactive deoxidizer, and MODURAN S manufactured by NIPPONKAYAKU FOOD TECHNO.

The injection solution preparation of pemetrexed which can inhibit the coloration of the solution during storage of the present invention can inhibit the relative retention time (RRT) of the pemetrexed retention time (RT) as an index in the HPLC analysis is 1.07 during storage Generation of components of ±0.03. In addition, it is possible to suppress the production of a compound (ketoamine body) represented by formula (IX) having an RRT of 0.94±0.03. These similar substances are added to the preservation of pemetrexed solution preparations. Although the relationship between these components and the coloring of the solution is not clear, the solution preparation of the present invention is characterized by the low content of these components during storage.

Specifically, when the solution preparation was stored at 60° C. for 2 weeks, the component with an RRT of 1.07±0.03 was 0.05% or less (area percentage). It is preferably 0.03% or less, and more preferably less than 0.01%. Further, under the same storage conditions, the compound represented by formula (IX) (RRT: 0.94±0.03, ketamine body) is 0.05% or less (area percentage), more preferably 0.03% or less. In addition, the injectable solution preparation of pemetrexed of the present invention can inhibit the production of all similar substances during storage. Specifically, when the solution preparation is stored at 60° C. for 2 weeks, the content of all similar substances is 0.70% or less (area percentage), more preferably 0.50% or less.

The injectable solution preparation of pemetrexed of the present invention can inhibit the coloring of the solution during storage. The solution preparation of pemetrexed is usually yellow gradually during storage, and changes to a clear yellow clear solution with time, but the solution preparation can be maintained in the colorless to very weak yellow color range under visual inspection Clarify the state of the solution. As the evaluation of the coloration of the solution preparation, if the b* value based on the color difference is used as an index, the b* value of the solution preparation of the present invention is ±30 or less. The b* value indicates chromaticity. If the value is positive, it indicates the yellow direction. If the value is negative, it indicates the blue direction. The closer the value is to zero, the colorless solution. The solution preparation of the present invention preferably has a b* value of ±20 or less, more preferably ±15 or less. That is, when the solution preparation of the present invention is stored at 60°C for 2 weeks, the b* value based on the color difference is ±30 or less, preferably ±20 or less, and more preferably ±15 or less.

The injectable solution preparation of pemetrexed of the present invention can be produced by a general procedure in the preparation of injectable solution preparations as shown in the following steps. However, the present invention is not limited by the following manufacturing methods. Step (a) Weigh the raw materials containing pemetrexed disodium, and optionally pharmaceutically acceptable additives, and dissolve them in a suitable solvent. Step (b) If necessary, add a pharmaceutically acceptable pH adjuster to the above solution. Step (c) The solution of step (b) is supplemented with pharmaceutically acceptable solvents as necessary to fill the final volume. Step (d) Filter sterilize the solution of step (c). Step (e) Fill the solution obtained in step (d) into a pharmaceutically acceptable container. Step (f) If necessary, flush the container with an inert gas that is pharmaceutically acceptable. Step (g) Use a rubber stopper to tightly seal the container, and seal it with an aluminum lid if necessary. Step (h) Pharmacologically tolerable final sterilization if necessary.

If necessary, an inert gas may be blown into the mixture during the steps from step (a) to step (c). Through the above steps, the solution preparation for injection of the present invention can be manufactured. Furthermore, the solution preparation for injection can be set as follows: by storing in an oxygen-proof bag together with any deoxidizer and sealing, the adverse effects caused by oxygen can be more suppressed. The oxygen-barrier bag can also be sealed after blowing inert gas. [Example]

Hereinafter, the present invention will be further described by examples. However, the present invention is not limited by these embodiments. The analysis of pemetrexed disodium salt and solution preparation for injection was performed under the following HPLC analysis conditions. [HPLC analysis] Detector: UV absorbance photometer (measurement wavelength: 228 nm) Column: Zorbax SB-C8, 150×4.6 mm, 3.5 μm (manufactured by Agilent) Column temperature: fixed temperature near 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Flow rate: 1.0 mL/min Area measurement range: 32 minutes after sample solution injection Liquid feeding of mobile phase: The mixing of mobile phases A and B is changed as shown in Table 4 to control the concentration gradient.

[Table 4]

Under the HPLC analysis conditions, the retention time (RT) of the dissolution of pemetrexed was 20.2 minutes. Each similar substance is specified based on the relative retention time (RRT) of each eluted component using it as an index.

The LC-MS analysis of the component with an RRT of 0.41 and the component with an RRT of 0.34 was performed by HPLC analysis and under the following conditions. [LC-MS analysis] Mobile phase flow: 0.2 mL/min Mobile phase A: 0.1% formic acid solution Mobile phase B: 0.1% formic acid in acetonitrile Liquid feeding of mobile phase: The mixing of mobile phases A and B is changed as follows to control the concentration gradient.

[table 5]

Column: Zorbax SB-C8, 150×4.6 mm, 3.5 μm (manufactured by Agilent) Ionization mode: ESI(+/-) Scanning range: m/z 350-900

[Evaluation of coloring of liquid medicine] The coloring of the drug solution was measured using a color difference meter CR-5 (manufactured by Konica Minolta), and the b* value was calculated. The b* value indicates chromaticity, if the value is positive, it indicates the yellow direction, and if it is negative, it indicates the blue direction. If the value is within the range of ±15, it is visually judged that there is no coloring.

[Example 1] Production of a raw material containing pemetrexed disodium used in a solution preparation for injection (1) Add 4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid ( 4.0 kg), N,N-dimethylformamide (18.9 kg), and N-methyl 𠰌olin (3.0 kg), after cooling to 10°C under a nitrogen atmosphere, add 2-chloro-4,6- Dimethoxy-1,3,5-tris (2.6 kg), stir. Diethyl L-glutamine hydrochloride (3.5 kg) was added, and the reaction was carried out at 25°C. The reaction solution was poured into a mixture of 15% saline solution (40.0 kg) and ethyl acetate (36.0 kg) and stirred, and then liquid separation was performed. The separated water layer was extracted with ethyl acetate (18.0 kg), and the extract was mixed with the separated ethyl acetate layer. The mixed ethyl acetate layer was heated to 50°C, and a solution of p-toluenesulfonic acid monohydrate (3.0 kg) in ethanol (31.6 kg) was added dropwise to precipitate crystals. After cooling to 25°C, the precipitated crystals were filtered and washed with ethanol. The obtained crystal was dried under reduced pressure at 50°C to obtain N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d ]Pyrimidine-5-yl)ethyl]benzyl}-L-glutamic acid diethyl p-toluenesulfonate (yield 7.7 kg).

(2) Add 2 mol/L sodium hydroxide solution (25.7 kg), cool to 5℃, add N-{4-[2-(2-amino-4-oxo-4,7-dihydro- 1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid diethyl p-toluenesulfonate crystal (7.7 kg) and purified water (3.1 kg), react in a nitrogen atmosphere. Dilute hydrochloric acid was added dropwise, and the pH was adjusted to 3.0 at 50°C to precipitate crystals. The suspension was heated to 70°C and stirred, and then cooled to 25°C. The precipitated crystals were filtered and washed with purified water and ethanol. The obtained crystal was dried under reduced pressure at 50° C. to obtain N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d ]Pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid (yield 4.9 kg).

(3) Add N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] The crystals of benzoyl}-L-glutamic acid (4.9 kg) and dimethyl sulfoxide (23.2 kg) were dissolved in a nitrogen atmosphere. Ethanol (33.3 kg) was added dropwise to precipitate crystals, which were then stirred at 45°C. After cooling to 5°C, the precipitated crystals were filtered and washed with ethanol to obtain N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrole And [2,3-d]pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid dimethyl sulfoxide solvate crude crystals. After repeatedly performing the same recrystallization operation, the obtained crystals were dried under reduced pressure at 50°C to obtain N-{4-[2-(2-amino-4-oxo-4,7-dihydro- Purified crystals of 1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid dimethyl sulfoxide solvate (yield 6.3 kg).

(4) Under a nitrogen atmosphere, after adding 0.5 mol/L sodium hydroxide solution (40.0 kg), add N-{4-[2-(2-amino-4-oxo-4,7-dihydro- Purified crystals of 1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid dimethyl sulfoxide solvate (5.2 kg) using purified water (6.3 kg). The pH value was adjusted to 8.0 with sodium hydroxide solution to dissolve the crystals, and then activated carbon was added to purified water and suspended, and stirred. Filter the activated carbon and wash the activated carbon with purified water. After the filtrate was heated to 50°C, ethanol (114.4 kg) was added dropwise to precipitate crystals. After cooling to 5°C, the precipitated crystals were filtered and washed with a mixture of ethanol and purified water. The obtained crystal was dried under reduced pressure at 50° C. to obtain N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl]benzyl}-L-glutamic acid disodium 2.5 hydrate (pemetrexed disodium 2.5 hydrate) (yield 4.9 kg). The purity of pemetrexed disodium salt 2.5 hydrate obtained in Example 1 was 99.80% (area percentage) by HPLC analysis. The component with RRT of 0.34 is 0.02% (area percentage), and the component with RRT of 0.41 is 0.05% (area percentage). The results of HPLC analysis including other similar substances are summarized in Table 6. In addition, the chromatogram is shown in FIG. 1.

[Example 2] Production of a raw material containing pemetrexed disodium used in a solution preparation for injection By the same manufacturing method as in Example 1, pemetrexed disodium 2.5 hydrate was obtained. The obtained pemetrexed disodium 2.5 hydrate had a purity of 99.83% (area percentage) by HPLC analysis. The component with RRT of 0.34 is 0.00% (area percentage), and the component with RRT of 0.41 is 0.01% (area percentage). The results of HPLC analysis including other similar substances are summarized in Table 6.

[Example 3] Production of a raw material containing pemetrexed disodium used in a solution preparation for injection By the same manufacturing method as in Example 1, pemetrexed disodium 2.5 hydrate was obtained. The obtained pemetrexed disodium 2.5 hydrate had a purity of 99.90% (area percentage) by HPLC analysis. The component with RRT of 0.34 is 0.01% (area percentage), and the component with RRT of 0.41 is 0.01% (area percentage). The results of HPLC analysis including other similar substances are summarized in Table 6.

[Comparative Example 1] Preparation of a raw material containing pemetrexed disodium used in an injection solution preparation By the same manufacturing method as in Example 1, pemetrexed disodium 2.5 hydrate was obtained. This was stored in an atmospheric atmosphere at a temperature of 40° C. for one and a half months, and the obtained was used as Pemetrexed Disodium 2.5 hydrate of Comparative Example 1. The HPLC purity of pemetrexed disodium 2.5 hydrate of Comparative Example 1 was 99.65%. The component with RRT of 0.34 is 0.05% (area percentage), and the component with RRT of 0.41 is 0.13% (area percentage). The results of HPLC analysis including other similar substances are summarized in Table 6.

Regarding the raw material containing Pemetrexed Disodium 2.5 Hydrate of Comparative Example 1, the RRT of 0.34 and the RRT of 0.41 in the HPLC analysis were analyzed by LC-MS analysis, and the RRT was detected to be 0.34 Both the RRT and 0.41 are m/z=478 ([M+H] ⁺ ) in the positive ion mode. The MS spectrum data of each component is shown in FIG. 4 and FIG. 5.

N.D.：未檢測出[Table 6]

ND: not detected

Similar substances with known structures (formulas (V) to (X)) are shown below. [Chem 8]

[Example 4] Preparation of a solution preparation for injection: Pemetrexed disodium 2.5 hydrate of Example 1 (RRT 0.34 component: 0.02%, RRT 0.41 component: 0.05%) 2719 mg (with pemetrexed) Disperse is 2250 mg) dissolved in 87.28 mL of water for injection (total 90 mL is 25 mg/mL with pemetrexed). The solution was aseptically filtered using a membrane filter with a pore size of 0.22 μm, and 4 mL of the filtered liquid was filled in a vial (manufactured by FUJI GLASS) made of borosilicate glass with a capacity of 10 mL and an inner diameter of 12.5 mm. Nitrogen is injected so that the oxygen concentration in the void part of the vial becomes 0.5% by volume or less, and it is plugged with a D713 butyl rubber stopper (thickness 2 mm) made of fluororesin laminated by Daikyo Seiko Co., Ltd., using aluminum Cover tightly. Then, put the capped vial together with a deoxidizer (manufactured by NIPPONKAYAKU FOOD TECHNO Co., Ltd., MODURAN S-500) into a bag made of inorganic vapor-deposited film (oxygen permeability 0.2 mL/m ² ·24 hr·atm In the following), it was sealed with a heat sealer to perform secondary packaging to prepare a solution formulation for injection of pemetrexed in Example 4.

[Example 5] Production of solution preparation for injection Using the pemetrexed disodium 2.5 hydrate of Example 2 (RRT 0.34 component: 0.00%, RRT 0.41 component: 0.01%), the injection for Example 5 was prepared by the same operation as Example 4 Solution preparation.

[Comparative Example 2] Production of solution preparation for injection Purchase pemetrexed disodium 2.5 hydrate as a pharmaceutical raw material. By HPLC analysis, the purity of pemetrexed was 99.25% (area percentage), the composition with RRT of 0.34 was 0.08% (area percentage), and the composition with RRT of 0.41 was 0.22% (area percentage). The results of HPLC analysis including other similar substances are summarized in Table 7.

Dissolve 952 mg of pemetrexed disodium 2.5 hydrate (788 mg as pemetrexed) into 30.55 mL of water for injection (total 31.5 mL), and perform the same operation as in Example 4 to prepare and compare Example 2 solution preparation for injection.

[Table 7]

[Test Example 1] 60°C storage stability test of the solution preparation for injection The solution preparations for injection of Examples 4 and 5 and Comparative Example 2 were stored at 60°C for 2 weeks. Each formulation was evaluated for coloration (b* value, visual evaluation) and similar substances derived from pemetrexed. The coloring of each preparation and the evaluation results of similar substances derived from pemetrexed are shown in Table 8. In addition, the HPLC charts at the start of the test in Example 4 and Comparative Example 2 (A) and after storage at 60° C. for 2 weeks (B) are shown in FIGS. 2 and 3.

N.D.：未檢測出[Table 8]

ND: not detected

In Comparative Example 2, compared with Examples 4 and 5, Compound (IX) is present at a high content, and the coloring is significantly increased. It is believed that the reason is that the raw material containing Pemetrexed Disodium used in Comparative Example 2 has a relatively large amount of similar substances with RRT of 0.34 and RRT of 0.41, and the injection solution containing Pemetrexed caused by this ingredient The color of the preparation increases during storage.

As described in Examples 4 and 5, it was clarified that by using a raw material containing pemetrexed disodium with a reduced content of similar substances with an RRT of 0.34 and an RRT of 0.41 as a drug substance for a solution preparation for injection, Suppress the coloring in preservation. In addition, it has been clarified that all analogues can be provided with an injection solution preparation which is less in quality and excellent in chemical stability.

[Example 6] Manufacture of a solution preparation for injection such that pemetrexed has a purity of 98.55% (area percentage), an ingredient with an RRT of 0.34 is 0.01%, and an ingredient with an RRT of 0.41 is 0.01% pemetrexed disodium 2.5 1960 mg of hydrate (1625 mg as pemetrexed) was dissolved into 63.04 mL of water for injection (65 mL total). The solution was aseptically filtered using a membrane filter with a pore size of 0.22 μm, and 4 mL of the filtered liquid was filled into a vial (manufactured by FUJI GLASS) made of borosilicate glass with a capacity of 10 mL and an inner diameter of 12.5 mm. Nitrogen gas is injected so that the oxygen concentration in the void part of the vial becomes 0.5% by volume or less, and it is stoppered with a D713 butyl rubber stopper (thickness 2 mm) made of fluororesin laminated by Daikyo Seiko Co., Ltd., with an aluminum cap Cover tightly. Then, put the capped vial together with a deoxidizer (manufactured by NIPPONKAYAKU FOOD TECHNO Co., Ltd., MODURAN S-500) into a bag made of inorganic vapor-deposited film (oxygen permeability 0.2 mL/m ² ·24 hr·atm In the following), it was sealed with a heat sealer to perform secondary packaging, and the pemetrexed solution preparation for injection of Example 6 was prepared.

[Comparative Example 3] Production of solution preparation for injection The raw material containing pemetrexed disodium was used as the raw material after pemetrexed disodium 2.5 hydrate used in Example 6 was stored in an atmospheric atmosphere at a temperature of 40°C for one and a half months. In the same manner as in Example 6, the solution preparation for injection of Comparative Example 3 was prepared. In addition, in the raw material containing pemetrexed disodium used in Comparative Example 3 (Pemetrexed disodium salt 2.5 hydrate after being stored in the atmosphere at a temperature of 40°C for one and a half months), the RRT was 0.34 The component is 0.05% (area percentage), and the RRT is 0.41 is 0.13% (area percentage).

[Test Example 2] 60°C storage stability test of injection solution preparation The injection solution preparations of Example 6 and Comparative Example 3 were stored at 60°C for 2 weeks. Each preparation was colored (b* value, visual evaluation), and similar substances derived from pemetrexed were evaluated. Table 9 shows the evaluation results of the coloring of each preparation and similar substances derived from pemetrexed.

N.D.：未檢測出[Table 9]

ND: not detected

Regarding Comparative Example 3, compared with Example 6, the compound (IX) is present at a high content, and the coloring is greatly increased. It is considered that the reason is that the pemetrexed disodium used in Comparative Example 3 was stored at a temperature of 40°C for one and a half months, so the mass of analogues with RRT of 0.34 and RRT of 0.41 increased, which resulted in the inclusion of pemetrexed The coloration of Qusai's injection solution preparation increased during storage. Based on the above verification results, it is clear that by using a raw material containing pemetrexed disodium salt with an RRT of 0.34±0.03 and an RRT of 0.41±0.03, the injection containing pemetrexed can be greatly suppressed Coloring with solution preparations during storage.

FIG. 1 is an HPLC chart of the pemetrexed disodium drug substance used in the injection solution preparation of Example 1. FIG. 2 is an HPLC chart of the solution preparation for injection of Example 4 (A: at the start of the test, B: analysis at 60° C. after 2 weeks). FIG. 3 is an HPLC chart of the solution preparation for injection of Comparative Example 2 (A: at the start of the test, B: analysis at 60° C. for 2 weeks). Fig. 4 is an LC-MS spectrum of a component with a relative retention time (RRT) of 0.34 analyzed by HPLC (upper graph: positive ion mode, lower graph: negative ion mode). Fig. 5 is an LC-MS spectrum of a component with a relative retention time (RRT) of 0.41 analyzed by HPLC (upper graph: positive ion mode, lower graph: negative ion mode).

Claims (11)

A method for manufacturing a solution preparation for injection, which is a method for manufacturing a solution preparation for injection containing pemetrexed disodium as an active ingredient, the method comprising: (1) The steps of preparing a solution for injection using raw materials containing pemetrexed disodium, and (2) The step of filling the above-mentioned injection solution into a container for a preparation, and tightening it with a rubber stopper in an atmosphere in which the oxygen concentration of the void is 1% by volume or less, The above raw materials contain components with a relative retention time (RRT) of 0.41±0.03 using retention time (RT) of pemetrexed as an indicator in HPLC analysis of 0.10% or less, The above HPLC analysis conditions are as follows: [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B, Flow rate: 1.0 mL/min Area measurement range: 32 minutes after injection of the sample solution. According to the manufacturing method of claim 1, the raw material containing pemetrexed disodium contains an ingredient with a relative retention time (RRT) of 0.34±0.03 in which the retention time of pemetrexed is used as an index in the HPLC analysis of 0.05% or less. According to the manufacturing method of claim 1 or 2, the HPLC purity of the raw material containing pemetrexed disodium is above 98.50%. The manufacturing method as claimed in claim 1 or 2, wherein a rubber stopper with an oxygen content of 0.0013 mmol or less that penetrates into the container during storage for 2 weeks at a temperature of 60°C is used for tightness. The manufacturing method according to claim 1 or 2, wherein the volume of the void portion of the container obtained by removing the volume of the injection solution from the volume of the container for the preparation is 60% or less relative to the volume of the container. According to the manufacturing method of claim 1 or 2, wherein the injection solution preparation containing pemetrexed disodium as an active ingredient contains less than 0.05% of HPLC analysis, the relative retention of pemetrexed retention time (RT) as an indicator Time (RRT) is 1.07±0.03. The manufacturing method according to claim 1 or 2, wherein the injection solution preparation containing pemetrexed disodium as an active ingredient contains the compound represented by the formula (IX) or a salt thereof at 0.05% or less, [Chem 1]

. A solution preparation for injection, which contains pemetrexed disodium as an active ingredient and contains less than 0.05% of HPLC analysis. The relative retention time (RRT) of pemetrexed retention time (RT) as an index is 1.07± For components of 0.03, the above HPLC analysis conditions are as follows: [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B, Flow rate: 1.0 mL/min Area measurement range: 32 minutes after injection of the sample solution. The solution preparation for injection as claimed in claim 8, which contains 0.05% or less of the compound represented by formula (IX), [Chem 2]

. A raw material containing pemetrexed disodium for injection solution preparations, which is used for the manufacture of pharmaceutical injection solution preparations, and contains the retention time (RT) of pemetrexed in HPLC analysis of less than 0.10% The relative retention time (RRT) of the indicator is 0.41±0.03, and the above HPLC analysis conditions are as follows: [HPLC analysis conditions] Measuring wavelength: 228 nm Column: C8 column, 150×4.6 mm, 3.5 μm Column temperature: 30℃ Mobile phase A: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 97/3 Mobile phase B: 25 mM sodium phosphate buffer (pH 2.5)/acetonitrile = 30/70 Mobile phase concentration gradient control (mobile phase A concentration (vol%) gradient (time after injection)): 100→75 (0-20 minutes), 75→0 (20-32 minutes), the rest is mobile phase B, Flow rate: 1.0 mL/min Area measurement range: 32 minutes after injection of the sample solution. If the raw material containing pemetrexed disodium for injection solution preparation according to claim 10 contains less than 0.05%, the relative retention time (RRT) with pemetrexed retention time as the index in the HPLC analysis is 0.34±0.03 Ingredients.

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