JP2019019075A - Liquid pharmaceutical composition containing pemetrexed - Google Patents

Abstract

To provide a novel liquid pharmaceutical composition that contains pemetrexed as an active ingredient, and storage stability is secured as a medicine, or a method for producing the composition.SOLUTION: The present invention provides a liquid pharmaceutical composition that contains pemetrexed or salt thereof, deoxidant, and anti-oxidant in aqueous solution, and to which heating treatment is applied, and a method for producing a liquid pharmaceutical composition which includes: a process of encapsulating aqueous solution containing pemetrexed or salt thereof, deoxidant, and anti-oxidant into a glass container; and a process of performing heating treatment to the encapsulated aqueous solution.SELECTED DRAWING: None

Description

  The present invention belongs to the technical field of pharmaceutical preparations containing organic active ingredients. The present invention relates to a liquid pharmaceutical composition containing pemetrexed or a salt thereof as an active ingredient, and relates to the liquid pharmaceutical composition having a storage stability as a pharmaceutical product, or a method for producing the liquid pharmaceutical composition.

  Pemetrexed (N- {4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl} -L-glutamic acid) Is a drug having the following chemical structure, and is mainly used as an anticancer agent for malignant pleural mesothelioma and small cell lung cancer. In Japan, a preparation containing sodium hydrate of the drug is sold by Eli Lilly Japan under the name Alimta (registered trademark). The preparation includes infusion and injection, but both are freeze-dried preparations and are preparations at the time of use that need to be dissolved and prepared in physiological saline or the like for use.

  Pemetrexed immediate-use preparations (Ready-to-use preparations), for example, liquid preparations in which pemetrexed is dissolved in physiological saline do not require preparation before use and are very useful. However, there is a problem that pemetrexed is easily decomposed in an aqueous solution with time, and related substances are remarkably produced. The production of many related substances also causes side effects and is undesirable.

Various means for suppressing oxidative degradation of pemetrexed in an aqueous solution have been proposed for the above problems.
For example, Patent Document 1 discloses a pharmaceutical composition in which oxidative degradation of pemetrexed in an aqueous solution is suppressed by containing an antioxidant such as monothioglycerol, L-cysteine, or thioglycolic acid. Patent Document 2 discloses a pharmaceutical composition that suppresses oxidative degradation of pemetrexed in an aqueous solution by containing an antioxidant such as disodium ethylenediaminetetraacetate, citric acid, or ascorbic acid.

  Patent Document 3 discloses a pharmaceutical composition that suppresses oxidative degradation of pemetrexed in an aqueous solution by containing a compound such as sulfurous acid, hydrogen sulfite, pyrosulfurous acid, nitrous acid, sulfur dioxide, and thiosulfuric acid. Yes. Patent Documents 4 and 5 disclose pharmaceutical compositions in which oxidative degradation of pemetrexed in an aqueous solution is suppressed by containing a chelating agent such as cysteine and sodium edetate.

Special table 2003-521518 gazette JP 2014-237607 A JP2015-124215A International Publication No. 2016/024369 JP 2016-41684 A

  It is a main object of the present invention to provide a novel liquid pharmaceutical composition containing pemetrexed or a salt thereof as an active ingredient and having a guaranteed storage stability as a pharmaceutical or a method for producing the same.

  As a result of intensive studies, the present inventors have found that the above-described problems can be solved by blending an oxygen-absorbing agent and an antioxidant into a pemetrexed-containing aqueous solution, and further subjecting to heat treatment, thereby completing the present invention. .

  Examples of the present invention include the following.

[1] A liquid pharmaceutical composition comprising pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in an aqueous solution and subjected to a heat treatment.
[2] The liquid pharmaceutical composition according to the above [1], wherein the oxygen scavenger is sulfurous acid, hydrogen sulfite, pyrosulfurous acid, nitrous acid, or a salt thereof.
[3] The liquid pharmaceutical composition according to the above [1] or [2], wherein the antioxidant is L-cysteine or a salt thereof, or α-thioglycerin.
[4] The liquid pharmaceutical composition according to any one of [1] to [3] above, wherein the liquid property of the liquid pharmaceutical composition is within a range of pH 6.5 to 9.0.

[5] The liquid pharmaceutical composition according to any one of the above [1] to [4], wherein the liquid pharmaceutical composition is an injection encapsulated in a glass container.
[6] The liquid pharmaceutical composition according to the above [5], wherein the space in the glass container is 5% or less as an oxygen concentration or is a vacuum.
[7] The liquid pharmaceutical composition according to the above [5] or [6], wherein the amount of an unknown related substance after storage at 25 ° C. for 3 months is 0.2% or less.

[8] The method includes the steps of enclosing an aqueous solution containing pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in a glass container, and subjecting the encapsulated aqueous solution to a heat treatment. A method for producing a liquid pharmaceutical composition.
[9] The method for producing a liquid pharmaceutical composition according to the above [8], further comprising a step of adjusting the oxygen concentration in the glass container inner space to 5% or less, or a step of evacuating the glass container inner space.
[10] The method for producing a liquid pharmaceutical composition according to the above [8] or [9], further comprising a step of adjusting the liquid property of the liquid pharmaceutical composition within the range of pH 6.5 to 9.0.
[11] The method for producing a liquid pharmaceutical composition according to any one of the above [8] to [10], wherein the glass container is a vial.
[12] The method for producing a liquid pharmaceutical composition according to any one of the above [8] to [11], wherein the oxygen scavenger is sulfurous acid, hydrogen sulfite, pyrosulfurous acid, nitrous acid, or a salt thereof.
[13] The method for producing a liquid pharmaceutical composition according to any one of the above [8] to [12], wherein the antioxidant is L-cysteine or a salt thereof, or α-thioglycerin.

According to the present invention, a pharmaceutically preservable and stable liquid pharmaceutical composition containing pemetrexed as an active ingredient, in which decomposition of pemetrexed or generation of related substances (including unknown related substances) is suppressed, is provided and provided. be able to.

1 Liquid Pharmaceutical Composition According to the Present Invention A liquid pharmaceutical composition according to the present invention (hereinafter referred to as “the present composition”) contains pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in an aqueous solution, It is characterized by being subjected to heat treatment.
Here, examples of the “liquid pharmaceutical composition” include liquid injections and infusions. In the present invention, a liquid injection is preferred.

1.1 Pemetrexed or a salt thereof The composition of the present invention contains pemetrexed or a salt thereof (hereinafter also simply referred to as “pemetrexed”) in an aqueous solution.
The salt of pemetrexed is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, sodium salt, potassium salt, lithium salt, magnesium salt, aluminum salt, ammonium salt, trimethylammonium salt, triethylammonium salt, monoethanol Mention may be made of alkali metal salts, alkaline earth metal salts, non-toxic metal salts, ammonium salts and substituted ammonium salts such as ammonium salts, triethanolammonium salts, pyridinium salts, substituted pyridinium salts. The salt may be a hydrate. Preferred salts of pemetrexed include, for example, sodium salts and sodium salt hydrates.

  The amount of pemetrexed in the composition of the present invention varies depending on the dosage form, type of salt, etc. For example, in the case of a liquid injection, the amount of pemetrexed per 1 mL of unit form is suitably in the range of 1 to 100 mg. Yes, within the range of 5-50 mg, more preferably 25 mg.

1.2 Oxygen absorber The composition of the present invention contains an oxygen absorber in an aqueous solution.
The oxygen scavenger is not particularly limited as long as it is generally used for liquid preparations. Examples thereof include sulfite, hydrogen sulfite, pyrosulfite, nitrous acid, and salts thereof.

  Sulfurous acid, hydrogen sulfite, pyrosulfurous acid, and nitrous acid salt are not particularly limited as long as they are pharmaceutically acceptable. For example, alkali metal salts such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt Alkaline earth metal salts such as zinc salts, iron salts, cobalt salts, copper salts and other transition metal salts, salts with basic ammonium, salts with triethanolamine, L-histidine, L-arginine, L-lysine And salts with amino acids such as Of these, sodium bisulfite and sodium sulfite are preferable. One or more of these can be used in combination as appropriate.

  The compounding amount of the oxygen scavenger in the composition of the present invention varies depending on the type and dosage form of the oxygen scavenger. For example, in the case of a liquid injection, it is within the range of 0.1 to 10 mg per 1 mL of unit form. Appropriate, preferably in the range of 0.5-6 mg, more preferably in the range of 1-4 mg. If it is less than 0.1 mg, the stability of the composition of the present invention (pemetrexed) may not be sufficiently maintained.

1.3 Antioxidant The composition of the present invention contains an antioxidant in an aqueous solution.
The antioxidant is not particularly limited as long as it is generally used in a liquid preparation, and examples thereof include L-cysteine or a salt thereof, α-thioglycerin, ascorbic acid or a salt thereof.

  The salt of L-cysteine is not particularly limited as long as it is pharmaceutically acceptable. For example, hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, iodine Inorganic acid salts such as hydrohalide, formate, acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, mandelate , Glutarate, malate, benzoate, phthalate, ascorbate, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, aspartate And organic acid salts such as glutamate. The salt of ascorbic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include the same salts as the salts of sulfurous acid. These salts may be hydrates. Among these, L-cysteine or a salt thereof (eg, hydrochloride) and α-thioglycerin are preferable, and L-cysteine hydrochloride is more preferable. One or more of these can be used in combination as appropriate.

  The blending amount of the antioxidant in the composition of the present invention varies depending on the type and dosage form of the antioxidant. For example, in the case of a liquid injection, the amount is 0.1 to 10 mg per mL of unit form. Appropriate, preferably in the range of 0.5-6 mg, more preferably in the range of 1-4 mg. If it is less than 0.1 mg, the stability of the composition of the present invention (pemetrexed) may not be sufficiently maintained.

1.4 Heat treatment The composition of the present invention is subjected to a heat treatment.
Conventionally, in the case of injections with poor stability, final sterilization is generally performed by filtration sterilization using a membrane filter or the like. And since heat processing (heat sterilization) has the possibility of destabilizing a formulation, generally it is not selected as a sterilization method of those formulations. The present inventors have surprisingly compared the case where a liquid pharmaceutical composition containing pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in an aqueous solution is subjected to heat treatment as compared with the case where it is not applied. It was found that stability was maintained, production of unknown related substances of pemetrexed was suppressed, and increase of other related substances could also be suppressed. Therefore, the composition of the present invention has been heat-treated.

  The temperature of the heat treatment may be a temperature generally used for heat sterilization of drugs or a temperature lower than that. Specifically, the temperature in the range of 50 to 150 ° C. can be mentioned, and is usually in the range of 60 to 140 ° C., preferably in the range of 80 ° C. to 130 ° C., and in the range of 105 to 121 ° C. Is more preferable.

  The time for the heat treatment varies depending on the set temperature and is appropriately set, but is generally longer when the heating temperature is lower and shorter when the heating temperature is higher. For example, it can be set within a range of 5 minutes to 15 days. Specifically, within a temperature range of 100 ° C. to 150 ° C., a relatively short time of 5 to 120 minutes (preferably within a range of 10 to 60 minutes) is sufficient and lower than 100 ° C., for example, If it is 60 ° C. or 70 ° C., it usually takes a relatively long time of 4 to 12 days (preferably within a range of 6 to 10 days).

  The said heat processing can also be performed using the apparatus generally used for heat sterilization of chemical | medical agents, such as an autoclave. Therefore, for example, by performing the heat treatment at a temperature of 100 ° C. or higher using an autoclave, a sterilization treatment can also be performed. The said heat processing is normally performed at the last stage in manufacture of this invention composition.

1.5 Container Enclosing the Composition of the Present Invention The container (packaging material) enclosing the composition of the present invention is not particularly limited, and examples thereof include glass, resin, and metal containers. Among these, since the composition of the present invention is produced by heat treatment, a glass container is preferable.
Although the shape of the container for enclosing the composition of the present invention is not particularly limited, for example, a vial shape, an ampule shape, a cup shape, a bag shape and the like are appropriately selected. In particular, in consideration of portability and convenience during administration or administration, a vial-like one is preferable, although it depends on the final form of the composition of the present invention.
The container for the composition of the present invention is preferably a container that can block oxygen and can be produced in a sealed state.

The oxygen concentration in the container space is suitably 5% or less. As a result, the stability of pemetrexed in the composition of the present invention can be further improved, and the production of decomposition products (mainly related substances of pemetrexed) can be suppressed.
The smaller the oxygen concentration in the space in the container, the better, and 2% or less is preferable. In addition, it is more preferable to remove the oxygen-containing gas from the container and create a vacuum state. Here, the vacuum state is a state in a space filled with a gas having a pressure lower than the atmospheric pressure, and means a state where the pressure is reduced from the surrounding pressure by a vacuum dryer or a vacuum pump.

  Adjustment of the oxygen concentration in the internal space of the container can be easily performed by sealing an inert gas such as nitrogen gas or argon gas.

The related substances produced by long-term storage of pemetrexed include LY338979-1, LY33879-2, Imp. B, and Imp. C is known. In addition to these, it is also known that there are unknown related substances whose structures are not specified (hereinafter referred to as “unknown related substances”).
In the composition of the present invention, the amount of unknown affinity after storage at 25 ° C. for 3 months is preferably 0.2% or less to 0.249% or less, more preferably 0.15% or less. What is 0.1% or less is still more preferable. Here, the amount% of the unknown affinity represents the ratio of the peak area of the unknown affinity in the total peak area derived from pemetrexed in the analysis by HPLC.

1.6 Liquidity, Additives, Others The composition of the present invention is usually adjusted within the range of pH 5-10. Preferably it exists in the range of pH 6.5-9.0, More preferably, it exists in the range of pH 7-8. A pH lower than 5 or higher than pH 10 is not preferable for the stability of the composition of the present invention (pemetrexed).

  For adjusting the liquidity, a pH adjuster can be used, and the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable. Specifically, examples of the pH adjuster include hydrochloric acid, phosphoric acid or a salt thereof, citric acid or a salt thereof, carbonic acid or a salt thereof, maleic acid, glycine, and sodium hydroxide. One or more of these can be used in combination as appropriate. Moreover, buffer solutions, such as a phosphate buffer, a citrate buffer, a citrate phosphate buffer, and a carbonate buffer, can also be used.

  Additives other than those described above can be added in appropriate amounts as long as the effects of the present invention are not impaired. Examples of such additives include solubilizers, surfactants, sweeteners, flavoring agents, fragrances, thickeners, preservatives, and excipients.

Water as a solvent of the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include water for injection, physiological saline, purified water, and distilled water. In the case of liquid injections and infusions, water for injection and physiological saline are usually used.

2. Manufacturing method of the composition of the present invention The manufacturing method of the composition of the present invention (hereinafter referred to as “the manufacturing method of the present invention”) encloses an aqueous solution containing pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in a glass container. And a step of performing heat treatment. The terms pemetrexed salt, oxygen scavenger, antioxidant, water and the like are as defined above.

Hereinafter, the production method of the present invention will be described in detail.
(1) A step of enclosing an aqueous solution containing pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in a glass container In this step, the step of adjusting the pH of the composition of the present invention, the oxygen concentration in the glass container space The process of adjusting, the process of evacuating the inside of glass container space, etc. can be included.

First, a predetermined amount of each desired pemetrexed, oxygen scavenger, antioxidant, and other additives is dissolved in water by a conventional method, and usually at a desired pH (for example, pH 6.5-9. 0), and the aqueous solution is filled into a glass container such as a glass vial by a conventional method. And when adjusting the oxygen concentration of the space in a glass container, an inert gas (for example, nitrogen, argon) is enclosed so that it may become a desired oxygen concentration (for example, 2%). In order to make the glass container inner space into a vacuum, it can be made into a vacuum by an ordinary method using, for example, a vacuum dryer or a vacuum pump. After adjusting the oxygen concentration in the glass container inner space or evacuating the glass container inner space, this step can be carried out by sealing or sealing the glass container containing the liquid composition.
When the composition of the present invention is an injection or a drop, this step is preferably performed in a clean room.

(2) The process which heat-processes The heat processing in this process can be performed by a conventional method. For example, by placing the glass container containing the liquid composition obtained in the above step in a heater or autoclave used in the manufacture of a pharmaceutical preparation and heating the liquid composition at a predetermined temperature for a predetermined time, A process can be performed.

  The temperature of the heat treatment may be a temperature generally used for heat sterilization of drugs or a temperature lower than that. Specifically, the temperature in the range of 50 to 150 ° C. can be mentioned, and is usually in the range of 60 to 140 ° C., preferably in the range of 80 ° C. to 130 ° C., and in the range of 105 to 121 ° C. Is more preferable.

  The time for the heat treatment varies depending on the set temperature and is appropriately set, but is generally longer when the heating temperature is lower and shorter when the heating temperature is higher. For example, it can be set within a range of 5 minutes to 15 days. Specifically, within a temperature range of 100 ° C. to 150 ° C., a relatively short time of 5 to 120 minutes (preferably within a range of 10 to 60 minutes) is sufficient and lower than 100 ° C., for example, If it is 60 ° C. or 70 ° C., it usually takes a relatively long time of 4 to 12 days (preferably within a range of 6 to 10 days).

  Since the heat treatment can also be performed using an apparatus generally used for heat sterilization of drugs such as an autoclave, the heat treatment is performed at a temperature of 100 ° C. or higher using an autoclave. Can also be performed.

(3) Other steps The production method of the present invention may include steps other than those described above. For example, as another process, a filtration sterilization process using a membrane filter can be exemplified.
Moreover, another process may exist between the said processes, and may exist before and after the said processes.

  Hereinafter, the present invention will be described with reference to examples, comparative examples, and test examples, but the present invention is not limited to these examples.

<Stability test>
(1) Thermal stability test The thermal stability test was performed by storing for 1 to 6 months at 25 ° C or 40 ° C.

(2) Method for Measuring Related Substances Each related substance in a sample solution (related 1 (LY338979-1), related 2 (LY338879-2), related 3 (Imp. B), related 4 (Imp. C), unknown related ) And total related substances were measured by HPLC method. The amount of each related substance or total related substance was expressed as a percentage (%) of the peak area of each related substance or total related substance in the total peak area derived from HPLC pemetrexed.
The HPLC measurement conditions used for this measurement are as follows.

[HPLC measurement conditions]
Detector: UV absorptiometer (measurement wavelength: 250 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 3.5 μm octylsilylated silica gel for liquid chromatography.
Column temperature: A constant temperature around 25 ° C. Mobile phase A: pH 3.5 ammonium formate buffer Mobile phase B: Acetonitrile Mobile phase feed: Adjust the mixing ratio of mobile phase A and mobile phase as appropriate to control the concentration gradient . In the concentration gradient control, mobile phase A: mobile phase B = 95%: 5% for 0 to 3 minutes after injection, and mobile phase A: mobile phase B = 95 → 30%: 5 → 70% for 3 to 45 minutes after injection. In the period of 45 to 45.1 minutes after injection, mobile phase A: mobile phase B = 30 → 95%: 70 → 5%, and in the period of 45.1 to 57 minutes after injection, mobile phase A: mobile phase B = 95%: 5% I went there.
Flow rate: 1.0 mL per minute

  Each related substance has the following structure. An unknown related means an related substance with unspecified structure other than these four related substances. Further, the total related substance (hereinafter referred to as “total related”) is a combination of all impurities including related 1, related 2, related 3, related 4, and unknown related.

[Example 1]
According to Formula 1 shown in Table 1 below, 264 mg of L-cysteine hydrochloride hydrate, 352 mg of sodium bisulfite, and 73 mg of α-thioglycerin were dissolved in 80 mL of water for injection. Subsequently, pemetrexed sodium 2.5 hydrate 3,035 mg (2,500 mg as pemetrexed) was added to the solution and dissolved. The aqueous solution was adjusted to pH 7.4 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 100 mL.

The solution obtained above was aseptically filtered through a PVDF membrane filter with a pore size of 0.22 μm, filled with 4 mL of the filtered liquid in a glass vial, and the oxygen concentration in the vial was 2% in a glove box filled with nitrogen. did. Finally, it was stoppered and sealed with an aluminum cap.
The sealed vial was placed in a high-pressure steam sterilizer and heat-treated at 115 ° C. for 30 minutes to prepare the composition of the present invention.

[Comparative Examples 1 and 2]
A comparative composition (Comparative Example 1) was prepared in the same manner as in Example 1 except that no heat treatment was performed. A comparative composition (Comparative Example 2) was prepared in the same manner as in Example 1 except that the oxygen concentration in the vial was 0.5% and no heat treatment was performed.

[Test Example 1] Stability test (Example 1, Comparative Example 1, Comparative Example 2)
The stability test was performed on the composition of the present invention of Example 1 and the compositions of Comparative Examples 1 and 2. The results are shown in Tables 2 to 4, respectively.

  As shown in Tables 2 to 4, the composition of the present invention of Example 1 subjected to the heat treatment was suppressed in the generation of unknown relationships over a period of 6 months at the predetermined storage temperature, and other related substances. The storage stability was also good. On the other hand, the compositions of Comparative Examples 1 and 2 that were not subjected to the heat treatment exceeded 0.2%, which is a threshold required for confirmation of safety according to ICH guidelines after storage at 25 ° C. for 3 months.

[Example 2]
A composition of the present invention was prepared in the same manner as in Example 1 according to the formulation 2 shown in Table 5 below.

[Test Example 2] Stability test (Example 2)
The stability test was performed on the composition of the present invention of Example 2. The results are shown in Table 6.

  As shown in Table 6, the composition of the present invention of Example 2 subjected to the heat treatment was suppressed in the generation of unknown related substances and increased in other related substances over a period of 6 months at a predetermined storage temperature. Was also suppressed, and the storage stability was good.

[Example 3]
The composition of the present invention was prepared in the same manner as in Example 1 according to the formulation 3 shown in Table 7 below.

[Comparative Example 3]
A comparative composition (Comparative Example 3) was prepared in the same manner as in Example 1, except that no heat treatment was performed.

[Test Example 3] Stability test (Example 3, Comparative Example 3)
The stability test was performed on the composition of the present invention of Example 3 and the composition of Comparative Example 3. The results are shown in Tables 8 and 9, respectively.

  As shown in Tables 8 and 9, the composition of the present invention of Example 3 subjected to the heat treatment was suppressed in the generation of an unknown affinity over a period of 6 months at a predetermined storage temperature, and other related substances. The storage stability was also good. On the other hand, the composition of Comparative Example 3 that was not subjected to the heat treatment had higher generation of unknown relationships and total relationships than the composition of the present invention of Example 3.

[Example 4]
A composition of the present invention was prepared in the same manner as in Example 1 except that heat treatment was performed under the following conditions according to the formulation 4 shown in Table 10 below.

-105 degreeC, 30 minutes (Example 4-1)
115 ° C., 10 minutes (Example 4-2)
115 ° C., 30 minutes (Example 4-3)
115 ° C. for 60 minutes (Example 4-4)
-121 degreeC, 20 minutes (Example 4-5)

[Test Example 4] Stability test (Examples 4-1 to 4-5)
About Examples 4-1 to 4-5, the stability test was done. The results are shown in Tables 11 to 15, respectively.

  As shown in Tables 11 to 15, the inventive compositions of Examples 4-1 to 4-5 were all inhibited from generating unknown relatives for 3 months at a predetermined storage temperature, and The increase in other related substances was also suppressed, and the storage stability was good.

[Example 5]
According to prescription 5 shown in Table 16 below, heat treatment for 9 days (Example 5-1) in a thermostat set at 70 ° C. or 7 days (Example 5-2) in a thermostat set at 60 ° C. A composition of the present invention was prepared in the same manner as in Example 1 except that.

[Test Example 5] Stability test (Examples 5-1 and 5-2)
A stability test was performed on the compositions of the present invention of Example 5-1 and Example 5-2. The results are shown in Tables 17 and 18, respectively.

  As shown in Tables 17 and 18, even in the composition of the present invention that was heat-treated at a lower temperature, the formation of unknown related substances was suppressed, and the increase of other related substances was also suppressed.

[Example 6]
Fill a glass vial with 4 mL of the filtrate prepared in the same manner as in Example 1 and adjust the oxygen concentration, and put the glass vial containing 4 mL of the filtrate into a lyophilizer. The inside of the vial was evacuated under vacuum (about 5,000 Pa) and then stoppered to prepare the composition of the present invention.
In addition, after preparing this invention composition, the inside of a freeze dryer was returned to atmospheric pressure, this invention composition (glass vial) was taken out from the freeze dryer, and it used for the following tests.

[Test Example 6] Stability test (Example 6)
The composition of the present invention of Example 6 was subjected to a stability test. The results are shown in Table 19.

  As shown in Table 19, the glass container (vial) was evacuated and subjected to heat treatment as compared with the composition of the present invention (Table 2) of Example 1 subjected to oxygen concentration adjustment and heat treatment. The composition of the present invention was more stable.

  The composition of the present invention is useful as a pharmaceutical product because the production of related substances (including unknown related substances) which is a degradation product of pemetrexed is suppressed and storage stability is ensured. Moreover, since the production method of the present invention can produce a storage-stable liquid pharmaceutical composition in which the production of the related substance is suppressed, it is useful in the production of a liquid medicine containing pemetrexed.

Claims (13)

A liquid pharmaceutical composition comprising pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in an aqueous solution and subjected to a heat treatment. The liquid pharmaceutical composition according to claim 1, wherein the oxygen scavenger is sulfurous acid, hydrogen sulfite, pyrosulfurous acid, nitrous acid, or a salt thereof. The liquid pharmaceutical composition according to claim 1 or 2, wherein the antioxidant is L-cysteine or a salt thereof, or α-thioglycerin. The liquid pharmaceutical composition as described in any one of Claims 1-3 whose liquid property of a liquid pharmaceutical composition exists in the range of pH 6.5-9.0. The liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the liquid pharmaceutical composition is an injection encapsulated in a glass container. The liquid pharmaceutical composition according to claim 5, wherein the space in the glass container is 5% or less as an oxygen concentration, or is a vacuum. The liquid pharmaceutical composition according to claim 5 or 6, wherein the amount of unknown related substances after storage at 25 ° C for 3 months is 0.2% or less. A liquid pharmaceutical composition comprising a step of enclosing an aqueous solution containing pemetrexed or a salt thereof, an oxygen scavenger, and an antioxidant in a glass container, and a step of heat-treating the enclosed aqueous solution. Manufacturing method. Furthermore, the manufacturing method of the liquid pharmaceutical composition of Claim 8 including the process of adjusting the oxygen concentration of the space in a glass container to 5% or less, or the process of evacuating the space in a glass container. Furthermore, the manufacturing method of the liquid pharmaceutical composition of Claim 8 or 9 including the process of adjusting the liquid property of a liquid pharmaceutical composition in the range of pH 6.5-9.0. The manufacturing method of the liquid pharmaceutical composition as described in any one of Claims 8-10 whose glass container is a vial. The method for producing a liquid pharmaceutical composition according to any one of claims 8 to 11, wherein the oxygen scavenger is sulfurous acid, hydrogen sulfite, pyrosulfurous acid, nitrous acid, or a salt thereof. The manufacturing method of the liquid pharmaceutical composition as described in any one of Claims 8-12 whose antioxidant is L-cysteine or its salt, or (alpha) thioglycerin.