JP2019123684A - Solution formulation for injection including pemetrexed - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a highly convenient solution-form RTU (Ready-to-use) preparation, which does not require a complicated dissolution step and can be diluted and immediately administered, rather than a freeze-dried preparation in the medical field. It is an object of the present invention to provide an injectable solution preparation containing pemetrexed, which suppresses the production of related substances and suppresses solution coloring during the storage period. SOLUTION: The injectable solution preparation containing pemetrexed of the present invention is an injectable solution preparation filled in a container with an oxygen concentration of 1% or less in the voids in the container and sealed with a rubber stopper, and the rubber to be used. By using a rubber stopper having a physical characteristic of 0.0013 mmol or less of oxygen permeating into the container during the storage period of 2 weeks under a temperature environment of 60 ° C., the formation of a related substance which is a decomposition product of pemetrexed. It is possible to provide an injectable solution preparation of pemetrexed having excellent storage stability. [Selection diagram] None

Description

  The present invention relates to injectable solution formulations in which the stability of pemetrexed is maintained.

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the preparation is sufficiently dissolved by adding physiological saline, and the required amount of solution is withdrawn, mixed with the physiological saline and used as 100 mL.

It is known that pemetrexed disodium rapidly undergoes an oxidation reaction with oxygen in an aqueous solution to generate a related substance. For this reason, pemetrexed disodium is provided to medical institutions as a lyophilised preparation, and no solution preparation is provided. However, as mentioned above, there is a demand for simplification of operation at the time of administration in medical institutions, and research and development of ready-to-use (RTU) preparations in the form of solutions are also performed for pemetrexed disodium preparations that are easily oxidized in solution. Is in progress.
Although pemetrexed disodium solution formulations have been reported for formulation formulations using various antioxidants, in many reported examples, treatments for reducing the oxygen content in the formulations are given. For example, Patent Document 1 discloses a pemetrexed disodium solution preparation having an oxygen partial pressure of 0.2% or less, and a vacuum degassing, distillation degassing, nitrogen bubbling, membrane degassing, catalyst resin degassing method, etc. It describes what is used. Moreover, in patent documents 2 and 3, after stirring a pemetrexed aqueous solution at room temperature for 2 hours in nitrogen atmosphere, the solution of oxygen concentration is 0.1-2.0 volume% or less by filtering with a 0.2 micrometer filter. The preparation is being prepared.
According to Patent Document 4, a pemetrexed disodium solution preparation in which the amount of oxygen in the void (head space) in the vial is adjusted to 3 to 5 v / v% by dispensing a drug solution into a vial and thereafter purging with nitrogen is prepared ing. Further, Patent Document 5 discloses a method in which a solution is frozen in a sealed chamber using a lyophilizer, depressurized, decompressed with nitrogen, and taped. The dissolved oxygen concentration of the solution is 0. It is described that it was removed to about 5 ppm.

International Publication 2012/121523 International Publication 2015/145911 International Publication 2015/050230 Japanese Patent Publication No. 2016-518404 gazette JP-A-2017-506213

As described above, in order to prepare a solution preparation of pemetrexed, it is known that it is effective to reduce the dissolved oxygen in the solution and the oxygen content in the void in the sealed unit preparation. . Although various methods are known as methods for reducing the oxygen content at the time of production, it is necessary to prevent the flow of oxygen into the container even during the storage period and to maintain the container in a low oxygen state.
By the way, the solution formulation of pemetrexed secures airtightness by filling a drug solution in a glass vial container and sealing with a rubber stopper. That is, in the preparation of pharmaceutical preparations, rubber plugs are used as sealing materials having no gas permeability. However, as a result of examination by the present inventors, it was found that the rubber plug had oxygen permeability at a slight level. And in the case of pemetrexed which is extremely sensitive to oxygen, even if measures are taken to reduce the oxygen content, during the storage period, the formation of similar substances and the coloring of the solution are sufficiently suppressed due to the oxygen permeation from the rubber stopper. It turned out that I could not do it.
Therefore, the problem to be solved by the present invention is to provide a solution preparation for injection containing pemetrexed, which suppresses the formation of a related substance and suppresses the coloring during the storage period. In particular, it is an object of the present invention to provide an injectable solution formulation containing pemetrexed in which the formation of a related substance is suppressed and the coloring is suppressed under storage conditions in a wide temperature range of 5 ° C. to room temperature or higher.

The present invention relates to a liquid preparation for injection comprising pemetrexed as an active ingredient, which suppresses decomposition of pemetrexed which is the active ingredient and finds conditions and materials of containers and packaging which can suppress coloring of the solution. It is set as the summary of the invention as described in [1]-[7].
[1] A solution for injection containing pemetrexed or a solution containing a pharmaceutically acceptable salt thereof is filled in a container and sealed with a rubber stopper, which is for a storage period of 2 weeks under a temperature condition of 60 ° C. An injectable solution preparation containing pemetrexed using a rubber plug whose oxygen amount permeating into the container is 0.0013 mmol or less.
That is, in the preparation of a solution preparation of pemetrexed according to the present invention, it was found that the rubber plug had oxygen permeability, and that the transmitted oxygen had an adverse effect on pemetrexed in the solution. By adopting a rubber plug having a low temperature dependency, the invention is effective in that it is possible to suppress the generation of a related substance and / or the coloration of a solution.
[2] The volume of the void portion of the container excluding the volume of the solution containing pemetrexed or a pharmaceutically acceptable salt thereof from the volume of the container is 60% or less of the volume of the container described in the above [1] Solution formulation for injection.
[3] The injectable solution preparation according to the above [1] or [2], wherein a container having an inner diameter of 20 mm or less is used.
[4] The injectable solution preparation according to any one of the above [1] to [3], wherein the thickness of the rubber plug is 1.5 mm or more.

[5] The injectable solution preparation according to any one of the above [1] to [4], wherein the injectable solution preparation is disposed in an atmosphere having an oxygen concentration of 1% by volume or less.
In addition, in consideration of the effect of oxygen permeation of the rubber plug, it is preferable to reduce the oxygen content in the atmosphere as well.
[6] The injectable solution preparation according to the above [5], wherein the injectable solution preparation is inserted into an oxygen shielding bag together with an oxygen scavenger and sealed.
[7] The injectable preparation according to [6], wherein the material of the material of the oxygen barrier bag is an oxygen barrier film having an oxygen permeability of 1 mL / m ² · 24 hr · atm or less.

  The injectable solution preparation containing pemetrexed according to the present invention uses a rubber plug whose amount of oxygen permeated into the container is 0.0013 mmol or less during a storage period of 2 weeks under a temperature environment of 60 ° C. It is possible to provide an injectable solution preparation of pemetrexed excellent in storage stability, which can suppress the formation of a related substance which is a degradation product of pemetrexed during the storage period. In particular, it is possible to provide an injectable solution formulation containing pemetrexed in which formation of a related substance is suppressed and coloring is suppressed under storage conditions in a wide temperature range of 5 ° C. to room temperature or higher.

The injectable solution preparation of the present invention is an injectable solution preparation prepared by filling a container with a solution containing pemetrexed or a pharmaceutically acceptable salt thereof and sealing it with a rubber stopper.
Pemetrexed is known to produce analogues mainly by oxidation. Therefore, the injectable solution preparation of the present invention has a low concentration of oxygen dissolved in a solution containing pemetrexed or a pharmaceutically acceptable salt thereof and oxygen in a space (head space) atmosphere other than the filled solution in the container. By doing so, related substances are suppressed. The dissolved oxygen concentration of the solution affects the partial pressure of oxygen in the head space in the container. In order to reduce the concentration of dissolved oxygen, it is effective to remove oxygen in the head space, and it is preferable to be filled with an inert gas such as nitrogen or argon. Specifically, it is preferable that the oxygen concentration in the space of the container of the preparation is 1% by volume or less.
As a method of controlling the concentration of dissolved oxygen in the solution in the injectable solution preparation of the present invention, an inert gas such as nitrogen or argon is directly injected into a container filled with the solution, and a fixed amount of inert gas is injected. After filling, the container may be sealed with a rubber stopper or the like. By using this method, it is possible to control the void oxygen concentration in the container to 1.0% by volume or less.
In addition, a container filled with the solution for injection according to the present invention is installed in a sealed space, the pressure in the space is reduced to a level not lower than the vapor pressure at any temperature of the drug solution, and then inert gas such as nitrogen or argon is After pouring to atmospheric pressure and leaving it to stand for several hours, a method of sealing with a rubber plug or the like may be used. By using this method, it is possible to control the void oxygen concentration in the container to 1.0% by volume or less.
The concentration of oxygen in the head space of the preparation container is preferably 1% by volume or less, more preferably an injectable solution preparation in which the concentration of oxygen in the head space of the container is 0.5% by volume or less. More preferably, the oxygen concentration in the container void is 0.2% by volume or less.
The oxygen concentration of the voids in the solution can be measured by an oxygen concentration meter using an oxygen sensor. For example, the void oxygen concentration of the container in the sealed preparation according to the present invention can be measured by using an oximeter (Microx TX3, manufacturer: PreSens) to which a needle type oxygen sensor is connected.

  The volume of the space (head space) other than the filled solution in the container also affects the stability of pemetrexed. As the ratio of the volume of the head space portion to the filled volume increases, the amount of oxygen in the container increases and the oxidative decomposition of pemetrexed is more likely to proceed. Therefore, it is preferable that the volume of the head space in the container be small. Specifically, the volume ratio of the head space is preferably 70% or less, more preferably 60% or less, with respect to the volume of the container.

The injectable solution preparation of the present invention is aseptically filled into a container and prepared as a sealed filling preparation sealed with a highly airtight rubber stopper.
The container to be used is not particularly limited in the form of a vial, a syringe or the like, as long as it can be sealed by a rubber stopper or the like, but a vial is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer.
Since pemetrexed forms a complex with a divalent metal ion to form insoluble fine particles, it is preferable to use a vial in which the elution of the glass component is suppressed. In particular, a vial filled with water and sealed by high-pressure steam sterilization at 121 ° C. for one hour is preferably a vial having 1 ppm or less of silicon eluting into water. As such a glass vial in which the elution of silicon is suppressed, it is preferable to use a container which has been surface-treated according to the purpose such as the suppression of the elution of a glass component. Examples of the vial in which the elution of the glass component is suppressed include VIST vial (manufactured by Daiwa Special Glass Co., Ltd.), VIALEX (manufactured by Nipro Co., Ltd.), type 1 plus (manufactured by SCHOTT Co., Ltd.), and the like. In particular, it is preferable to use a borosilicate glass vial internally treated with silica. As an example of the vial internally surface-treated with silica, mention may be made of a sili coat vial (manufactured by Fuji Glass Co., Ltd.).
The container is used for deoxygenation treatment according to the method of the present invention and sealed with a highly airtight rubber plug, whereby a highly deoxygenated injectable solution preparation can be prepared.

The injectable solution preparation of the present invention is an injectable solution preparation prepared by filling a container containing a solution containing pemetrexed or a pharmaceutically acceptable salt thereof in a container and sealing it with a rubber plug, and oxygen permeation It is characterized by using a specific rubber plug whose temperature dependency is low with respect to sex.
That is, it was found that pemetrexed also increased related substances even with a slight amount of oxygen inflow. For this reason, the rubber plug used for the solution preparation for injection needs to be one in which the permeation of oxygen is highly suppressed. In particular, it is preferable that oxygen permeability does not change with temperature. In the present invention, it has been found that a solution preparation of pemetrexed, even with very small amounts of oxygen, leads to the formation of related substances and coloring of the solution during storage period, and a rubber plug having a low temperature dependency of oxygen permeation. It was found that, by finding it and applying it to a solution preparation of pemetrexed, it is possible to prepare an injection solution preparation capable of maintaining stability even under storage conditions in a wide temperature range of 5 ° C. to room temperature or more. . As a result, it is possible to provide a solution formulation for injection of pemetrexed of which quality is maintained even when the temperature around the preparation becomes high due to troubles during storage or distribution of the preparation.
Specifically, it is necessary to use a rubber plug whose amount of oxygen which passes through the rubber plug into the cavity of the container during storage for 2 weeks at 60 ° C. is 0.0013 mmol or less. More preferably, it is a rubber plug whose oxygen permeation amount is 0.0010 mmol or less, more preferably 0.0008 mmol or less, under the same conditions.

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

As the material of the rubber plug, any material may be selected as long as it is not more than the above-mentioned oxygen permeation amount, but it is preferable to use a butyl rubber-made one, and a butyl rubber-made rubber plug laminated with a fluorine resin. . More specifically, a rubber stopper of a material laminated with a fluorine resin of D 713 and D 777 manufactured by Daikyo Seiko Co., Ltd. is preferable.
As for the thickness of the rubber plug, in general, if the material is the same material, the amount of oxygen permeation decreases as the thickness is increased. As a preferable thickness of the rubber plug, the minimum thickness of the portion to be wetted is 1.5 mm or more, more preferably 2 mm or more.
In addition, the smaller the area of the wetted portion of the rubber plug, the lower the oxygen permeation amount. Since the area of the wetted portion of the rubber plug depends on the inner diameter of the opening of the container, the smaller the inner diameter of the opening of the container, the smaller the area of the wetted portion of the rubber plug, and the oxygen permeation amount decreases. Therefore, the inside diameter of the container is preferably 20 mm or less, more preferably 15 mm or less.
These sealable containers are preferably packaging materials that have been sterilized by an appropriate method for both the container and the rubber stopper.

In the present invention, it has become apparent that the rubber stopper is very slightly permeable to oxygen. Therefore, the said solution formulation for injection can suppress the oxygen permeate | transmitted in a formulation container by lowering | hanging the oxygen concentration of the periphery of a container, and can ensure stability. In particular, by disposing the solution preparation for injection in an atmosphere having an oxygen concentration of 1% by volume or less, storage stability can be reliably ensured.
As a specific method of placing the solution preparation for injection in an atmosphere having an oxygen concentration of 1% by volume or less, the container is put in an oxygen barrier bag and the inside of the bag is filled with an inert gas such as nitrogen or argon. Sealing etc. are mentioned. The oxygen concentration inside the bag at this time is preferably 1% by volume or less, more preferably 0.5% by volume or less. In addition, oxygen can be absorbed inside the bag by inserting an oxygen scavenger into the space between the injectable solution preparation container and the oxygen barrier bag, and sealing can be performed, thereby further improving the stability. . In addition, the oxygen concentration inside the bag is 1 volume of the oxygen concentration inside the bag by applying an oxygen scavenger corresponding to the oxygen adsorption capacity to the oxygen content corresponding to the volume inside the bag. It can be adjusted to% or less, preferably 0.5% 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, still more preferably 0.2 mL / m m ² · 24 hr · atm or less. The material of the oxygen barrier film used for the oxygen barrier bag is aluminum foil, nylon, polyvinylidene chloride, ethylene / vinyl alcohol copolymer, inorganic vapor deposition film (for example, alumina vapor deposition polyethylene terephthalate, silica vapor deposition Polyethylene terephthalate etc. are used.

  As an oxygen scavenger, AGELESS S, SP, ZP, Z-PKC, ZJ-PT manufactured by Mitsubishi Gas Chemical Co., Ltd., which are iron-based autogenous reaction type oxygen scavengers, manufactured by Nippon Kayaku Food Techno Co., Ltd. Moduran S etc. are mentioned.

  Pemetrexed in the present invention is N- [4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo) by the chemical name, which is used as an active ingredient of the antimetabolite antitumor agent. [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] L-glutamic acid, a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt includes sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, ammonium salt, trimethyl ammonium salt, triethyl ammonium salt, monoethanol ammonium salt, triethanol ammonium salt, pyridinium salt, substitution Pharmaceutically acceptable alkali metal salts such as pyridinium salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts and the like. It is preferred to use a sodium salt, preferably a disodium salt. That is, in the present invention, it is preferable to use pemetrexed disodium salt. The pemetrexed or pharmaceutically acceptable salt thereof may be an anhydride or a hydrate or a solvate. As the hydrate, 2.5 hydrate and heptahydrate are known, and can be used without particular limitation.

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

  The solution formulation used in the present invention is a solution formulation prepared using a solvent. The solvent can be used without particular limitation as long as it is acceptable as a solvent for parenteral administration. For example, water, ethanol, polysorbate 80, macrogols, glycerin, polyoxyethylene hydrogenated castor oil, etc. may be mentioned, and these may be used alone or in combination of two or more. The solvent is preferably of a quality that can be administered parenterally. Particularly preferable solvents are water-containing solvents containing water as a main component. The aspect which uses only water as a solvent may be sufficient.

The solution preparation used in the present invention may contain a pharmaceutically acceptable additive. In particular, those which can be administered parenterally can be used without particular limitation. The additives may contain an antioxidant, a buffer, a pH adjuster, a tonicity agent, a chelating agent, and a stabilizer.
Antioxidants are additives used to suppress the oxidative degradation of an active ingredient. For example, ascorbic acid, cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, alpha thioglycerin, citric acid, sodium thioglycolate, sodium edetate, methionine, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene and the like can be mentioned.
Buffering agents are additives used to keep the pH constant. For example, citrate, phosphate, acetate and the like are used.
The pH adjuster is an additive used to bring the pH within the set range. For example, hydrochloric acid, sodium hydroxide, acetic acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, tartaric acid or a salt thereof or the like is used.
Isotonic agents are additives used to approximate the osmotic pressure of serum. For example, sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, refined sucrose, mannitol, macrogol and the like can be mentioned.
The chelating agent is an additive which indirectly suppresses the decomposition due to the presence of the metal ion by forming a complex with the metal ion. For example, ethylenediaminetetraacetic acid disodium, citric acid and salts thereof, tartaric acid and salts thereof, gluconic acid and salts thereof and the like can be mentioned.
Stabilizers are used in accordance with various purposes such as suppression of decomposition of the active ingredient and stabilization of particles. For example, acetyl tryptophan, alanine, arginine and salts thereof, albumin, benzoic acid and salts thereof, inositol, ethanol, histidine and salts thereof, fructose, sodium caldiamide, sodium carbazochrome sulfonate, sodium carbonate, xylitol, glycine, glutamic acid and the like Salt, creatinine, sodium dihydrogen phosphate, sodium chondroitin sulfate, diethanolamine, diethylene triamine pentaacetic acid, cystine, dibutyl hydroxytoluene, calcium bromide, purified gelatin, purified soy lecithin, gelatin, sorbitan fatty acid ester, sorbitan sesquioleate, Sorbitol, sodium bicarbonate, potassium thiocyanate, dextran, calcium sugar acid, triethanolamine, trometamol, Thorium formaldehyde sulfosylate, nicotinic acid amide, lactic acid, lactose, urea, propyl parahydroxybenzoate, methyl parahydroxybenzoate, glacial acetic acid, butylhydroxyanisole, propylene glycol, benzalkonium, benzyl alcohol, benzethonium, polyoxyethylene hardened castor Oil, polyoxyethylene castor oil, polysorbate 20, polysorbate 80, macrogols, maltose, sodium pyrophosphate, maleic acid, phosphoric acid and its salts, meglumine, sodium metasulfobenzoate, monoethanolamine, lysine hydrochloride, magnesium sulfate Etc.
Since the solution preparation according to the present invention is a solution preparation using an active ingredient susceptible to oxidation, it is preferable to contain an antioxidant.

The injectable solution preparation containing pemetrexed of the present invention can be produced by the steps generally used in the preparation of injectable solutions as shown in the following steps. However, the present invention is not limited to the following production method.
Step (a) Pemetrexed or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable additive is dissolved in a pharmaceutically acceptable solvent.
Step (b) Optionally, a pharmaceutically acceptable pH regulator is added to the mixed substance.
Step (c) Optionally fill the final volume with the mixture of step (b) with pharmaceutically acceptable solvent.
Step (d) filtering the mixture of step (c).
Step (e) The mixture obtained by step (d) is filled into a pharmaceutically acceptable container.
Step (f) Purge the inside of the container with a pharmaceutically acceptable inert gas as required.
Step (g) Plug the container with a rubber plug and seal it with an aluminum cap if necessary.
Step (h) Perform pharmaceutically acceptable terminal sterilization as required.
If necessary, an inert gas can be blown into the mixture during the steps (a) to (c). Through the above steps, the injectable solution preparation according to the present invention can be manufactured. Furthermore, the solution preparation for injection may be contained in an oxygen barrier bag and sealed together with an optional oxygen scavenger, so that an adverse effect of oxygen can be further suppressed. The interior of the oxygen barrier bag may be sealed after blowing in an inert gas.

  The invention is further illustrated by the following examples. However, the present invention is not limited to these examples.

[Test Example 1] Evaluation of Oxygen Permeability of Rubber Plugs In order to evaluate the oxygen permeation of rubber plugs, reference examples 1, 2 and 3 are manufactured using water, and stored for 2 weeks at 60 ° C. The void oxygen concentration in the container was measured.

[Reference Example 1]
4 mL of water is filled in a borosilicate glass vial (manufactured by Fuji Glass Co., Ltd.) having a volume of 10 mL and an inner diameter of 12.5 mm, the inside of the container is purged with nitrogen, and laminated with a fluorine resin of Daikyo Seiko Co., Ltd. It was stoppered with the D713 butyl rubber stopper (thickness 2 mm). The stoppered vial was tightened with an aluminum cap.

[Reference Example 2]
Example 6 is the same as Example 1 except that a D777 butyl rubber (thickness 2 mm) plug laminated with a fluorocarbon resin manufactured by Daikyo Seiko Co., Ltd. was used.

[Reference Example 3]
Except for using a D21-7 chlorinated butyl rubber stopper (thickness 2 mm) laminated with a fluorine resin manufactured by Daikyo Seiko Co., Ltd., the rubber stopper is the same as the reference example 1.

[Measurement of air gap oxygen of container]
An oximeter (Microx TX3, manufacturer: PreSens) connected to a needle type oxygen sensor was used. There is a fiber coated with a fluorescent dye (oxygen sensor) sensitive to oxygen at the tip of the needle, and the rubber stopper of the solution preparation for injection of the example and comparative example is pierced with the needle type oxygen sensor. Oxygen was measured.

Immediately after the production of Reference Examples 1, 2 and 3, the void oxygen concentration in the container after 2 weeks storage at 60 ° C. was measured, and the oxygen permeation amount (mmol) of the rubber plug was calculated. The formula is as follows. The results are shown in [Table 1].

Oxygen permeation amount (mmol) = oxygen increase amount (volume%) ÷ 100 × in-container void volume (mL) ÷ (0.082 × (273 + temperature (° C.)))
Increase amount of oxygen (volume%) = void oxygen concentration after storage for 2 weeks at 60 ° C. (vol%)-void oxygen concentration immediately after production (vol%)

  From the results of Table 1, while the oxygen permeation amount of the rubber plug used in Reference Example 3 was 0.00169 mmol when stored at 60 ° C. for 2 weeks, D713 used in Reference Example 1 and Reference Example 2 In the D777 rubber plug, the oxygen permeation amount was 0.0010 mmol or less, and it was found that the rubber plug was lower in oxygen permeability. In addition, when these rubber plugs were stored for 2 weeks at 25 ° C., the oxygen permeation amount of each rubber plug was 0.0010 mmol or less, and no difference was observed between the materials of the rubber plugs. Accordingly, it was found that the oxygen permeability of the butyl rubber stopper of D713 and D777 was less dependent on temperature, and was a rubber stopper capable of maintaining the oxygen permeability low even at high temperatures.

Example 1
Dissolve 5437 mg of pemetrexed disodium salt 2.5 hydrate (4500 mg in terms of pemetrexed) in an appropriate amount of water for injection, adjust to pH 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution, and add water for injection The total volume was adjusted to 180 mL.
This solution was subjected to sterile filtration using a membrane filter with a pore diameter of 0.22 μm, and filled with a solution of 10 mL and a borosilicate glass vial with a bore diameter of 12.5 mm (Fuji Glass Co., Ltd.) filled with 4 mL Then, nitrogen was injected into the void portion of the vial and stoppered with a D713 butyl rubber stopper (2 mm in thickness) laminated with a fluorine resin manufactured by Daikyo Seiko Co., Ltd. Then, it wound-fastened with the aluminum cap, and prepared the solution formulation for injection of Example 1.

Example 2
Place the injectable solution preparation of Example 1 in an aluminum bag (oxygen permeability: 0.1 mL / m ² · 24 hr atm or less) together with an oxygen scavenger (Moduran S-500, manufactured by Nippon Kayaku Food Techno Co., Ltd.) The solution was sealed with a heat sealer, and secondary packaging was performed to prepare an injectable solution preparation of Example 2.

Comparative Example 1
A rubber plug was subjected to the same operation as in Example 1 except that a D21-7 chlorinated butyl rubber plug (2 mm in thickness) laminated with a fluorine resin manufactured by Daikyo Seiko Co., Ltd. was used, and a comparative example A solution formulation for injection was prepared.

Comparative Example 2
Put the solution preparation for injection of Comparative Example 1 into an aluminum bag (oxygen permeability: 0.1 mL / m ² · 24 hr atm or less) together with an oxygen scavenger (Modulan S-500, manufactured by Nippon Kayaku Food Techno Co., Ltd.) Then, it was sealed with a heat sealer and secondary packaging was carried out to prepare an injectable solution preparation of Comparative Example 2.

Test Example 2 Storage Stability Test at 60 ° C. The injectable solution formulations of Examples 1 and 2 and Comparative Examples 1 and 2 shown below were stored at 60 ° C. for up to 2 weeks. The coloration, pH and related substances derived from pemetrexed were evaluated for each preparation.

[Analytical conditions of pemetrexed analogues]
The analogs derived from pemetrexed degradation of the examples and comparative examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: GL Science Inertsil ODS-3 (inner diameter 4.6 mm, length 25 cm)
Column temperature: 40 ° C
Mobile phase A: phosphate buffer (pH 6.8) / acetonitrile mixed solution (47: 3)
Mobile phase B: acetonitrile flow rate: 1.0 mL / min.
Wavelength: 225 nm
Delivery of mobile phase: Delivery was performed under the conditions shown in Table 2.

[Measurement of void oxygen in container and secondary package]
An oximeter (Microx TX3, manufacturer: PreSens) connected to a needle type oxygen sensor was used. There is a fiber coated with a fluorescent dye (oxygen sensor) sensitive to oxygen at the tip of the needle, and the rubber stopper of the solution preparation for injection of the example and the comparative example is pierced with the needle type oxygen sensor. The oxygen in the void was measured. Similarly, for the oxygen in the secondary package, the bag was pierced with a needle type oxygen sensor to measure the oxygen in the secondary package.

[Coloring evaluation of chemical solution]
The color of the chemical solution was measured with a color difference meter CR-5 (manufactured by Konica Minolta Co., Ltd.) to calculate the b ^* value. The b ^* value represents the chromaticity, and indicates a yellow direction if the value is positive, and a blue direction if the value is negative.

The color, pH, pemetrexed-derived analogues (each individual maximum (% of the individual solutions after storage for 2 weeks under the conditions of 60 ° C.) of the solution formulations for injection of Examples 1 and 2 and Comparative Examples 1 and 2 Table 3 shows the evaluation results of the total amount (%)).

ＰＥＭ^＊１：ペメトレキセド換算濃度
二次包装^＊２：包装内の酸素濃度は、０．２体積％以下

PEM ^{* 1} : Pemetrexed equivalent secondary packaging ^{* 2} : The oxygen concentration in the package is 0.2% or less by volume

In Example 1, compared to Comparative Example 1, the coloring and the related substances were largely suppressed. This is considered to be because oxygen inflow during the storage period was suppressed by using a rubber plug having a low oxygen permeation amount.
The difference in the amount of oxygen permeation depending on the material of the rubber stopper is slight, and in the case of many preparations other than pemetrexed, the stability is not affected, but in the case of the solution preparation containing pemetrexed as the active ingredient, the stability It became clear that the
These storage stability results are correlated with the oxygen permeation amount of the rubber plug shown in Test Example 1, and the storage stability of the solution preparation is improved by using the rubber plug having a low oxygen transmission amount. It became clear that
By producing a solution preparation using the rubber plug with a low oxygen permeation amount of the present invention, it is possible to suppress the inflow of oxygen into the container in the solution preparation during the storage period, and the storage stability is secured. It is considered possible to stably produce an injectable solution preparation containing the above-mentioned pemetrexed.
Further, from the results of Example 2 and Comparative Example 2, it is apparent that the storage stability is further improved by performing secondary packaging in which the container is put together with an oxygen scavenger in an oxygen-barrier aluminum bag and sealed. It became.

Claims (7)

A solution for injection containing pemetrexed or a solution containing a pharmaceutically acceptable salt thereof is filled in a container and sealed with a rubber stopper, and the inside of the container is stored for 2 weeks under a temperature condition of 60 ° C. An injectable solution preparation containing pemetrexed using a rubber plug having a permeating oxygen amount of 0.0013 mmol or less. The injectable solution according to claim 1, wherein the volume of the void portion of the container excluding the volume of the solution containing pemetrexed or a pharmaceutically acceptable salt thereof from the volume of the container is 60% or less of the volume of the container. Formulation. The injectable solution preparation according to claim 1 or 2, wherein a container having an inner diameter of 20 mm or less is used. The solution formulation for injection according to any one of claims 1 to 3, wherein the thickness of the rubber plug is 1.5 mm or more. The injectable solution preparation according to any one of claims 1 to 4, wherein the injectable solution preparation is disposed in an atmosphere having an oxygen concentration of 1% by volume or less. The injectable solution preparation according to claim 5, wherein the injectable solution preparation is inserted into an oxygen shielding bag together with an oxygen scavenger and sealed. The solution formulation for injection according to claim 6, wherein the material of the oxygen barrier bag is an oxygen barrier film having an oxygen permeability of 1 mL / m ² · 24 hr · atm or less.