JP2010162344A - Package - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable package for storage with which a container or the like for injections which is constituted by filling a bottle or the like with an aqueous solution agent containing a pyrazolone derivative such as edaravone as an active constituent, are not colored, alteration or the like of the content can be confirmed from outside the package, and the contents of the active constituents are not lowered. <P>SOLUTION: The package is constituted by introducing the aqueous solution agent into a plastic container and sealing the container, thereafter packaging the container with a gas-barrier outer packaging material having a resin layer consisting essentially of a cyclic polyolefin-based resin, as an innermost layer or a layer adjacent to the innermost layer. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a stable storage package for a container-filled product of an aqueous solution containing a pyrazolone derivative such as edaravone as an active ingredient.

  Pyrazolone derivatives such as edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) are used for intravenous infusion as a remedy for neurological symptoms associated with the acute phase of cerebral infarction, daily life movement disorders and functional disorders As a radiocut injection 30 mg, a 20 mL solution containing 30 mg edaravone is filled in a glass ampoule and is commercially available.

  However, the glass container is heavy and easily broken, and there is a concern that when the glass ampoule is opened, the glass fine pieces are mixed into the chemical solution or the fingers are damaged when the glass is broken. In particular, edaravone preparations must be administered within 24 hours after onset, and further caution is required for emergency handling. Further, the glass container has a problem of separation processing in the disposal of used containers. As a solution to this problem, a plastic container has been proposed.

  For example, Patent Document 1 proposes a high-concentration edaravone injection filled in a plastic disposable container. However, the problem of a decrease in the content of edaravone due to adsorption or permeation of a plastic disposable container is not recognized.

  For adsorption of active ingredients, Patent Document 2 discloses that an aqueous solution containing a pyrazolone compound is filled in a container such as polyethylene, polypropylene, and cyclic polyolefin, and is used as a packaging material for the container in a gas-impermeable container. It has been proposed to be housed together. However, although Patent Document 2 discloses the relationship between the color of the inner solution, particularly the chromaticity in the yellow direction and the container, the content of the pyrazolone compound due to the interaction such as adsorption and permeation to the container over time is disclosed. The problem of decline is not recognized. Moreover, although aluminum containers have been proposed as gas-impermeable containers for packaging containers, the contents of the aluminum containers cannot be confirmed from the outside, so the container is not only colored but also damaged or mixed with foreign matter. There is a problem that inspection such as cannot be performed.

JP 2006-257020 A WO2007 / 055312 Publication

  The present invention has been made in view of the above circumstances, and an object of the present invention is a package in which a plastic container filled with an aqueous solution containing a pyrazolone derivative such as edaravone as an active ingredient is packaged with an exterior material. Another object of the present invention is to provide a stable storage package in which the plastic container is not colored, the content can be confirmed from the outside of the package, and the content of the active ingredient does not decrease.

In order to solve the above-mentioned problems, the inventor of the present invention has studied the adsorption and coloring of plastic containers and packaging materials. As a result, an aqueous solution containing a pyrazolone derivative such as edaravone as an active ingredient is used as a plastic container. A container is formed so that the ratio A / B of the content A (mg) of the pyrazolone derivative in 1 mL of the aqueous solution and the inner surface area B (cm ² ) of the container is 0.003 or more, and the active ingredient is dissolved. -Packed with an exterior material that has a resin layer mainly composed of cyclic polyolefin (COP) resin and a transparent gas barrier layer from the outside, not only preventing coloring of plastic containers but also outside the package From the above, it has been found that the content of the contents can be confirmed, and a very stable package that does not cause a decrease in the content of the active ingredient is found. It has been completed.

That is, the present invention provides the following package.
Invention of Claim 1: After putting the aqueous solution agent which contains a pyrazolone derivative as an active ingredient into the container which consists of a polyethylene-type resin and / or a polypropylene resin, and sealing, the said container is a resin layer which has cyclic polyolefin resin as a main component. As a layer adjacent to the innermost layer or the innermost layer and hermetically sealed with an exterior material having a transparent gas barrier layer on the outer side thereof, the content A (mg of pyrazolone derivative in 1 mL of the aqueous solution) ) And the ratio A / B of the inner surface area B (cm ² ) of the container is 0.003 or more.
Invention of Claim 2: The package of Claim 1 which stored the oxygen absorber in the space part of the said container and exterior material in the said package.
Invention of Claim 3: The package body of Claim 1 or 2 in which the said exterior material is deep drawing molding or blister molding.
Invention of Claim 4: The aqueous solution which contains a pyrazolone derivative as an active ingredient is a pharmaceutical formulation for injection, The package in any one of Claims 1-3.
Invention of Claim 5: The packaging body in any one of Claims 1-4 whose pyrazolone derivative is edaravone.

  According to the present invention, an aqueous solution containing a pyrazolone derivative such as edaravone using a highly convenient plastic container as an active ingredient is used not only for preventing coloring of a plastic container or the like, but also for altering the contents from outside the package. Can be confirmed, and a package that can be stored stably without causing a decrease in the content of the active ingredient can be provided at low cost.

  According to the invention of claim 2, since the oxygen scavenger can be quickly removed by storing the oxygen scavenger in the space between the container and the exterior material in the package, coloring of the molded container or the like Furthermore, it is possible to more effectively prevent a decrease in the content of the active ingredient, and to enable storage for a long period of time.

  According to the invention of claim 3, since the exterior material is formed by deep drawing or blister molding, the injection-molded container or the like can be made into a compact package. Furthermore, it is convenient to handle if it can be peeled open.

Hereinafter, the present invention will be described in more detail.
Plastic containers that are directly filled with an aqueous solution containing a pyrazolone derivative such as edaravone are highly safe from the nature of storing pharmaceuticals, etc., and are not particularly limited as long as they are liquid-tight containers. It is preferable to be a molded container having a shape such as a bottle molded from a polyethylene (PE) resin or / and a polypropylene (PP) resin, but from a polyethylene (PE) resin or / and a polypropylene (PP) resin. The bag-shaped soft bag which consists of may be sufficient. The reason is that these resins are not easily colored, and in particular, molded containers such as bottles are excellent in cost. The reason why PE-based resins and PP-based resins are not easily colored by pyrazolone derivatives is not clear, but it is presumed that these resins do not have a functional group and thus are difficult to react with pyrazolone derivatives. That is, a resin container having a gas barrier property is not preferable when EVOH, nylon resin, or the like is used, which reacts with the internal solution and becomes unfavorable, and achieves the object of manufacturing the container at a low cost. I don't get it.

The size of the container used in the present invention is such that the content A (mg) of the pyrazolone derivative in 1 mL of the aqueous solution and the ratio A / B of the inner surface area B (cm ² ) of the container is 0.003 or more. In addition, by reducing the inner area of the container that can come into contact with the inner solution as much as possible, the reaction with the container and the reaction with the outside through the container are minimized, and the decrease in content can be kept at a certain level. In addition, the inner solution, the container, and the exterior material are not colored, which is preferable. When A / B is less than 0.003, the content of the inner solution is decreased, or discoloration, coloring, etc. are reduced due to the influence of the active ingredient in the inner solution from the container and the outside of the container.

Although there is no restriction | limiting in particular as a manufacturing method of the shaping | molding container used for this invention, The conventionally well-known single layer and multilayer extrusion blow molding and injection blow molding are employ | adopted suitably. As a multilayer coextrusion blow molding method, melt extrusion is performed using a multilayer extruder having at least two extruders, and each molten resin layer is placed inside the multilayer parison molding die or immediately after being discharged from the die. To obtain a multi-layer container by blow molding the multi-layer parison in a molten state, using a so-called direct blow molding method or a multi-layer injection molding machine having at least two extruders. A method in which a multilayer parison is obtained by injection molding and then blow molding during cooling or after reheating after cooling is suitably employed. When the multilayer parison is blow-molded, stretch blow molding, particularly biaxial stretch blow molding is preferred. Further, it is preferable to employ a blow / fill / seal method in which the aqueous solution is filled simultaneously with the molding because it is possible to produce more efficiently.
When a soft bag is used, the film can be obtained by multilayer or single-layer inflation molding or T-die extrusion molding. It is preferable that a part of the container is provided with a discharge port (port) part and a rubber stopper part for discharging the internal solution.

  The exterior material used in the present invention is a transparent gas barrier packaging material that allows the inside of the packaging to be visually observed from the outside. That is, this packaging material has a resin layer mainly composed of a transparent COP-based resin (hereinafter sometimes referred to as “COP rich layer”) as an innermost layer or a layer adjacent to the innermost layer, and on the outer side thereof. It has a transparent gas barrier layer. With such an exterior material, even if the resin layer of the PE-based resin or PP-based resin in the molded container permeates the pyrazolone derivative, it is blocked from the outside by the COP rich layer, so that the content of the active ingredient is reduced. There is nothing. Further, the gas barrier layer outside the COP rich layer prevents oxygen from entering, and the innermost layer of the exterior material also hardly reacts with the pyrazolone derivative. As a result, the exterior material is not colored and the content of the active ingredient is not lowered, which is preferable. In particular, when the innermost layer of the exterior material is an olefin resin layer of PE or PP and the adjacent layer is a resin layer mainly composed of a cyclic polyolefin resin, the molded container moves in the package during transportation. The COP rich layer is not damaged by friction or contact, and is more preferable from the viewpoint of the stability of the active ingredient.

  As such an olefin-based resin layer, conventionally known resins can be used, such as high-density PE, linear low-density PE (LLDPE), medium-density PE, PP, and thermoplastic elastomers thereof, and these It is possible to use a blend of In particular, when LLDPE is contained in an amount of 50% by mass or more and the innermost layer is formed in the range of 5 μm or more and 50 μm or less, the adhesion strength with the adjacent COP rich layer is good, and there is no problem of a decrease in the content of active ingredients More preferred.

  As the gas barrier layer of the exterior material used in the present invention, for example, ethylene / vinyl alcohol copolymer (EVOH), polyvinyl alcohol or a coating film thereof, MXD nylon, a transparent metal oxide vapor deposition layer such as silica or alumina, polychlorinated The resin layer which consists of a film coated with vinylidene (PVDC) or PVDC can be mentioned, and these gas barrier layers may be used alone or in combination of two or more. Further, the exterior material may be laminated with a transparent film such as PET or nylon for securing physical strength outside the COP rich layer. As a method for producing the exterior material, a conventionally known method such as a method of dry laminating each layer using an adhesive, a method of extrusion laminating using a meltable resin, heat lamination, multilayer coextrusion, or the like can be appropriately employed. . In the case of dry lamination, a two-component curing type polyester urethane adhesive or polyether urethane adhesive is preferable from the viewpoint of adhesiveness.

There is no restriction | limiting in particular as COP type resin, A conventionally well-known resin can be used. Examples thereof include polymers of various cyclic olefin monomers, copolymers of cyclic olefin monomers and other monomers such as ethylene, hydrogenated products thereof, and the like. Examples of the cyclic olefin monomer include norbornene, norbornadiene, methylnorbornene, dimethylnorbornene, ethylnorbornene, chlorinated norbornene, chloromethylnorbornene, trimethylsilylnorbornene, phenylnorbornene, cyanonorbornene, dicyanonorbornene, methoxycarbonylnorbornene, pyridylnorbornene, nadic anhydride Products, bicyclic cycloolefins such as nadic imides; tricyclocycloolefins such as dicyclopentadiene, dihydrodicyclopentadiene and their alkyl, alkenyl, alkylidene, and aryl substituents; dimethanohexahydronaphthalene, dimethanooctahydronaphthalene, Tetracyclic cycloolefins such as alkyl, alkenyl, alkylidene and aryl substituents Pentacyclic cycloolefins such as tricyclopentadiene; and hexacyclic cycloolefins such as hexamethylene cycloheptanone decene and the like. Further, dinorbornene, a compound in which two norbornene rings are bonded by a hydrocarbon chain or an ester group, and a compound containing a norbornene ring such as an alkyl or aryl substituent thereof can be used. The COP resin used in the present invention is a polynorbornene resin obtained by polymerizing one or more of norbornene monomers containing a norbornene skeleton in the molecular skeleton such as dicyclopentadiene, norbornene, and tetracyclododecene. , Or its hydrogenated product and a mixture of one or more of them, when used as the innermost layer of a multilayer film, the aqueous solution agent is adsorbed or sorbed on the container, so that the content of its components decreases. It is preferable that the aqueous solution agent can be prevented from being deteriorated or contaminated by interaction with the container.
In the present invention, the polymerization method and polymerization mechanism of the monomer molecules of the COP resin may be ring-opening polymerization or addition polymerization. Moreover, as a polymerization method and a polymerization mechanism in the case of using a plurality of types of monomers in combination, a known method can be used, and copolymerization may be carried out by blending at the time of the monomer, or after blending to some extent, the block is blended. It may be copolymerized.

（式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は互いに同一または異種の炭素数１〜２０の有機基を示し、また、Ｒ^１とＲ^２、および／またはＲ^３とＲ^４は互いに環を形成していてもよい。ｍ、ｐは０または１以上の整数を示す。ｌ、ｎは１以上の整数を示す。）
上記炭素数１〜２０の有機基として、より具体的には、例えばメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチル、ｓｅｃ−ブチル、ｔ−ブチル、ｉ−ペンチル、ｔ−ペンチル、ｎ−ヘキシル、ｎ−ヘプチル、ｎ−オクチル、ｔ−オクチル（１，１−ジメチル−３，３−ジメチルブチル）、２−エチルヘキシル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシル、ノナデシル、イコシル等のアルキル基；シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等のシクロアルキル基；１−メチルシクロペンチル、１−メチルシクロヘキシル、１−メチル−４−ｉ−プロピルシクロヘキシル等のアルキルシクロアルキル基；アリル、プロペニル、ブテニル、２−ブテニル、ヘキセニル、シクロヘキセニル等のアルケニル基；フェニル基、ナフチル基、メチルフェニル基、メトキシフェニル基、ビフェニル基、フェノキシフェニル基、クロロフェニル基、スルホフェニル基等のアリール基；ベンジル基、２−フェニルエチル基（フェネチル基）、α−メチルベンジル基、α，α−ジメチルベンジル基等のアラルキル基等を挙げることができるが、これらに限定されるものではない。また、これらは１種を単独で、あるいは２種以上を併用しても良い。 As a specific structure of the COP resin, for example, a structural formula represented by the following general formula (1) or (2) can be shown.

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same or different organic group having 1 to 20 carbon atoms, and R ¹ and R ² and / or R ³ and R ⁴ are (The ring may form a ring. M and p represent 0 or an integer of 1 or more. L and n represent an integer of 1 or more.)
More specifically, examples of the organic group having 1 to 20 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, i-pentyl, t-pentyl, n-hexyl, n-heptyl, n-octyl, t-octyl (1,1-dimethyl-3,3-dimethylbutyl), 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, Alkyl groups such as pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl; cycloalkyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; 1-methylcyclopentyl, 1-methylcyclohexyl, 1-methyl-4-i-propyl Alkylcycloalkyl groups such as cyclohexyl; Alkenyl groups such as phenyl, propenyl, butenyl, 2-butenyl, hexenyl, cyclohexenyl; aryl groups such as phenyl, naphthyl, methylphenyl, methoxyphenyl, biphenyl, phenoxyphenyl, chlorophenyl, and sulfophenyl Aralkyl groups such as benzyl group, 2-phenylethyl group (phenethyl group), α-methylbenzyl group, α, α-dimethylbenzyl group and the like can be mentioned, but not limited thereto. These may be used alone or in combination of two or more.

The glass transition temperature of such a COP resin can be appropriately adjusted by appropriately selecting the values of l, m, n, and p in the above general formulas (1) and (2) or substituents. is there. The glass transition temperature of the COP resin other than the above general formulas (1) and (2) is also arbitrarily adjusted by appropriately setting the monomer species to be used, the blending ratio of the monomer species, the monomer arrangement, the type of substituents, and the like. can do.
Commercially available products can be used as the COP resin represented by the general formula (1), and for example, ZEONEX and ZEONOR manufactured by ZEON CORPORATION can be suitably used. Commercially available products can be used as the COP-based resin represented by the general formula (2), and for example, APPEL manufactured by Mitsui Chemicals, Inc. and TOPAS manufactured by TICONA can be preferably used.

  When the exterior material used in the present invention is a deep-drawn or blister-formed packaging material composed of a top material and a bottom material, the area of the exterior material to be used is reduced, and a package that can be stored in a compact and inexpensive manner is obtained. Therefore, it is preferable. Moreover, it is convenient for handling if the top material and the bottom material are heat-sealed and packaged with an peelable peelable peel. In the method of heat sealing with easy peel, when the innermost layer is a COP rich layer, the heat sealing temperature is set low, or at least one of the thermoplastic elastomers typified by styrene elastomer is 10% by mass. There is a method of containing the above. When the innermost layer of at least one of the top material and the bottom material is an olefin resin layer of PE or PP, the other innermost layer is formed of a mixed resin of PE and PP, or at least one of the top material and the bottom material There is a method in which the innermost layer is formed of a mixture of PE or PP and a thermoplastic elastomer typified by a styrene elastomer in an amount of 10% by mass or more.

  It is preferable that the thickness of the COP rich layer after deep drawing or blister molding is 5 μm or more and 100 μm or less because there is no problem of moldability and a decrease in the content of the active ingredient and it can be produced at low cost. If the thickness of the COP rich layer is less than 5 μm, the effect of preventing the decrease in the content is reduced and the risk of cracking increases, which is not preferable. Although it may be 100 μm or more, the active ingredient of the aqueous solution is blocked. Despite the fact that the effect is not improved, it takes time for molding and the amount of very expensive COP resin increases, which causes an increase in cost.

The oxygen scavenger used in the present invention preferably absorbs and removes oxygen in the internal space of the package and has a large amount of oxygen absorption. As the oxygen scavenger, for example, those containing, as a main component, reducing polyhydric alcohols such as ascorbic acid or erythorbic acid and their salts, and inorganic salts such as iron powder and ferrous sulfite are suitably used. Is done. An oxygen detector that can be identified by a change in color (for example, manufactured by Mitsubishi Gas Chemical Co., Ltd.) in case the oxygen flows into the package due to distribution or handling in stock. It is preferred to place (Ageless Eye) together with the oxygen scavenger in the package.
In addition, if the exterior material used in the present invention is a deep-drawn or blister-molded packaging material composed of a top material and a bottom material, the space between the molded container and the exterior material may become large. It is preferable to store an oxygen scavenger in this space.
On the other hand, when the exterior material is a soft packaging material such as a bag, vacuum packaging is preferable because the amount of residual oxygen is significantly reduced. In this case, it is not necessary to store the oxygen scavenger in the space between the molded container and the exterior material, but storing the oxygen scavenger is preferable because the effect of the present invention becomes more reliable.

  Next, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited to these.

Example 1
After dissolving 300 mg of edaravone, 200 mg of sodium bisulfite, 500 mg of citric acid and 1500 mg of sodium chloride and adjusting the pH using an appropriate amount of sodium hydroxide, the total volume was adjusted to 200 mL and filtered through a membrane filter to prepare an injection solution. 20 mL of the injection solution was filled into a polyethylene bottle having an internal volume of 20 mL, an inner surface area of about 60 cm ² and an average thickness of 800 μm, and the space inside the bottle was replaced with nitrogen and sealed to prepare an injection container. This container was packaged with a gas-barrier transparent exterior material to prepare an injection package.
In preparing the injection package, the following materials were used as the top material and the bottom material. After placing a plastic container on the deep-drawn bottom material, AGELESS Z (deoxygenating agent, registered trademark, Mitsubishi Gas Chemical Co., Ltd.) is placed in the space between the injection container and the exterior material in the injection package. The top material imparted with easy peel properties was welded and sealed with a heat seal to prepare an injection package. The thickness of the COP resin layer used for the bottom material at this time was 10 μm or more as the thickness after deep drawing.

[Top material layer structure]
From the outside, silica-deposited PET film (Mitsubishi Chemical) 12 μm, nylon film (Unitika) 15 μm, LLDPE (Nippon Polyethylene) 25 μm / COP (Nippon Zeon, glass transition temperature 102 ° C.) 20 μm / LLDPE (Nippon Polyethylene) Made of 5μm / PE and a polystyrene co-extruded multilayer co-extruded film of 70μm made of polystyrene elastomer, 70μm, each using a two-component curable polyester urethane adhesive (manufactured by Mitsui Chemicals) for dry lamination. And laminated. “/” Is a portion laminated by a coextrusion method. This top material had an oxygen gas barrier property of 0.6 cc (m ² · day · atm · 30 ° C · 70% RH).

[Layer structure of bottom material]
Multi-layer co-extruded film of 30 μm LLDPE (manufactured by Nippon Polyethylene) 30 μm / adhesive resin (manufactured by Mitsui Chemicals) 20 μm / EVOH (manufactured by Kuraray) 30 μm / adhesive resin (manufactured by Mitsui Chemicals) 20 μm / LLDPE (manufactured by Nippon Polyethylene) 130 μm And LLDPE (manufactured by Nippon Polyethylene) 40 μm / COP (manufactured by Nippon Zeon with a glass transition temperature of 102 ° C.) 30 μm of multilayer coextruded film 70 μm is dried using a two-component curing type polyester urethane adhesive (manufactured by Mitsui Chemicals). Lamination was performed by a laminating method. “/” Is a portion laminated by a coextrusion method. The oxygen gas barrier property of the bottom material was 0.8 cc (m ² · day · atm · 30 ° C. · 70% RH).

[Content A of pyrazolone derivative in 1 mL of aqueous solution and ratio A / B of inner surface area B of container]
The inner surface area of the container was 60 cm ² with respect to 1.5 mg of edaravone contained as an active ingredient in 1 mL of the aqueous solution, and A / B = 0.025.

(Example 2)
An injection container was prepared in the same manner as in Example 1 except that the injection container was changed to polypropylene having an average thickness of 600 μm. An injection package was prepared in the same manner as in Example 1 except that the following materials were used as the top material and the bottom material. As in Example 1, the thickness of the COP-based resin layer used for the bottom material was 10 μm or more as the thickness after deep drawing.

[Top material layer structure]
Example 1 was repeated except that 12 μm of silica-deposited PET film was replaced with 12 μm of alumina-deposited PET film (manufactured by Toppan Printing). The oxygen gas barrier property of this top material was 0.5 cc (m ² · day · atm · 30 ° C. · 70% RH).

[Bottom material composition]
The inner multilayer co-extruded film was changed from the outer side to LLDPE (manufactured by Nippon Polyethylene) 25 μm / COP (manufactured by Nippon Zeon with a glass transition temperature of 102 ° C.) 20 μm / LLDPE (manufactured by Nippon Polyethylene) 15 μm multilayer co-extruded film 60 μm. The same as in Example 1. The oxygen gas barrier property of the bottom material was 0.8 cc (m ² · day · atm · 30 ° C. · 70% RH).

[Content A of pyrazolone derivative in 1 mL of aqueous solution and ratio A / B of inner surface area B of container]
The inner surface area of the container was 60 cm ² with respect to 1.5 mg of edaravone contained as an active ingredient in 1 mL of the aqueous solution, and A / B = 0.025.

(Example 3)
20 mL of an injection solution prepared in the same manner as in Example 1 was diluted to 50 mL, and filled into a polyethylene multilayer soft bag having an inner surface area of about 145 cm ² and an average thickness of 250 μm having a rubber plug portion and a discharge port portion, The space inside the bottle was replaced with nitrogen and sealed to prepare an injection container. This container was packaged with a gas-barrier transparent exterior material to prepare an injection package.
In preparing the injection package, the following materials were used as exterior materials. After packaging a plastic container (soft bag) with an exterior material, AGELESS Z (deoxygenating agent, registered trademark, manufactured by Mitsubishi Gas Chemical Co., Ltd.) is placed in the space between the injection container and the exterior material in the injectable package. After storing, it was welded and sealed to prepare an injection package. At this time, the thickness of the COP resin layer used for the exterior material was 15 μm or more.

[Exterior material layer structure]
Silica-deposited PET film (Mitsubishi Chemical) 12 μm, nylon film (Unitika) 15 μm, LLDPE (Ube Maruzen Polyethylene) 15 μm / COP (Nihon Zeon, glass transition temperature 70 ° C.) 15 μm / LLDPE (Ube Maruzen Polyethylene) ) A 20 μm multilayer coextruded film of 50 μm was laminated by a dry laminating method using a two-component curable polyester urethane adhesive (manufactured by Mitsui Chemicals). “/” Is a portion laminated by a coextrusion method. The exterior material had an oxygen gas barrier property of 0.2 cc (m ² · day · atm · 30 ° C. · 70% RH).

[Content A of pyrazolone derivative in 1 mL of aqueous solution and ratio A / B of inner surface area B of container]
The inner surface area of the container was 145 cm ² with respect to 0.6 mg of edaravone contained as an active ingredient in 1 mL of the aqueous solution, and A / B = 0.004.

(Comparative Example 1)
An injection container was prepared in the same manner as in Example 1. This injection container was preserve | saved without packaging with an exterior material. This method has the same form as that of Patent Document 1.

(Comparative Example 2)
Deep-draw molding of gas barrier exterior material made by laminating PET (Toyobo) 12 μm, EVOH (Kuraray) 20 μm, nylon (Unitika) 15 μm, easy peel film 30 μm containing styrene elastomer by dry lamination An injectable package was prepared in the same manner as in Example 1 except that the product was packaged.

(Comparative Example 3)
Except for packaging (without deep-drawing) a gas barrier exterior material in which PET (manufactured by Toyobo) 12 μm / aluminum foil (manufactured by Japan) 9 μm / LLDPE (manufactured by Nippon Polyethylene) 40 μm was laminated by the dry lamination method. An injection package was prepared in the same manner as in Example 1. This method has the same form as that of Patent Document 2.

(Comparative Example 4)
A 20 mL injection solution prepared in the same manner as in Example 1 was diluted to 100 mL, and the soft bag was a polypropylene multilayer bag having an inner surface area of about 250 cm ² and an average thickness of 200 μm having a rubber plug part and a discharge port part. Except for this, the procedure was the same as in Example 3.

[Content A of pyrazolone derivative in 1 mL of aqueous solution and ratio A / B of inner surface area B of container]
The inner surface area of the container was 250 cm ² with respect to 0.3 mg of edaravone contained as an active ingredient in 1 mL of the aqueous solution, and A / B = 0.0012.

[Visual inspection]
After the injection packaging bodies of Examples 1, 2, 3 and Comparative Examples 1, 2, 3, and 4 were stored at 60 ° C., visual appearance confirmation was performed for the purpose of examining the color of the injection container and the packaging material. . Table 1 shows changes in appearance over time. At this time, since the colored state cannot be confirmed as it is using the aluminum foil, the outer bag was opened and the inner surfaces of the container and the outer material were checked.

According to the results in Table 1, in Comparative Example 1, coloring of the container was observed in one week, and in Comparative Examples 2 and 3, coloring of the exterior material was recognized in two weeks, while coloring of the container was not recognized. In Comparative Example 4, coloring of the outer packaging material was observed in 1 week and in 2 weeks.
On the other hand, in Examples 1-3, coloring of the container was not recognized, and it was found that coloring to the exterior material could be suppressed by packaging with a gas barrier exterior material having a COP rich layer on the inside. .

[Quantitative test]
Next, after each injectable package was stored at 60 ° C. and 40 ° C., a quantitative test for edaravone was conducted for the purpose of examining changes in the edaravone content. Table 2 shows the results of the residual rate over time, with the value immediately after production being 100.0%.

According to the results of Table 2, as shown in Comparative Example 1, in the injection solution only filled in the plastic container of Comparative Example 1, Examples 1 to 3 were obtained under both storage conditions of 60 ° C. and 40 ° C. In comparison with, the edaravone content decreased significantly.
In Comparative Examples 2 and 3, as in Comparative Example 1, a significant decrease in the edaravone content was observed as compared with Examples 1-3. And although the method of the comparative example 3 is a method described in patent document 2, it turned out that this method cannot suppress the fall of an edaravone content. In Comparative Example 4, the ratio A / B between the content A of the pyrazolone derivative and the inner surface area B of the container in 1 mL of the aqueous solution was 0.0012, and it was found that the decrease in the edaravone content could not be suppressed.

  From the above results, it was found that a stable injection package can be obtained by packaging an injection container with a gas barrier outer packaging material having a COP rich layer on the inside, which is a package of the present invention.

Claims (5)

An aqueous solution containing a pyrazolone derivative as an active ingredient is sealed in a container made of a polyethylene resin or / and a polypropylene resin, and then the container is composed of a resin layer mainly composed of a cyclic polyolefin resin as an innermost layer or an innermost layer. A package that is hermetically packaged with an exterior material having a transparent gas barrier layer on the outer side thereof, and a content A (mg) of a pyrazolone derivative in 1 mL of the aqueous solution, and The package body, wherein the ratio A / B of the inner surface area B (cm ² ) is 0.003 or more.   The package according to claim 1, wherein an oxygen scavenger is stored in a space between the container and the exterior material in the package.   The package according to claim 1 or 2, wherein the exterior material is formed by deep drawing or blister molding.   The package according to any one of claims 1 to 3, wherein the aqueous solution containing a pyrazolone derivative as an active ingredient is a pharmaceutical preparation for injection.   The package according to any one of claims 1 to 4, wherein the pyrazolone derivative is edaravone.