JP2018192139A - Medical liquid storage plastic container - Google Patents

Abstract

To provide a plastic container comprising a flexibility, transparency, a non-adsorption property and low elution property, being excellent in storage stability and barrier property of a medical liquid, especially a medicine component.SOLUTION: There is provided a plastic container which stores a water solution containing a pyrazolone derivative or a pharmaceutically accepted salt thereof, in which a water solution storage part of the plastic container has a multilayer structure formed by overlapping a layer formed of a linear low-density polyethylene, and a layer which is mainly formed of an amorphous polymer formed of an olefin monomer component having at least two kinds of different structures, and in the olefin monomer component forming the amorphous polymer, at least one kinds is a monomer having a cyclic hydrocarbon skeleton.SELECTED DRAWING: None

Description

  The present invention relates to a plastic container containing an aqueous solution containing a medicine, particularly a pyrazolone derivative or a pharmaceutically acceptable salt thereof. More specifically, the aqueous solution container of the plastic container is a layer mainly composed of an amorphous polymer composed of a linear low density polyethylene layer and an olefin monomer component having at least two different structures. And at least one of the olefin monomer components constituting the amorphous polymer is a monomer having a cyclic hydrocarbon skeleton.

In recent years, a soft bag formulation has been developed in which a drug for injection is diluted and prepared in advance as a formulation for intravenous infusion and filled in a flexible container (plastic container) made of plastic or the like. In addition to convenience and quickness at the time, it is said that it is useful because it reduces the risk of breakage and is superior in disposal compared to glass bottles and ampoules.
However, some chemicals, including radical scavenging preparations, are ordinary polyolefins such as polyethylene (hereinafter sometimes referred to as “PE”) and polypropylene (hereinafter sometimes referred to as “PP”). It is known to adsorb or permeate a resin (hereinafter sometimes referred to as “PO resin”) and a film formed of a resin generally used as a material for pharmaceutical containers such as vinyl chloride. Challenges in developing soft bag formulations, such as the active ingredients of chemicals being adsorbed on plastic containers and the interaction of chemicals with additives and low molecular components contained in the resin film that makes up plastic containers It was.

Therefore, it has been proposed to use a cyclic polyolefin-based resin as a resin having a barrier (shielding) property that does not adsorb or permeate chemicals in a plastic container.
For example, JP-A-2002-301796 (Patent Document 1) is a multi-layer film composed of five layers, and the first layer and the fifth layer are linear in a density of 0.930 to 0.950 g / cm ^3. A linear ultra-low-density ethylene having a density of 0.860 to 0.920 g / cm ^{3 made of} an ethylene / α-olefin copolymer, wherein the second layer and the fourth layer are manufactured using (1) a metallocene catalyst An α-olefin copolymer alone or (2) a linear ultra-low density ethylene / α-olefin copolymer having a density of 0.860 to 0.920 g / cm ³ produced using a metallocene catalyst; It is made of a resin obtained by mixing a high density polyethylene having a density of 0.955 to 0.970 g / cm ^{3 so} that the content ratio of the high density polyethylene is 10% by weight or less, and the third layer is Cyclic olefin A multilayer film made of a copolymer and a container using the same are disclosed.
However, since the container using the multilayer film described in Patent Document 1 uses linear ultra-low density polyethylene having low impact resistance and shielding properties in the second layer and the fourth layer, it is flexible. It is difficult to obtain a soft bag that satisfies all of properties, impact resistance and shielding properties. In addition, when the second layer and the fourth layer contain high-density polyethylene, the drug solution storage portion is not sufficiently flexible, and there is a risk of causing a large difference in the infusion rate between the start and end of the drug solution administration. In addition, the transparency of multilayer films and containers decreases due to the inclusion of high-density polyethylene components, and it is difficult to find insoluble foreign substances due to chemical changes in the preparation after visual inspection and before use. It has a problem.

JP-A-2006-022092 (Patent Document 2) discloses an infusion bag having a configuration in which an outer layer (surface layer) is PP, an innermost layer is cyclic polyolefin, and an intermediate layer between both layers is PP. It is described that the container contains "edaravone". Evaluation of a container having such a structure revealed that the storage stability of the preparation was sufficient, but after sterilization, the interlaminar adhesion between the intermediate layer and the innermost layer was reduced, and during the drop durability test, the seal part As a result, it was found that sufficient peeling as a bag could not be obtained.

As mentioned above, in plastic containers that contain radical scavengers, it has excellent transparency as a pharmaceutical application, flexibility, and physical properties as a storage container, but excellent storage stability of chemical components as containers An excellent plastic container has not been obtained, and its development is desired.

JP 2002-301796 A JP 2006-022092 A

  The present invention has been made in view of the above circumstances, and has excellent transparency and flexibility, and a pharmaceutical component such as an aqueous solution containing a drug, particularly a pyrazolone derivative or a pharmaceutically acceptable salt thereof. It is an object of the present invention to provide a plastic container excellent in storage stability and barrier (shielding) properties of an aqueous solution containing.

  In order to solve the above problems, the inventors of the present invention provide a plastic container containing an aqueous solution containing a pyrazolone derivative or a pharmaceutically acceptable salt thereof, wherein the aqueous solution containing portion is a layer comprising at least a specific resin component. The present invention has been completed by finding that the chemical solution can be stably stored by having a multi-layer structure in which are stacked.

In the plastic container of the present invention, the material constituting the container is mainly composed of an amorphous polymer composed of a layer composed of linear low density polyethylene and an olefin monomer component having at least two different structures. Of the olefin monomer components constituting the amorphous polymer, at least one kind is a monomer having a cyclic hydrocarbon skeleton. By containing an aqueous solution containing a pyrazolone derivative or a pharmaceutically acceptable salt thereof in such a plastic container, the flexibility and transparency of the drug can be maintained consistently from the time of manufacture of the drug to the time of use. It was found that a soft bag formulation capable of stable storage was obtained.

  That is, the present invention is a plastic container containing an aqueous solution containing a pyrazolone derivative or a pharmaceutically acceptable salt thereof, wherein the aqueous solution container of the plastic container is a layer made of linear low-density polyethylene. And an olefin monomer component constituting the amorphous polymer having a multilayer structure in which a layer mainly composed of an amorphous polymer composed of at least two different olefin monomer components having different structures is superposed Among these, at least one kind is a monomer having a cyclic hydrocarbon skeleton, and a plastic container is provided.

  The glass transition temperature of the amorphous polymer is preferably 80 ° C. or higher.

  It is preferable that the amorphous polymer has a glass transition temperature equal to or higher than the sterilization temperature.

  It is preferable that the amorphous polymer is a copolymer of a monomer having a cyclic hydrocarbon skeleton and an ethylene monomer.

  Moreover, this invention provides the plastic container provided with the opening part for discharging | emitting the aqueous solution which is a container.

  The present invention also provides a plastic container in the form of an infusion bag or blow molded container.

  It is also a preferred embodiment from the viewpoint of storage stability of the chemical solution that the chemical solution-containing plastic container of the present invention is accommodated in a container having a gas barrier property together with the oxygen scavenger.

  According to the present invention, it is possible to provide a plastic container having excellent transparency, flexibility, and impact resistance, and excellent storage stability of a chemical solution, particularly an aqueous solution containing a pharmaceutical ingredient.

Hereinafter, the present invention will be described based on preferred embodiments.
The pyrazolone derivative used in the present invention has the following formula (I)

（式中、Ｒ1は水素原子、アリール、炭素数１〜５のアルキル又は総炭素数３〜６のアルコキシカルボニルアルキルを表し、Ｒ2は、水素原子、アリールオキシ、アリールメルカプト、炭素数１〜５のアルキル又は炭素数１〜３のヒドロキシアルキルを表し、あるいは、Ｒ1及びＲ2は、共同して炭素数３〜５のアルキレンを表し、Ｒ3は水素原子、炭素数１〜５のアルキル、炭素数５〜７のシクロアルキル、炭素数１〜３のヒドロキシアルキル、ベンジル、ナフチル又はフェニル、又は炭素数１〜５のアルコキシ、炭素数１〜３のヒドロキシアルキル、総炭素数２〜５のアルコキシカルボニル、炭素数１〜３のアルキルメルカプト、炭素数１〜４のアルキルアミノ、総炭素数２〜８のジアルキルアミノ、ハロゲン原子、トリフルオロメチル、カルボキシル、シアノ、水酸基、ニトロ、アミノ、及びアセトアミドからなる群から選ばれる同一若しくは異なる１〜３個の置換基で置換されたフェニルを表す。）で表される化合物を用いることができる。
また、式（Ｉ）で表される化合物のほか、その薬学的に許容され得る塩を用いることもできる。薬学的に許容され得るとしては、塩酸、硫酸、臭化水素塩、リン酸等の鉱酸との塩；メタンスルホン酸、ｐ−トルエンスルホン酸、酢酸、シュウ酸、クエン酸、リンゴ酸、フマル酸等の有機酸との塩；ナトリウム、カリウム等のアルカリ金属との塩；マグネシウム等のアルカリ土類金属との塩；アンモニア、エタノールアミン、２−アミノ−２−メチル−１−プロパノール等のアミンとの塩が挙げられる。この他、薬学的に許容され得るものであれば、その塩の種類は特に限定されない。
さらに、式（Ｉ）で示されるピラゾロン誘導体またはその薬学的に許容され得る塩のほか、それらの水和物若しくは溶媒和物を薬液の有効成分とすることもできる。

(In the formula, R 1 represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms in total, and R 2 represents a hydrogen atom, aryloxy, aryl mercapto, C 1 to 5 carbon atoms. Represents alkyl or hydroxyalkyl having 1 to 3 carbon atoms, or R1 and R2 together represent alkylene having 3 to 5 carbon atoms, R3 represents a hydrogen atom, alkyl having 1 to 5 carbon atoms, 5 to 5 carbon atoms, 7 cycloalkyl, C1-C3 hydroxyalkyl, benzyl, naphthyl or phenyl, or C1-C5 alkoxy, C1-C3 hydroxyalkyl, C2-C5 alkoxycarbonyl, C 1-3 alkyl mercapto, C1-C4 alkylamino, C2-C8 dialkylamino, halogen atom, trifluoromethyl, carbon Hexyl, be cyano, hydroxyl, nitro, amino, and be used a compound represented by the representative.) Phenyl substituted with same or different 1 to 3 substituents selected from the group consisting of acetamide.
In addition to the compound represented by formula (I), a pharmaceutically acceptable salt thereof can also be used. Pharmaceutically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrobromide, phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, citric acid, malic acid, fumaric acid Salts with organic acids such as acids; Salts with alkali metals such as sodium and potassium; Salts with alkaline earth metals such as magnesium; Amines such as ammonia, ethanolamine and 2-amino-2-methyl-1-propanol And the salt. In addition, the kind of the salt is not particularly limited as long as it is pharmaceutically acceptable.
Furthermore, in addition to the pyrazolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof can be used as an active ingredient of a drug solution.

  All of the compounds represented by formula (I) are known compounds and can be easily synthesized by those skilled in the art by the method described in Japanese Patent Publication No. 5-31523.

  An aqueous solution containing the pyrazolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, contained in the plastic container of the present invention, for example, In the case of an infusion bag preparation, the concentration of the pyrazolone derivative is about 0.06 mg / mL or more and about 2 mg / mL or less, preferably about 0.3 mg / mL or more and about 0.6 mg / mL or less. It can be prepared by dissolving in a solvent (for example, an infusion solution, etc.), adjusting the pH by adding a pH adjusting agent as desired, and adding other additives as desired.

  The chemical solution used for the preparation of the aqueous solution containing the pyrazolone derivative may be any chemical solution as long as it is generally used as a chemical solution. Preferably, electrolytes, saccharides, vitamins, protein amino acids, etc. 1 or two or more types arbitrarily selected from those dissolved in water (for example, distilled water for injection) at an arbitrary concentration. In addition, what melt | dissolved electrolytes may be called electrolyte solution, and what melt | dissolved saccharides may be called a sugar solution. Examples of the electrolyte include sodium chloride. These optional components can be used alone or in combination at any concentration. In the present invention, as a preferable chemical solution, for example, sodium chloride or the like is dissolved in water (for example, distilled water for injection) at an arbitrary concentration. The content of these substances is preferably sodium chloride, for example, equal to that of physiological saline, that is, 0.9% (W / V).

  As a pH adjuster used for the preparation of an aqueous solution containing a pyrazolone derivative, any pH adjuster that is generally used as a pH adjuster for injections can be used without particular limitation.

  The liquidity of the aqueous solution containing the pyrazolone derivative, that is, the pH can be arbitrarily adjusted by using the above-mentioned pH adjusting agent.

  Other additives used for the preparation of an aqueous solution containing a pyrazolone derivative can be used without particular limitation as long as they are generally used as additives for injections. In the present invention, preferable other additives include, for example, pharmaceutical additives as described in Yakuji Nippo Co., Ltd. 2000 “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association). These additives may be added as a salt (for example, a monovalent alkali metal salt such as a sodium salt or a potassium salt) or may be added as a hydrate as desired. These additives are generally blended in a proportion usually used for injections. It is easy for those skilled in the art, and these additives may be used according to the purpose of use, as described in “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association) published in 2000. E.g. stabilizers, surfactants, buffers, solubilizers, antioxidants, antifoaming agents, isotonic agents, emulsifiers, suspending agents, preservatives, soothing agents, solubilizers, solubilizers It can be properly used as an auxiliary agent. These additives can be added to the injection container of the present invention in combination of two or more components as desired.

  When the pH adjustor and other additives are added to the plastic container of the present invention, the addition and mixing operations in the preparation of the aqueous solution can be performed according to ordinary pharmaceutical methods. For example, when preparing an aqueous solution containing only a pyrazolone derivative and a pH adjusting agent, the pyrazolone derivative and the pH adjusting agent may be weighed and mixed, and then dissolved in water, or the aqueous solution containing the pyrazolone derivative may be dissolved in water. The weighed pH adjuster may be dissolved. Further, a weighed pyrazolone derivative may be dissolved in an aqueous solution containing a pH adjuster. It is also possible to prepare an aqueous solution containing a pH regulator and an aqueous solution containing a pyrazolone derivative, and mix these aqueous solutions so that the concentration of the pyrazolone derivative is the above-mentioned concentration. Also, when other additives are included, it can be similarly prepared.

  In the plastic container of the present invention, the aqueous solution storage part is a layer mainly composed of an amorphous polymer composed of a layer composed of linear low density polyethylene and an olefin monomer component having at least two different structures. And a plastic container in which at least one of the olefin monomer components constituting the amorphous polymer is a monomer having a cyclic hydrocarbon skeleton. In the present invention, the “main component” in the layer constituting the multilayer structure of the aqueous solution container means that the ratio of the component of interest to the entire matrix including the component exceeds 50% by mass. It is.

  The plastic container of the present invention can be a bag-like container in which the peripheral edge of a film-shaped or tube-shaped laminated container material is welded, or a blow-molded container.

When the plastic container of the present invention is a bag-like container, at least using a laminated container material having a multilayer structure in which the respective layers are laminated, the laminated container material is overlaid and the periphery is sealed to form a bag shape Can be manufactured.
Although the thickness of the said laminated container material is not specifically limited, 70-400 micrometers is preferable. The peripheral seal width is not particularly limited, but is 2 to 20 mm, and preferably 3 to 7 mm.
In a layered container material, a layer mainly composed of an amorphous polymer that has barrier (shielding) properties (hereinafter, a “layer composed mainly of an amorphous polymer” may be referred to as a “barrier layer”). Is 5 to 100 μm, more preferably 10 to 50 μm. If the thickness of the layer is less than 5 μm, the barrier property is lowered, and cracks may occur when stress is applied to the container from the outside. The drug component permeates through this portion and diffuses outside the container. The storage stability of may be insufficient. Further, when the thickness of the layer exceeds 100 μm, the flexibility as a container is lowered, so that there is a possibility that a large difference is caused in the infusion rate at the start and end of the administration of the drug solution. Further, it is not preferable in terms of cost.

  The position where the layer mainly composed of the amorphous polymer is disposed is a three-layer structure in which layers composed of linear low density polyethylene are disposed on both sides, and the intermediate layer is a layer composed mainly of the amorphous polymer. Any structure in which a layer mainly composed of an amorphous polymer is disposed as the innermost layer in the case of a container and a layer composed of linear low-density polyethylene is disposed outside the innermost layer can be employed. In addition, in order to improve the required performance required for containers such as flexibility and transparency, the layer made of linear low density polyethylene can be blended with multiple grades or different grades can be multilayered by coextrusion molding May be used.

As a method for laminating the laminated container material, a known method can be adopted as a method for producing an ordinary container. For example, lamination can be performed by coextrusion molding such as multilayer inflation molding and multilayer T die casting, extrusion lamination in which molten resin is directly laminated, or dry lamination using an adhesive.
In addition, when laminating a layer composed mainly of an amorphous polymer and a resin layer adjacent to the layer by coextrusion, Mitsui Chemicals Co., Ltd. “Admer”, Mitsubishi Chemical Co., Ltd. “Modic”, etc. A representative adhesive resin can also be used, but a sufficient strength can be obtained by arranging a layer made of linear low density polyethylene adjacent to a layer mainly composed of an amorphous polymer. it can.

  When the plastic container is a blow molded container, for example, multilayer extrusion blow molding is preferably employed. As a multilayer coextrusion blow molding method, using a multilayer extruder having a plurality of extruders, an amorphous polymer and a PO resin, and if necessary, an adhesive resin and other synthetic resins are used in each extruder. Extrusion is performed by melting, and blow molding is performed by blowing air. In blow molding, the preform may be once blow molded after being formed into a preform, or each molten resin layer may be formed into a tubular multilayer parison inside a multilayer parison molding die, and direct blow molding may be performed. Good.

The linear low density polyethylene used for the plastic container of the present invention is a copolymer of ethylene and α-olefin, and has a density in the range of 0.880 to 0.935 g / cm ³ , preferably 0.910. The range is preferably 0.930 g / cm ³ , particularly preferably more than 0.920 to 0.925 g / cm ³ .
The α-olefin has 12 or less carbon atoms, and examples thereof include propylene, butene-1, hexene-1, 4-methylpentene-1, and octene-1. As said linear low density polyethylene, what is manufactured with a metallocene catalyst is preferable. Linear low-density polyethylene polymerized with a metallocene catalyst is excellent in transparency and the like because of its small structure heterogeneity. Moreover, since the molecular weight distribution is uniform, when the linear low density polyethylene is heated, the polyethylene has few bleeds and is less likely to be clouded.
The linear low density polyethylene preferably has a melting peak temperature of 110 ° C. or higher, more preferably 120 ° C. or higher. The linear low density polyethylene having the above temperature characteristics is necessary for sterilization of plastic containers. Heat resistance can be imparted.

In the plastic container of the present invention, the amorphous polymer that is the main component of the barrier layer is composed of at least two types of olefin monomers having different structures, and at least one of the olefin monomers is a monomer having a cyclic hydrocarbon skeleton. It is an amorphous polymer.
The amorphous polymer that is the main component of the barrier layer used in the plastic container of the present invention is a copolymer composed of two or more types of cyclic olefin monomers such as norbornene compounds, and other than cyclic olefin monomers such as cyclic olefin monomers and α-olefins. Addition polymer obtained by copolymerization with other olefin monomers, including cyclic olefin monomers such as norbornene compounds, and polymers obtained by hydrogenating remaining double bonds after ring-opening metathesis polymerization. The cycloolefin monomer homo-addition polymer (see, for example, paragraph No. 0015 of WO 2007/135887) is not included.

  As the amorphous polymer that is the main component of the barrier layer used in the plastic container of the present invention, the above cyclic olefin-based polymer can be used. Examples of such a cyclic olefin polymer include the following.

In general, a method for producing a cyclic olefin polymer is known in which a ring-opening metathesis polymer of norbornene is hydrogenated and a method in which a norbornene and α-olefin are copolymerized. The basic structure of the cyclic olefin polymer can be expressed as, for example, [Chemical Formula 2] described in JP2011-237572A (see Formula (II) below). That is, it is described as a polymer in which cyclic unit skeletons and ethylene unit skeletons are alternately arranged.

（ｎは１以上の整数であり、Ｒ1およびＲ2は水素原子またはアルキル基を示し、それぞれ同じであってもよいし、異なっていてもよい。Ｒ1およびＲ2は、それらが結合して環を形成していてもよい。）

(N is an integer of 1 or more, and R1 and R2 each represent a hydrogen atom or an alkyl group, and may be the same or different. R1 and R2 are bonded to form a ring. You may do it.)

  The above structure is described as a homopolymer of one kind of cyclic olefin monomer, that is, a homopolymer-like, but actually, for example, as shown in [Chemical Formula 4] of JP-A No. 2014-124927 ( The following is also included in the case of a copolymer composed of a plurality of cyclic olefin monomers. Japanese Patent Application Laid-Open No. 2014-124927 discloses that the chemical structure of “ZEONOR” 1060R manufactured by Nippon Zeon Co., Ltd. is described as the following formula (III) (paragraph 0098).

（ここでｍおよびｎは１以上の整数であり、Ｒ1およびＲ2は水素原子またはアルキル基を示し、それぞれ同じであってもよいし、異なっていてもよい。Ｒ1およびＲ2は、それらが結合して環を形成していてもよい。）

(Here, m and n are integers of 1 or more, and R1 and R2 each represent a hydrogen atom or an alkyl group, and may be the same or different. R1 and R2 are bonded to each other. And may form a ring.)

In addition, in the request lecture of the 39th Petroleum and Petrochemical Conference held in 2009 (Session ID: 1C12 “Research on ring-opening metathesis polymerization of cyclic olefins”), “ZEONEX”, “ The main chain structure of “ZEONOR” is a random copolymer controlled atactically. From this fact, the production of the cyclic olefin copolymer by the alkene metathesis reaction is industrially performed and can be easily obtained by those skilled in the art, and even in the plastic container of the present invention, the amorphous component of the innermost layer is amorphous. It can be used as a conductive polymer.

Further, a copolymer selected from norbornenes and one kind of ethylene, propylene, and α-olefin is also shown as [Chemical Formula 1] in the aforementioned Japanese Patent Application Laid-Open No. 2011-237572, and has the following chemical structure. Can be represented (formula (IV)).

（ここでｍおよびｎは１以上の整数であり、Ｒ1、Ｒ2およびＲ3は水素原子またはアルキル基を示し、それぞれ同じであってもよいし、異なっていてもよい。また、Ｒ1およびＲ2は、それらが結合して環を形成していてもよい。）

(Here, m and n are integers of 1 or more, and R1, R2 and R3 each represent a hydrogen atom or an alkyl group, and may be the same or different from each other. They may combine to form a ring.)

  Here, the structure in which R1, R2, and R3 are all hydrogen atoms is typically known as “TOPAS” sold by Polyplastics Co., Ltd., and is introduced in the general catalog of “TOPAS”. The structure in which R1 and R2 are alkyl groups and R3 is a hydrogen atom corresponds to “Apel” sold by Mitsui Chemicals, Inc., and is described as a typical structure in the “Apel” product catalog. .

These cyclic olefin polymers are resins having excellent water vapor barrier properties and are easily available. As described above, in the plastic container of the present invention, these cyclic olefin polymers can be used as the amorphous polymer which is the main component of the innermost layer. These can be used alone or in combination of two or more polymers.

  As the cyclic olefin polymer, commercially available products as described above can also be used. Although overlapping with the above description, examples of the commercially available products include ZEONEX (registered trademark) (manufactured by Nippon Zeon Co., Ltd., ring-opening metathesis polymer hydrogenated polymer of norbornene monomer), TOPAS (registered trademark) (polyplastics). Co., Ltd., a copolymer of norbornene and ethylene), ZEONOR (registered trademark) (manufactured by Nippon Zeon Co., Ltd., a copolymer based on ring-opening polymerization of dicyclopentadiene and tetracyclopentadodecene), Apel (registered trademark) (Mitsui Chemicals) Co., Ltd., a copolymer of ethylene and tetracyclododecene), Arton (registered trademark) (manufactured by JSR Corporation, cyclic olefin resin containing dicyclopentadiene and methacrylic acid-containing polar group) it can.

As a composition of the material which comprises the barrier layer of laminated container material, you may contain another resin component other than a cyclic olefin type polymer. Other resin components include polyethylene, polypropylene, polybutene, ethylene / α-olefin copolymer, ethylene / (meth) acrylic acid copolymer, ethylene / vinyl acetate copolymer, ethylene / (meth) acrylic acid ester copolymer. Examples thereof include polyolefin resins such as polymers, urethane resins, rubber resins, polyester resins, polyester urethane resins, acrylic resins, amide resins, styrene resins, and silane resins.
By containing these resins, the performance desired as a container having an infusion bag shape is improved, such as impact resistance at low temperatures of plastic containers, maintenance of transparency immediately after high-pressure steam sterilization, and improvement of flexibility. It is possible.

  The material constituting the barrier layer of the laminated container material is preferably composed only of a cyclic olefin polymer (containing 100% by mass of the cyclic olefin polymer). In a layer, it is preferable to contain a cyclic olefin type polymer as a main component, that is, 50% by mass or more, and particularly preferably 70% by mass or more. When the composition ratio of the cyclic olefin polymer is low, a drug component having a high affinity with a trace component or plastic may be adsorbed, and the storage stability of the drug component to be accommodated may be insufficient.

  In order to improve the appearance of the container, stabilize the quality, and provide other required performance, the materials that make up the barrier layer of the laminated container material are antioxidants and UV absorbers as long as they do not impair safety and health. Various additives such as an agent, an antistatic agent, a lubricant, and an antiblocking agent may be contained.

  The plastic container of the present invention is preferably heat-treated at a temperature of 60 ° C. or higher, or autoclaved at a temperature of 105 ° C. or higher, more preferably 110 ° C. after filling with a chemical solution. It is very important to design the molecular structure and determine the glass transition temperature so that the molecular motion of the amorphous polymer constituting the innermost layer, that is, the micro-Brownian motion does not occur. It is necessary to have a glass transition temperature at least equal to or higher than the temperature of heat treatment or autoclaving of the container. When the glass transition temperature is lower than this sterilization temperature, the micro-Brownian motion occurs during the heat treatment and high-pressure steam sterilization treatment, and the molecular chain performs a rotational motion. Intrusion and dissipation cannot be prevented, and the content of active ingredients is reduced. The glass transition temperature of the optimum amorphous polymer (cyclic polyolefin) that prevents such a phenomenon must be at least equal to or higher than the temperature of the heat treatment or high-pressure steam sterilization treatment of the container. It is effective that the glass transition temperature of the polymer is 80 ° C. or higher, preferably 130 ° C. or higher.

  The amorphous polymer constituting the barrier layer of the laminated container material in the plastic container of the present invention is not particularly limited as long as it is the above amorphous polymer, but considering the flexibility of the plastic container, the cyclic olefin component, The polymer preferably has 5 to 60 mol%, particularly preferably 10 to 50 mol%. In consideration of the shielding property, barrier property, non-adsorption property and low elution property of the plastic container, the polymer preferably has a cyclic olefin component of more than 60 to 100 mol%, and 70 to 100 mol%. It is particularly preferable to have it.

In the present invention, a plastic container may be provided with at least one or more mouths for discharging an aqueous solution that is a container. The mouth part can be used not only for discharging but also for filling.
When the plastic container is a bag-shaped container, the inner part of the laminated container material that is the sealant layer can be overlapped with each other, and the mouth part can be inserted between them to be welded by heat sealing. .
When the plastic container is blow-molded, it can be welded at the time of molding the plastic container by insert molding in which the mouth portion is inserted into the mold at the time of molding. Alternatively, a plastic container having an opening can be formed, and the mouth can be inserted into the opening later and welded by heat sealing.

  The plastic container of the present invention is a sealable container, and may be in any form as long as the container can maintain the sterility of the contents. Containers in the form of blow molded containers such as infusion bags and syringes, ampoules, and vials that are generally used for filling and containing injection solutions are preferred, and infusion bags are particularly preferred. In addition, these forms of containers are preferably transparent and non-colored for the purpose of visual confirmation and confirmation of the formation and mixing of foreign substances, particularly insoluble foreign substances, but the light resistance of the contents and the design of the containers Considering the property and convenience, it may be opaque and colored.

  The drug solution-containing plastic container of the present invention can be produced by filling the above-mentioned plastic container (infusion bag, blow molded container, etc.) with an aqueous solution containing the above-mentioned pyrazolone derivative and sealing it. Moreover, it can be set as the plastic container holding sterility by attaching | subjecting sterilization operation in the arbitrary processes of these manufacturing processes. Moreover, you may perform operation, such as filtration using a dustproof filter, before filling to these containers as needed. In the production of the plastic container of the present invention, specific sterilization methods at the time of sterilization include, for example, a hot water immersion sterilization method, a hot water shower sterilization method, and a high-pressure steam sterilization (autoclave) method.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited to the following Example.

[Example 1]
Sheet (laminated container material) film forming T-die type multi-layer film forming machine is used for coextrusion so that the thickness ratio of the surface layer / intermediate layer / innermost layer (barrier layer) becomes 110/100/40 (μm), respectively. A laminated container material (hereinafter sometimes referred to as “sheet”) was formed into a film by the construction method.
For the surface layer and the intermediate layer, a metallocene polyethylene “Umerit” having physical properties of a density of 0.924 g / cm ³ and a melting peak temperature of 124 ° C. manufactured by Ube Maruzen Polyethylene Co., Ltd. was used. As the amorphous polymer for the barrier layer, a copolymer polymer “TOPAS” of ethylene and norbornene sold by Polyplastics Co., Ltd. was used. As the amorphous polymer, glass transition temperatures of 33 ° C., 65 ° C., 78 ° C., 110 ° C., and 138 ° C. were used individually.

Evaluation of heat resistance Five kinds of sheets having different glass transition temperatures of the innermost layer were prepared by the above-described sheet film forming procedure. Using the film-formed sheet, the innermost layers were overlapped, the outer periphery was heat sealed, and an infusion bag-shaped container (hereinafter sometimes referred to as “pouch”) having an outer dimension of 172 mm × 115 mm was created. . Trimming was performed so that the outer peripheral seal width was 5 mm, and the inside of the pouch was filled with 105 mL of water and hermetically sealed.
The containers prepared were sterilized using a high-pressure steam sterilizer under the three conditions shown in Table 1 below. After the heat treatment, the temperature was quickly lowered with cooling water, and then the film surface and side surfaces were visually observed to confirm the state.

  The appearance evaluation results after sterilization are summarized in Table 2 below.

  When an amorphous polymer having a low glass transition temperature (33 ° C., 65 ° C.) is used, it causes significant deformation and shrinkage of the container when heated at 105 ° C. or higher, which is a general sterilization condition for pharmaceuticals. This is not preferable because it impairs the commercial value. On the other hand, when an amorphous polymer having a glass transition temperature of 80 ° C. was selected, at the sterilization temperature of 110 ° C. or less, although the shrinkage of the entire container was not observed, some deformation such as undulation of the seal end was observed. When an amorphous polymer having a glass transition temperature of 110 ° C. or higher is used, no significant deformation or shrinkage is observed with respect to a generally performed sterilization temperature of 105 to 115 ° C. It was found to have From these, it becomes clear that the heat resistance against sterilization is largely related to the glass transition temperature of the amorphous polymer constituting the innermost layer. In the amorphous polymer constituting the innermost layer, the glass transition temperature is However, it can be said that it is desirable to select one having a temperature equal to or higher than the sterilization heating temperature.

Acquisition of Storage Stability Data Using the five types of sheets obtained by the above-mentioned sheet film formation, an infusion bag-shaped container having the same size as that subjected to appearance evaluation after sterilization was formed. In the container, edaravone-containing aqueous solution having a composition shown in Table 3 below (composition of edaravone model preparation) and adjusted to pH 3.85 was used as a preparation, and the container was filled with 105 mL and sealed.
The container containing the preparation was sterilized at 105 ° C. for 30 minutes using a high-pressure steam sterilizer, and after cooling was completed, the outside of the container was dried to obtain a back preparation. The bag preparation that has undergone the sterilization operation is placed in a dry laminate outer bag consisting of three layers of biaxially stretched polyester / aluminum foil / linear low density polyethylene, and an oxygen scavenger (“AGELESS” manufactured by Mitsubishi Gas Chemical Co., Ltd.). ) And the opening was heat sealed to complete the preparation of the specimen.

  The prepared bag sample containing the preparation was stored for a predetermined period under the storage conditions shown in Table 4 below, and then the component residual ratio was measured for evaluating the storage stability of the bag. 25 ° C. is the environment in which the preparation is normally stored, 40 ° C. is the accelerated test condition, 60 ° C. is the severe test condition for evaluating in a shorter period, and 70 ° C. is the storage condition used for screening evaluation in a very short period of time. The conditions were set assuming

The residual ratio of the preparations that had been stored under the conditions described in Table 4 above was measured by liquid chromatography under the following conditions.

Detector: UV absorptiometer (measurement wavelength: 243 nm)
Column: A column for liquid chromatography, in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 150 mm is packed with octadecylsilylated silica gel having a particle diameter of 5 μm.
Column temperature: constant temperature around 40 ° C. Mobile phase: methanol: water: acetic acid = 49.8: 49.8: 0.4
Flow rate: 1.0 mL / min.
Injection volume: 20 μL

A volume corresponding to about 0.9 mg of edaravone was collected from the test specimen bag, and the mobile phase was added to make a sample solution of 10 mL. 1 mL of this solution was accurately weighed, and the mobile phase was added to make exactly 100 mL to obtain a standard solution. The sample solution and 20 μL of the standard solution were tested by liquid chromatography under the test conditions described above. Each peak area was measured by the automatic integration method, and the residual rate of the edaravone component was determined for each test condition by the following formula.
Residual rate of edaravone (%) = (peak area of edaravone after completion of storage test) / peak area of edaravone of standard solution) × 100 (%)

  Table 5 shows the component residual ratio (%) of the edaravone preparation after the storage test was completed under various conditions.

  From the results shown in Table 5, it was revealed that there is a clear correlation between the storage temperature and the storage stability of the container. When the glass transition temperature of the amorphous polymer in the innermost layer was lower than the storage condition temperature, the residual ratio of the active ingredient after long-term storage was greatly reduced. On the other hand, when an amorphous polymer with a glass transition temperature higher than the storage temperature for obtaining storage stability data for normal pharmaceuticals is used, it shows a high component residual ratio and sufficient storage stability. It became clear that

[Example 2]
Using a T-die type multilayer film forming machine, a layered container material (hereinafter referred to as the following) is obtained by coextrusion so that the thickness ratio of the surface layer / intermediate layer (barrier layer) / innermost layer is 160/20/70 (μm) Sample preparation / evaluation was performed in the same manner as in Example 1 except that the film was sometimes referred to as “sheet”.

  Table 6 shows a list of the results of evaluating the heat resistance against the sterilization treatment using the sheet having the barrier layer disposed in the intermediate layer of Example 2. When the barrier layer is placed in the middle, due to the heat resistance of the polyethylene layers present on both sides, the appearance after treatment when sterilized under the same conditions as compared to the type with the barrier layer placed on the innermost layer However, when an amorphous polymer having a low glass transition temperature was used, there was a possibility that a good appearance could not be maintained.

  Table 7 shows the component residual ratio (%) of the edaravone preparation after the storage test was completed under various conditions using the sheet in which the barrier layer was arranged in the intermediate layer of Example 2.

From the results shown in Table 7, when using a sheet having a barrier layer disposed in the intermediate layer, the storage stability tends to be about several percent lower than the container in which the innermost layer is a barrier layer. became. However, in the case of an amorphous polymer having a glass transition temperature of 80 ° C. or higher, the component residual ratio is maintained at 95% or higher, and it can be said that the storage stability performance of pharmaceuticals is sufficient.
It has been clarified that the glass transition temperature of the amorphous polymer is greatly related to the storage environment of the pharmaceutical specimen regardless of the position where the barrier layer is disposed.

Claims (6)

  A plastic container containing an aqueous solution containing a pyrazolone derivative or a pharmaceutically acceptable salt thereof, wherein the aqueous solution container of the plastic container includes a layer made of linear low density polyethylene and at least two kinds of At least one of the olefin monomer components constituting the amorphous polymer having a multilayer structure in which layers composed mainly of amorphous polymers composed of olefin monomer components having different structures are superposed. Is a monomer having a cyclic hydrocarbon skeleton.   The plastic container according to claim 1, wherein the amorphous polymer has a glass transition temperature of 80 ° C. or higher.   The plastic container according to claim 1 or 2, wherein the amorphous polymer has a glass transition temperature equal to or higher than a sterilization temperature.   The plastic container according to any one of claims 1 to 3, wherein the amorphous polymer is a copolymer of a monomer having a cyclic hydrocarbon skeleton and an ethylene monomer.   The plastic container according to any one of claims 1 to 4, further comprising a mouth for discharging an aqueous solution that is a contained item. The plastic container according to any one of claims 1 to 5, which is in the form of an infusion bag or a blow molded container.