Container-packaged formulations and packaging

Abstract

The present invention provides a containerized pharmaceutical preparation and packaging that can suppress the adsorption of the active ingredient in the contained preparation onto the container. [Solution] A packaged pharmaceutical preparation in which the pharmaceutical preparation is contained in a medical container, wherein the medical container comprises a cyclic olefin-based (co)polymer (P) and includes: [X-1]; a random copolymer comprising a constituent unit (A) derived from an α-olefin having 2 to 20 carbon atoms and a constituent unit (B) derived from a cyclic olefin without an aromatic ring; [X-2]; a copolymer comprising a constituent unit (A), a constituent unit (B), and a constituent unit (C) derived from a cyclic olefin having an aromatic ring; [X-3]; one or two ring-opening polymers or ring-opening copolymers selected from the group consisting of cyclic olefins without an aromatic ring and cyclic olefins having an aromatic ring; [X-4]; a hydride of [X-3]; [X-5]; a graft-modified product of [X-1], [X-2], [X-3], or [X-4], selected from the above.

Description

[Technical Field]

[0001] This invention relates to a containerized pharmaceutical product and packaging. [Background technology]

[0002] In the field of medical containers, plastic containers, which are lightweight, less prone to breakage, and easier to handle, have become widely used in recent years as a replacement for heavy and easily damaged glass medical containers.

[0003] Patent Document 1 describes a medical molded article comprising a cyclic polyolefin (A), wherein the cyclic polyolefin (A) comprises a hydrogenated block copolymer which is a hydrogenated form of a block copolymer containing at least one aromatic vinyl monomer unit and at least one conjugated diene monomer unit, the hydrogenated block copolymer having hydrogenated aromatic vinyl polymer block units which are hydrogenated forms of polymer blocks consisting of the aromatic vinyl monomer units, and hydrogenated conjugated diene polymer block units which are hydrogenated forms of polymer blocks consisting of the conjugated diene monomer units, the hydrogenated block copolymer having at least two hydrogenated aromatic vinyl polymer block units and at least one hydrogenated conjugated diene polymer block unit. Furthermore, Patent Document 1 states that a medical molded article made of a specific cyclic polyolefin according to Patent Document 1 is excellent in transparency, low adsorption, and radiation resistance, and is suitable as a medical molded article.

[0004] In the medical field, packaged solution preparations, such as protein preparations, contained in syringes, cartridges, or other containers, have been used for a long time.

[0005] Patent Document 2 describes a medical container for containing a protein solution preparation, which is formed from a cyclic olefin polymer, is autoclaved, and is characterized by suppressing the oxidation of amino acid residues in the protein in the protein solution preparation contained within the medical container. Furthermore, Patent Document 2 states that even if a protein solution preparation is contained and stored in the medical container described in Patent Document 1, protein denaturation, particularly oxidation of amino acid residues in the protein, does not occur. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2020-180301 [Patent Document 2] Japanese Patent Publication No. 2020-022809 [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention provides a containerized pharmaceutical formulation and packaging that can suppress the adsorption of the active ingredient in the contained formulation onto the container. [Means for solving the problem]

[0008] According to the present invention, the following containerized formulations and packaging are provided.

[0009] 1. A packaged preparation in which the preparation is contained within a medical container, The medical container contains a cyclic olefin-based (co)polymer (P), The cyclic olefin-based (co)polymer (P) comprises one or more selected from the group consisting of [X-1], [X-2], [X-3], [X-4], and [X-5] below. A containerized preparation wherein the water contact angle of the medical container is 60.0° or more and 90.0° or less. [X-1] A random copolymer comprising a structural unit (A) derived from an α-olefin having 2 to 20 carbon atoms, and a structural unit (B) derived from a cyclic olefin that does not have an aromatic ring; [X-2] A copolymer comprising the constituent unit (A), the constituent unit (B), and a constituent unit (C) derived from a cyclic olefin having an aromatic ring; [X-3] One or two ring-opening polymers or ring-opening copolymers selected from the group consisting of cyclic olefins without the aromatic ring and cyclic olefins having the aromatic ring; [X-4] The hydride of [X-3]; [X-5] A graft-modified product of [X-1], [X-2], [X-3], or [X-4]. 2. The containerized preparation described in 1., wherein the medical container is radiation-sterilized. 3. The containerized formulation according to 1. or 2., wherein the cyclic olefin-based (co)polymer (P) comprises one or more selected from the group consisting of [X-1], [X-2], and [X-3]. 4. The containerized formulation according to 3, wherein the cyclic olefin (co)polymer (P) contains [X-2]. 5. A containerized formulation according to any one of 1 to 4, wherein when the total content of constituent unit (A), constituent unit (B), and constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 100 mol%, the content of constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 0.1 mol% or more and 50 mol% or less. 6. A containerized formulation according to any one of 1 to 5, wherein, when the total content of the constituent unit (B) and the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is set to 100 mol%, the content of the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 5.0 mol% or more and 95.0 mol% or less. 7. When the total content of the structural unit (A), the structural unit (B), and the structural unit (C) in the cyclic olefin-based (co)polymer (P) is 100 mol%, the content of the structural unit (A) in the cyclic olefin-based (co)polymer (P) is 10.0 mol% or more and 80.0 mol% or less. The preparation in a container according to any one of 1. to 6. 8. The cyclic olefin having no aromatic ring contains a compound represented by the following formula (B-1). The preparation in a container according to any one of 1. to 7.

Chemical formula

Chemical formula

[0010] According to the present invention, it is possible to provide a containerized pharmaceutical preparation and packaging that can suppress the adsorption of the active ingredient in the contained preparation onto the container. [Modes for carrying out the invention]

[0011] In this specification, the notations "XX or greater and YY or less" and "XX to YY" that represent numerical ranges mean a numerical range that includes the lower and upper limits, unless otherwise specified. Furthermore, when numerical ranges are listed in steps, the upper and lower limits of each numerical range can be combined in any way. Furthermore, each monomer constituting the cyclic olefin-based (co)polymer according to this embodiment may be a monomer obtained from fossil raw materials, or a monomer obtained from animal or plant-based raw materials. In this specification, polymers containing structural units derived from cyclic olefins and structural units derived from compounds other than cyclic olefins are referred to as cyclic olefin copolymers, and polymers consisting of structural units derived from cyclic olefins are referred to as cyclic olefin polymers. Both are collectively referred to as cyclic olefin (co)polymers.

[0012] 1. Packaged preparations The following describes the containerized formulation according to this embodiment.

[0013] The containerized formulation according to this embodiment is a containerized formulation in which the formulation is contained in a medical container, wherein the medical container contains a cyclic olefin-based (co)polymer (P), and the cyclic olefin-based (co)polymer contains one or more selected from the group consisting of [X-1], [X-2], [X-3], [X-4] and [X-5] below, and the water contact angle of the medical container is 60.0° or more and 90.0° or less. [X-1] A random copolymer comprising a structural unit (A) derived from an α-olefin having 2 to 20 carbon atoms, and a structural unit (B) derived from a cyclic olefin that does not have an aromatic ring; [X-2] A copolymer comprising the constituent unit (A), the constituent unit (B), and a constituent unit (C) derived from a cyclic olefin having an aromatic ring; [X-3] One or two ring-opening polymers or ring-opening copolymers selected from the group consisting of cyclic olefins without the aromatic ring and cyclic olefins having the aromatic ring, [X-4] The hydride of [X-3] above, [X-5] A graft-modified version of [X-1], [X-2], [X-3], or [X-4].

[0014] The water contact angle of the medical container is preferably 65.0° or higher, more preferably 67.0° or higher, and even more preferably 69.0° or higher, from the viewpoint of further suppressing the adsorption of the active ingredient in the formulation, and is preferably 85.0° or lower, more preferably 83.0° or lower, even more preferably 81.0° or lower, and even more preferably 79.0° or lower. The water contact angle of the aforementioned medical container can be measured, for example, by the contact angle method. Furthermore, the water contact angle can be analyzed using the 2θ method.

[0015] The diiodomethane contact angle of the medical container is preferably 25.0° or higher, more preferably 30.0° or higher, even more preferably 32.0° or higher, even more preferably 34.0° or higher, and even more preferably 36.0° or higher, and also preferably 50.0° or lower, more preferably 45.0° or lower, even more preferably 43.0° or lower, even more preferably 41.0° or lower, and even more preferably 39.0° or lower, from the viewpoint of further suppressing the adsorption of the active ingredients in the formulation. The diiodomethane contact angle of the aforementioned medical container can be measured, for example, by the contact angle method. Furthermore, the water contact angle can be analyzed using the 2θ method.

[0016] In the field of medical containers, sterilization by radiation is commonly practiced. However, a problem has arisen when pharmaceutical preparations are placed in radiation-sterilized medical containers, as the active ingredients in the preparations are adsorbed onto the surface of the container. For example, if the preparation is a nucleic acid preparation or a protein preparation, the adsorption of nucleic acids or proteins onto the surface of the container causes the nucleic acid molecules (protein molecules) to move closer together and aggregate. Aggregation of nucleic acid molecules (protein molecules) can lead to a decrease or loss of their original physiological activity, which is particularly undesirable.

[0017] The detailed mechanism by which the active ingredients in a pharmaceutical product are adsorbed onto radiation-sterilized containers is not yet clear, but the following mechanism is considered possible. When a container is irradiated with radiation, the chemical bonds in the resin that makes up the container are broken, generating radicals. The amount of radicals generated by radiation decreases over time after the radiation is finished, but some remain. It is thought that these remaining radicals change the physical properties of the container's surface, making it easier for the active ingredients in the formulation to be adsorbed onto the medical container.

[0018] The inventors investigated the decay rate of radicals after radiation irradiation and the amount of radicals remaining after decay. As a result, they found that the containerized formulation according to this embodiment accelerates the decay rate of radicals and further reduces the amount of radicals remaining after decay. Although the mechanism by which this phenomenon occurs in the containerized formulation according to this embodiment is not clear, it is expected that the cyclic olefin resin constituting the medical container according to this embodiment has a specific chemical structure, which contributes to the reduction of residual radicals.

[0019] <Cyclic olefin-based (co)polymer (P)> The cyclic olefin-based (co)polymer (P) included in the medical container according to this embodiment will be described below.

[0020] The cyclic olefin-based (co)polymer (P) comprises one or more selected from the group consisting of [X-1], [X-2], [X-3], [X-4], and [X-5], and from the viewpoint of further suppressing the adsorption of the active ingredient in the formulation, it preferably comprises one or more selected from the group consisting of [X-1], [X-2], and [X-3], more preferably comprises one or two selected from the group consisting of [X-2] and [X-3], and even more preferably comprises [X-2]. [X-1] A random copolymer comprising a structural unit (A) derived from an α-olefin having 2 to 20 carbon atoms, and a structural unit (B) derived from a cyclic olefin that does not have an aromatic ring; [X-2] A copolymer comprising the constituent unit (A), the constituent unit (B), and a constituent unit (C) derived from a cyclic olefin having an aromatic ring; [X-3] One or two ring-opening polymers or ring-opening copolymers selected from the group consisting of cyclic olefins without the aromatic ring and cyclic olefins having the aromatic ring; [X-4] The hydride of [X-3]; [X-5] A graft-modified version of [X-1], [X-2], [X-3], or [X-4].

[0021] The constituent units (A) to (C) of the cyclic olefin-based (co)polymer (P) according to this embodiment will be described below.

[0022] • Component unit (A) The constituent unit (A) according to this embodiment is a constituent unit derived from an α-olefin having 2 to 20 carbon atoms.

[0023] The α-olefins having 2 to 20 carbon atoms in this embodiment may be linear or branched. From the viewpoint of further suppressing the adsorption of active ingredients in the formulation, for example, linear α-olefins having 2 to 20 carbon atoms such as ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-decene, 1-dodecene, 1-tetradecene, 1-hexadecene, 1-octadecene, 1-eicosene; 3-methyl-1-butene, 3-methyl It comprises one or more branched α-olefins having 4 to 20 carbon atoms, such as -1-pentene, 3-ethyl-1-pentene, 4-methyl-1-pentene, 4-methyl-1-hexene, 4,4-dimethyl-1-hexene, 4,4-dimethyl-1-pentene, 4-ethyl-1-hexene, and 3-ethyl-1-hexene, preferably comprising linear α-olefins having 2 to 4 carbon atoms, and more preferably comprising ethylene.

[0024] When the total content of the above-mentioned constituent units (A), (B), and (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is set to 100 mol%, the content of the above-mentioned constituent unit (A) in the cyclic olefin-based (co)polymer (P) according to this embodiment is preferably 10.0 mol% or more, more preferably 20.0 mol% or more, even more preferably 30.0 mol% or more, even more preferably 40.0 mol% or more, even more preferably 50.0 mol% or more, and even more preferably 60.0 mol% or more, from the viewpoint of improving the heat resistance and dimensional stability of the medical container, and preferably 80.0 mol% or less, more preferably 75.0 mol% or less, even more preferably 70.0 mol% or less, and even more preferably 65.0 mol% or less, from the viewpoint of improving the moldability of the resulting medical container.

[0025] In this embodiment, the content of each constituent unit is, for example, 1 H-NMR or 13 It can be measured by 13C-NMR.

[0026] • Component unit (B) The structural unit (B) according to this embodiment is a structural unit derived from a cyclic olefin having no aromatic ring.

[0027] From the viewpoint of further improving the refractive index of the medical container and further suppressing the adsorption of the active ingredient in the preparation, the cyclic olefin having no aromatic ring according to this embodiment preferably contains a structural unit derived from a compound represented by the following formula (B-1).

[0028]

Chemical formula

[0029] In the above formula (B-1), n is 0 or 1, m is 0 or a positive integer, q is 0 or 1, and R 1 ~R 18 as well as R a and R b are each independently a hydrogen atom, a halogen atom, or a hydrocarbon group which may be substituted with a halogen atom. R 15 ~R 18 may be bonded to each other to form a monocyclic or polycyclic ring, and the monocyclic or polycyclic ring may have a double bond. Also, R 15 and R 16 , or R 17 and R 18 may form an alkylidene group. However, it does not contain an aromatic ring.

[0030] From the viewpoint of further suppressing the adsorption of the active ingredient in the preparation, the cyclic olefin having no aromatic ring according to this embodiment is more preferably one or more selected from the group consisting of bicyclo[2.2.1]-2-heptene, tetracyclo[4.4.0.1 2,5 .1 7,10 -3-dodecene, hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14 heptadecene-4 and cyclopentadiene, and more preferably bicyclo[2.2.1]-2-heptene, tetracyclo[4.4.0.1 2,5.1 7,10 It comprises one or more selected from the group consisting of ]-3-dodecene and cyclopentadiene, and more preferably tetracyclo[4.4.0.1 2,5 .1 7,10 It comprises one or two selected from the group consisting of ]-3-dodecene and cyclopentadiene, and more preferably tetracyclo[4.4.0.1 2,5 .1 7,10 Contains ]-3-dodecene.

[0031] When the total content of the above-mentioned constituent units (A), (B), and (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is 100 mol%, the content of the above-mentioned constituent unit (B) in the cyclic olefin-based (co)polymer (P) according to this embodiment is preferably 10.0 mol% or more, more preferably 20.0 mol% or more, and even more preferably 27.0 mol% or more, and even more preferably 70.0 mol% or less, more preferably 60.0 mol% or less, even more preferably 50.0 mol% or less, even more preferably 45.0 mol% or less, and even more preferably 40.0 mol% or less, from the viewpoint of further suppressing the adsorption of the active ingredient in the formulation.

[0032] • Component unit (C) The constituent unit (C) according to this embodiment is a constituent unit derived from a cyclic olefin having an aromatic ring.

[0033] The cyclic olefin according to this embodiment includes one or more compounds selected from the group consisting of the compound represented by the following formula (C-1), the compound represented by the following formula (C-2), and the compound represented by the following formula (C-3), from the viewpoint of further suppressing the adsorption of the active ingredient in the formulation.

[0034] [ka]

[0035] In the above equation (C-1), n ​​and q are independently 0, 1, or 2, and R1 ~R 17 Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms which may be substituted with a halogen atom other than a fluorine atom, and R 10 ~R 17 One of them is a bond, and when q=0, R 10 and R 11 , R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , R 14 and R 15 , R 15 and R 10 They may be bonded to each other to form a monocycle or polycycle, and when q=1 or 2, R 10 and R 11 , R 11 and R 17 , R 17 and R 17 , R 17 and R 12 , R 12 and R 13 , R 13 and R 14 , R 14 and R 15 , R 15 and R 16 , R 16 and R 16 , R 16 and R 10 These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring.

[0036] In this embodiment, from the viewpoint of further suppressing the adsorption of active ingredients in the formulation, it is preferable that the cyclic olefin includes the compound represented by the following formula (C-1A) among the compounds represented by (C-1). n and R in formula (C-1A) 1 ~R 14 The definition is the same as the definition in equation (C-1).

[0037] [ka]

[0038] [ka]

[0039] In the above equation (C-2), n and m are independently 0, 1, or 2, q is 1, 2, or 3, and R 18 ~R 31 Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms that may be substituted with a halogen atom other than a fluorine atom, and when q=1, R 28 and R 29 , R 29 and R 30 , R 30 and R 31 They may be bonded to each other to form a monocycle or polycycle, and when q=2 or 3, R 28 and R 28 , R 28 and R 29 , R 29 and R 30 , R 30 and R 31 , R 31 and R 31 These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring.

[0040] [ka]

[0041] In the above equation (C-3), q is 1, 2, or 3, and R 32 ~R 39 Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms that may be substituted with a halogen atom other than a fluorine atom, and when q=1, R 36 and R 37 , R 37 and R38 , R 38 and R 39 They may be bonded to each other to form a monocycle or polycycle, and when q=2 or 3, R 36 and R 36 , R 36 and R 37 , R 37 and R 38 , R 38 and R 39 , R 39 and R 39 These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring.

[0042] Each hydrocarbon group having 1 to 20 carbon atoms independently comprises, for example, one or more selected from the group consisting of alkyl groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 15 carbon atoms, and aromatic hydrocarbon groups.

[0043] Specifically, alkyl groups having 1 to 20 carbon atoms include, for example, one or more selected from the group consisting of methyl, ethyl, propyl, isopropyl, amyl, hexyl, octyl, decyl, dodecyl, and octadecyl groups.

[0044] Specifically, cycloalkyl groups having 3 to 15 carbon atoms include, for example, a cyclohexyl group.

[0045] Specifically, the aromatic hydrocarbon group includes, for example, one or more selected from the group consisting of aryl groups such as phenyl, tolyl, naphthyl, benzyl, and phenylethyl groups, and aralkyl groups, and preferably one or more selected from the group consisting of benzonorbornadiene, indenenorbornene, and methylphenylnorbornene.

[0046] These hydrocarbon groups may be substituted with halogen atoms other than fluorine atoms.

[0047] The aromatic ring-containing cyclic olefin according to this embodiment preferably comprises one or more selected from the group consisting of benzonorbornane, indenenorbornene, and methylphenylnorbornene, more preferably comprises one or more selected from the group consisting of benzonorbornane and indenenorbornene, and even more preferably comprises benzonorbornane.

[0048] When the total content of the above-mentioned constituent units (A), (B), and (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is 100 mol%, the content of the above-mentioned constituent unit (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is preferably 0.1 mol% or more, more preferably 1.0 mol% or more, even more preferably 3.0 mol% or more, even more preferably 5.0 mol% or more, and even more preferably 7.0 mol% or more, and even more preferably 50.0 mol% or less, more preferably 40.0 mol% or less, even more preferably 30.0 mol% or less, even more preferably 25.0 mol% or less, and even more preferably 20.0 mol% or less.

[0049] When the total content of the above-mentioned constituent units (B) and (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is 100 mol%, the content of the above-mentioned constituent units (C) in the cyclic olefin-based (co)polymer (P) according to this embodiment is preferably 5.0 mol% or more, more preferably 10.0 mol% or more, even more preferably 15.0 mol% or more, and even more preferably 20.0 mol% or more, and even more preferably 95.0 mol% or less, more preferably 85.0 mol% or less, even more preferably 75.0 mol% or less, even more preferably 65.0 mol% or less, even more preferably 55.0 mol% or less, even more preferably 45.0 mol% or less, and even more preferably 35.0 mol% or less.

[0050] The following explains each of [X-1] through [X-5].

[0051] ·[X-1] [X-1] is a random copolymer containing a constituent unit (A) derived from α-olefins having 2 to 20 carbon atoms and a constituent unit (B) derived from cyclic olefins that do not have an aromatic ring.

[0052] [X-1] preferably has a substantially linear structure in which constituent units (A) and (B) are randomly arranged and bonded. The fact that this copolymer is substantially linear and does not substantially have a gel-like crosslink structure can be confirmed by the absence of insoluble matter in the solution when the copolymer is dissolved in an organic solvent. For example, when measuring the intrinsic viscosity [η], this can be confirmed by the complete dissolution of the copolymer in decalin at 135°C.

[0053] [X-1] can be produced by conventionally known methods using an α-olefin having 2 to 20 carbon atoms and a cyclic olefin without an aromatic ring. For example, it can be produced by selecting appropriate conditions according to the production methods disclosed in Japanese Patent Publication Nos. 60-168708, 61-120816, 61-115912, 61-115916, 61-271308, 61-272216, 62-252406, 62-252407 and International Publication No. 2008 / 068897.

[0054] ·[X-2] [X-2] is a copolymer comprising structural unit (A), structural unit (B), and structural unit (C) derived from a cyclic olefin having an aromatic ring.

[0055] [X-2] can be produced by conventionally known methods using α-olefins having 2 to 20 carbon atoms, cyclic olefins without aromatic rings, and cyclic olefins having aromatic rings. For example, it can be produced by selecting appropriate conditions according to the production method disclosed in the above publication.

[0056] • [X-3] [X-3] is one or two ring-opening polymers or copolymers selected from the group consisting of cyclic olefins without aromatic rings and cyclic olefins having aromatic rings.

[0057] [X-3] can be produced by polymerizing or copolymerizing one or two cyclic olefins selected from the group consisting of cyclic olefins without aromatic rings and cyclic olefins having aromatic rings, in the presence of a ring-opening polymerization catalyst, using conventionally known methods. Furthermore, [X-3] may be produced by copolymerizing one or two cyclic olefins selected from the group consisting of cyclic olefins without aromatic rings and cyclic olefins having aromatic rings with an α-olefin having 2 to 20 carbon atoms in the presence of a ring-opening polymerization catalyst, using a conventionally known method. For example, the product can be manufactured by selecting appropriate conditions according to the manufacturing method disclosed in the above publication. Alternatively, it may be manufactured according to the manufacturing method disclosed in Japanese Patent Publication No. 7-324108.

[0058] As a ring-opening polymerization catalyst, a catalyst consisting of a metal halide, nitrate, or acetylacetone compound selected from ruthenium, rhodium, palladium, osmium, indium, and platinum, and a reducing agent can be used. Alternatively, a catalyst consisting of a metal halide or acetylacetone compound selected from titanium, palladium, zirconium, tungsten, and molybdenum, and an organoaluminum compound can be used.

[0059] • [X-4] [X-4] is a hydride of [X-3].

[0060] [X-4] can be produced by hydrogenating [X-3] using a conventionally known method. For example, it can be obtained by hydrogenating in the presence of a hydrogenation catalyst disclosed in Japanese Patent Application Publication No. 7-324108.

[0061] Examples of commercially available [X-4] products include the Zeonex1020R, 690R, and 790R manufactured by Zeon Corporation.

[0062] ·[X-5] [X-5] is a graft-modified version of [X-1], [X-2], [X-3], or [X-4].

[0063] [X-5] can be produced by graft-modifying [X-1], [X-2], [X-3], or [X-4] using conventionally known methods.

[0064] Modifying agents used for graft modification include, for example, unsaturated carboxylic acids, specifically (meth)acrylic acid, maleic acid, fumaric acid, tetrahydrophthalic acid, itaconic acid, citraconic acid, crotonic acid, isocrotonic acid, endocis-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (Nadic acid™), and derivatives of the above unsaturated carboxylic acids, such as unsaturated carboxylic acid anhydrides, unsaturated carboxylic acid halides, unsaturated carboxylic acid amides, unsaturated carboxylic acid imides, and ester compounds of unsaturated carboxylic acids. More specifically, derivatives of unsaturated carboxylic acids include maleic anhydride, citraconic anhydride, malenyl chloride, maleimide, monomethyl maleate, dimethyl maleate, and glycidyl maleate. Among these modifying agents, α,β-unsaturated dicarboxylic acids and α,β-unsaturated dicarboxylic acid anhydrides, such as maleic acid, nadic acid, and their anhydrides, are preferably used. These modifying agents may be used individually or in combination of two or more. Furthermore, it is desirable that the denaturation rate in [X-5] be, for example, 10 mol% or less.

[0065] The method of graft modification is not particularly limited; a modifying agent may be added to molten [X-1], [X-2], [X-3], or [X-4] to carry out the graft reaction, or a modifying agent may be added to a solution of [X-1], [X-2], [X-3], or [X-4] to carry out the graft reaction. The graft reaction is carried out at a temperature of, for example, 60°C to 350°C. The graft reaction is also carried out in the presence of a radical initiator, for example, an organic peroxide or an azo compound.

[0066] Properties of cyclic olefin (co)polymers (P) The following describes the physical properties of cyclic olefin (co)polymers (P).

[0067] The glass transition temperature (Tg) of the cyclic olefin-based (co)polymer (P) according to this embodiment, as measured by differential scanning calorimeter (DSC), is preferably 70°C to 180°C, more preferably 120°C to 180°C, even more preferably 125°C to 165°C, and even more preferably 130°C to 150°C, from the viewpoint of further improving heat resistance while maintaining good transparency of the resulting medical container.

[0068] The intrinsic viscosity [η] (in decalin at 135°C) of the cyclic olefin-based (co)polymer (P) according to this embodiment is, for example, 0.05 dl / g or more and 5.00 dl / g or less, preferably 0.20 dl / g or more and 4.00 dl / g or less, more preferably 0.30 dl / g or more and 2.00 dl / g or less, and even more preferably 0.40 dl / g or more and 1.00 dl / g or less. If the intrinsic viscosity [η] is above the lower limit, the mechanical strength of the medical container can be improved. Furthermore, if the intrinsic viscosity [η] is below the upper limit, the moldability can be improved.

[0069] <Medical containers> The following describes the medical containers that constitute the containerized formulation according to this embodiment.

[0070] The medical container according to this embodiment contains a cyclic olefin-based (co)polymer (P). The content of the cyclic olefin-based (co)polymer (P) in the medical container according to this embodiment is preferably 50% by mass or more, more preferably 70% by mass or more, even more preferably 80% by mass or more, even more preferably 90% by mass or more, and, for example, 100% by mass or less, for example 98% by mass or less, for example 95% by mass or less, when the total amount of the medical container is considered to be 100% by mass, from the viewpoint of further suppressing the adsorption of the active ingredient in the formulation.

[0071] The method for molding the cyclic olefin copolymer (P) according to this embodiment to obtain a medical container is not particularly limited, and known methods can be used. Depending on the application and shape, for example, extrusion molding, injection molding, inflation molding, blow molding, extrusion blow molding, injection blow molding, press molding, vacuum molding, powder slush molding, calendering, foam molding, etc., can be applied. Among these, injection molding is preferred from the viewpoint of moldability and productivity. Furthermore, the molding conditions are appropriately selected depending on the intended use or molding method, but for example, the resin temperature in injection molding is appropriately selected within the range of, for example, 150°C to 400°C, preferably 200°C to 350°C, and more preferably 230°C to 330°C.

[0072] The medical container according to this embodiment is preferably radiation-sterilized. The type of radiation is not particularly limited, but examples include electromagnetic radiation such as gamma rays, X-rays, and ultraviolet rays; particle radiation such as alpha rays, beta rays, electron beams, proton beams, neutron beams, and heavy ion beams; solar cosmic rays; and galactic cosmic rays. Preferably, it is electromagnetic radiation such as gamma rays, X-rays, and ultraviolet rays, and more preferably gamma rays or X-rays.

[0073] Furthermore, the irradiation dose is not particularly limited, but is, for example, 5 kilogray (kGy) or more, preferably 10 kGy or more, more preferably 25 kGy or more, and also, for example, 100 kGy or less, or for example, 80 kGy or less.

[0074] The type of medical container according to this embodiment is not particularly limited, but examples include cartridges, ampoules, bottles, pouches, or blister packs used in syringes, vials, infusion bags, pen-type injectors, etc.

[0075] <Pharmaceutical Products> The following describes the formulations that constitute the containerized formulation according to this embodiment.

[0076] The containerized formulation according to this embodiment is one in which the formulation is contained within the above-mentioned medical container.

[0077] The formulations constituting the containerized formulation according to this embodiment may include formulations containing a low-molecular-weight drug obtained by chemical synthesis as an active ingredient (hereinafter sometimes referred to as a chemical drug formulation), as well as biopharmaceuticals such as nucleic acid formulations and protein formulations, without any particular limitations. In particular, the formulation is preferably a nucleic acid formulation or a protein formulation, and more preferably a protein formulation. In this specification, "protein" refers to a single or multiple high-molecular-weight compound formed by the chain-like linkage (polymerization) of numerous amino acids via amide bonds (also called peptide bonds), and is not limited to the number of constituent amino acids. Therefore, so-called peptides are also included in the proteins of this invention. Furthermore, glycoproteins, which are formed by the linkage of sugar and protein, and lipoproteins, which are formed by the linkage of lipid and protein, are also included in the proteins of this invention. Furthermore, the amino acid in question can be a natural or unnatural α- or β-amino acid, and may include both L- and D forms. Specifically, natural amino acids include alanine, leucine, arginine, lysine, asparagine, methionine, aspartic acid, phenylalanine, cysteine, proline, glutamine, serine, glutamic acid, threonine, glycine, tryptophan, histidine, tyrosine, isoleucine, and valine. Unnatural amino acids include, for example, norvaline, norleucine, homophenylalanine, and phenylglycine. Furthermore, the nucleic acid may be single-stranded DNA, double-stranded DNA, single-stranded RNA, or double-stranded RNA, and may be in chain form or as an aptamer.

[0078] For biopharmaceuticals such as nucleic acid and protein preparations, it is important to suppress the adsorption of the active ingredients, proteins and nucleic acids, to the container. This is because when proteins and nucleic acids adsorb to the container, causing the protein molecules (nucleic acid molecules) to come into close proximity and aggregate, the three-dimensional structure of the proteins and nucleic acids is lost, resulting in a loss of physiological activity.

[0079] According to the containerized formulation of this embodiment, the adsorption of the active ingredient in the formulation to the container can be suppressed. Therefore, the containerized formulation of this embodiment is suitable for applications such as containing biopharmaceuticals such as protein formulations and nucleic acid formulations, and is more suitable for applications such as containing protein formulations.

[0080] The concentration of the active ingredient in the formulation is preferably 0.01 mg / mL or higher, more preferably 0.1 mg / mL or higher, preferably 100 mg / mL or lower, and more preferably 10 mg / mL or lower. If the concentration of the active ingredient is 0.01 mg / mL or higher, the desired effect can be sufficiently obtained when the formulation is administered to the human body, and if the concentration of the active ingredient is 100 mg / mL or lower, the adsorption of the active ingredient in the formulation to the container can be further suppressed when the containerized formulation is stored for a long period of time.

[0081] When the preparation is a protein preparation, the type of protein preparation according to this embodiment is not particularly limited, but may include, for example, one or more selected from the group consisting of antibodies, blood coagulation factors, peptide hormones, protein hormones, interferons, enzymes, cytokines, insulin, erythropoietin, receptor Fc fusion proteins, and albumin.

[0082] The aforementioned antibody includes, for example, one or more selected from the group consisting of chimeric antibodies, human antibodies and humanized antibodies, and domain antibodies thereof. Examples of the aforementioned antibodies include antitumor antibodies such as trastuzumab, pertuzumab, rituximab, ofatumumab, cetuximab, panitumumab, alemtuzumab, gemtuzumab ozogamicin, ibritumomab tiuxetan, trastuzumab emtansine, and brentuximab vedotin; infliximab, adalimumab, golimumab, certolizumab pegol, and tocilizumab. Examples include immunomodulatory antibodies such as omalizumab, eculizumab, basiliximab, natalizumab, mogamulizumab, and nivolumab; anti-interleukin antibodies such as ustekinumab, canakinumab, and secukinumab; anti-cardiovascular modulatory antibodies such as bevacizumab; anti-bone-related molecule antibodies such as denosumab; antiviral antibodies such as palivizumab; and other antibodies such as ranibizumab.

[0083] The dosage form of the formulation according to this embodiment is not particularly limited and may be, for example, a solution, a gel, or a powder such as a freeze-dried powder.

[0084] The formulation may contain a nonionic surfactant. Such nonionic surfactants are not particularly limited, but examples include sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters (such as polyoxyethylene sorbitan oleate (Polysorbate 80) and polyoxyethylene sorbitan monolaurate (Polysorbate 20)), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene hydrogenated castor oil, polyoxyethylene beeswax derivatives, polyoxyethylene lanolin derivatives, and polyoxyethylene fatty acid amides. Furthermore, nonionic surfactants may be used individually or in combination of two or more types.

[0085] Other components besides nonionic surfactants that may be optionally included in the formulation include known components used in the preparation of the formulation. Examples of such known components include stabilizers (excluding the nonionic surfactants mentioned above), diluents, solubilizers, isotonic agents, excipients, pH adjusters, analgesics, buffers, sulfur-containing reducing agents, and antioxidants. Furthermore, other components include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate; and organic salts such as sodium citrate, potassium citrate, and sodium acetate.

[0086] The pH of the formulation is not particularly limited, but can be between 3.0 and 8.0.

[0087] The containerized formulation according to this embodiment is preferably a pre-filled syringe or a pre-filled cartridge. A pre-filled syringe is a syringe-shaped formulation that is pre-filled with a drug, and there are single-chamber types filled with one type of drug and double-chamber types filled with two types of drugs. A pre-filled cartridge is a cartridge-shaped formulation that is pre-filled with a drug, and is used by attaching it to a pen-type injector or the like. Pre-filled cartridges also come in single-chamber and double-chamber types, similar to pre-filled syringes. As mentioned above, the formulation according to this embodiment may be in solution or powder form. Therefore, the pre-filled syringe and pre-filled cartridge according to this embodiment may be a single-chamber type filled with one type of solution, a liquid-liquid type double-chamber type filled with two types of solutions, or a powder-liquid type double-chamber type consisting of powder and its dissolving solution.

[0088] According to the containerized formulation of this embodiment, the adsorption of the active ingredient in the formulation to the medical container can be suppressed. This effect is particularly pronounced when the formulation is a nucleic acid formulation or a protein formulation, and especially pronounced when it is a protein formulation.

[0089] 2.Packaging The packaging according to this embodiment will be described below.

[0090] The packaging according to this embodiment is a sealed package of the above-mentioned containerized formulation using an oxygen-impermeable packaging material.

[0091] The oxygen-impermeable packaging material according to this embodiment is not particularly limited, and commonly used oxygen-impermeable films and sheets can be used. For example, films, sheets, multilayer films, or multilayer sheets containing one or more selected from the group consisting of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), ethylene-vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC), vinylidene chloride-vinyl chloride copolymer, vinylidene chloride-acrylic acid ester copolymer, polyacrylonitrile, polyvinyl alcohol, and polyamide can be used.

[0092] Furthermore, from the viewpoint of suppressing the degradation of pharmaceuticals, it is preferable that the oxygen-impermeable packaging material according to this embodiment also has light-shielding properties in addition to being oxygen-impermeable. A packaging material having light-shielding properties in addition to being oxygen-impermeable can be obtained, for example, by providing a light-shielding layer such as an aluminum foil layer, an aluminum vapor-deposited layer, an aluminum oxide vapor-deposited layer, or a silicon oxide vapor-deposited layer on the surface or between the layers of the film, sheet, multilayer film, or multilayer sheet mentioned above.

[0093] The packaging according to this embodiment is preferably in the form of blister packaging. Blister packaging is a type of packaging that includes a main body with a recess for containing the contents, the contents contained in the recess of the main body, and a covering portion that covers the top of the main body containing the contents. The recess of the main body can be formed by methods such as vacuum forming. Compared to other packaging such as bags, blister packaging reduces the transmission of vibrations during transportation to the pharmaceutical product, thereby reducing physical stress on the product and suppressing protein denaturation. Furthermore, using transparent resin for the main body of the blister pack can improve the visibility of the contents.

[0094] The embodiments of the present invention have been described above, but these are merely examples, and various other configurations can also be adopted. Furthermore, the present invention is not limited to the embodiments described above, and any modifications, improvements, etc., that can achieve the objectives of the present invention are included in the present invention. [Examples]

[0095] The present disclosure will be further described below with reference to examples and comparative examples, but the disclosure is not limited thereto.

[0096] <Cyclic olefin-based (co)polymer (P)> [Production of cyclic olefin (co)polymer (P)] [Production Example 1: Cyclic Olefin Copolymer (P-1)] After passing nitrogen as an inert gas at a flow rate of 100 Nl / hr for 30 minutes through a 500 ml glass reaction vessel equipped with a stirring device, cyclohexane and tetracyclo[4.4.0.1 2,5 .1 7,10 ]-3-dodecene (hereinafter referred to as TD) (11 mmol) and benzonorbornadiene (hereinafter referred to as BNBD) (19 mmol) were added. Next, the polymerization solvent was stirred at a rotation speed of 600 rpm while the solvent temperature was raised to 50°C. After the solvent temperature reached the predetermined temperature, the flow gas was switched from nitrogen to ethylene, and ethylene was supplied to the reaction vessel at a rate of 90 Nl / hr and hydrogen at 0.2 Nl / hr. After 10 minutes, methylaluminoxane (hereinafter referred to as MMAO) (0.30 mmol), triphenylcarbenium tetrakis(pentafluorophenyl) borate (hereinafter referred to as compound 1) (0.0040 mmol), and 3,5-bismethylethyl-1-pyrazolate-t-butylcyclopentadienyltitanium dichloride (hereinafter referred to as metal compound 1) (0.00013 mmol) were added to the glass reaction vessel to initiate polymerization. After 10 minutes, 5 ml of isobutyl alcohol was added to stop the polymerization, and a polymerization solution containing a copolymer of ethylene, TD, and BNBD was obtained. Subsequently, the polymerization solution was transferred to a separate 2L beaker, and 5ml of concentrated hydrochloric acid and a stirring bar were added. The mixture was then contacted under strong stirring for 2 hours to perform a decalcification. The decalcified polymerization solution was then added to a beaker containing approximately three times the volume of acetone under stirring to precipitate the copolymer. The precipitated copolymer was then separated from the filtrate by filtration. The resulting polymer containing the solvent was dried under reduced pressure at 130°C for 10 hours, yielding 0.18g of white powdery ethylene-TD-BNBD copolymer. Based on the above, a cyclic olefin copolymer (P-1) was obtained. The content (mol%) of each constituent unit in the obtained copolymer (P-1) was measured by the method described below.

[0097] [Production Example 2: Cyclic Olefin Copolymer (P-2)] Following the method described in Polymerization Example 7 of International Publication No. 2008 / 068897, ethylene was charged at 66 mol% and TD at 34 mol% to obtain a cyclic olefin copolymer (P-2), which is a random copolymer of ethylene and TD. The content (mol%) of each constituent unit in the obtained copolymer (P-2) was measured by the method described below. The intrinsic viscosity [η] of the cyclic olefin copolymer (P-2) measured in decalin at 135°C was 0.60 dl / g. Furthermore, the cyclic olefin copolymer (P-2) completely dissolved in decalin at 135°C when the intrinsic viscosity [η] was measured. This indicates that the cyclic olefin copolymer (P-2) is substantially linear and does not substantially possess a gel-like crosslinking structure.

[0098] [Production Example 3: Cyclic Olefin Polymer (P-3)] In a polymerization reactor whose interior was purged with nitrogen, 7 parts by mass of monomer mixture (TD 40.0 mol%, dicyclopentadiene 40.0 mol%, indenorbornene 20.0 mol%), 1600 parts by mass of anhydrous cyclohexane, 0.6 parts by mass of 1-hexene, 1.3 parts by mass of diisopropyl ether, 0.33 parts by mass of isobutyl alcohol, 0.84 parts by mass of triisobutylaluminum, and 30 parts by mass of a cyclohexane solution of tungsten hexachloride (concentration: 0.66%) were added, and the entire mixture was stirred at 55°C for 10 minutes. Next, while continuing to stir, 693 parts by mass of the monomer mixture and 72 parts by mass of a cyclohexane solution of tungsten hexachloride (concentration: 0.77%) were added dropwise, each over 150 minutes at 55°C. After the dropwise addition was complete, stirring was continued for another 30 minutes, and then 1.0 part by mass of isopropyl alcohol was added to stop the polymerization reaction, yielding a polymerization solution containing a copolymer of TD, dicyclopentadiene, and indene norbornene. Next, 300 parts by mass of the polymerization reaction solution containing the above polymer was transferred to an autoclave equipped with a stirrer, and 100 parts by mass of cyclohexane and 2.0 parts by mass of diatomaceous earth-supported nickel catalyst (nickel load 58%) were added. After purging the autoclave with hydrogen, the hydrogenation reaction was carried out at 180°C and under a hydrogen pressure of 4.5 MPa for 6 hours. After the hydrogenation reaction was complete, the solution was filtered under pressure at 0.25 MPa using a pressure filter with diatomaceous earth as the filter bed to obtain a colorless, transparent solution. The solution was then added to a beaker containing three times the amount of acetone under stirring to precipitate the ring-opening polymer, and a cyclic olefin polymer (P-3) was obtained in the same manner as described in Production Example 1. The content (mol%) of each constituent unit in the obtained cyclic olefin polymer (P-3) was measured by the method described below.

[0099] [Pelletization] Using a twin-screw extruder, the cyclic olefin-based (co)polymer (P) obtained by the above method was kneaded at 280°C and extruded to obtain resin pellets.

[0100] [Content of each component] The content of each constituent unit was determined by measuring the cyclic olefin-based (co)polymer (P) obtained by the above method under the following conditions using a JEOL Corporation "ECA500" nuclear magnetic resonance spectrometer. Solvent: Deuterated tetrachloroethane Sample concentration: 50-100 g / l-solvent Pulse repetition time: 5.5 seconds Cumulative number of times: 6,000 to 16,000 Measurement temperature: 120℃ Measured under the above conditions 13 The composition of each constituent unit was quantified using 1C-NMR spectroscopy. The results are shown in Table 1.

[0101] [Glass transition temperature Tg (°C)] The glass transition temperature (Tg) of a cyclic olefin (co)polymer (P) was measured under an N2 (nitrogen) atmosphere using a Shimadzu Science DSC-6220. The cyclic olefin (co)polymer (P) was heated from room temperature to 200°C at a heating rate of 10°C / min, held for 5 minutes, and then cooled to -20°C at a cooling rate of 10°C / min, held for 5 minutes. The glass transition temperature (Tg) of the cyclic olefin (co)polymer (P) was then determined from the endothermic curve obtained when heating to 200°C at a heating rate of 10°C / min. The results are shown in Table 1.

[0102] [Intrinsic viscosity [η](dl / g)] Using a mobile viscometer (Rigousha, type VNR053U), 0.25-0.30 g of cyclic olefin (co)polymer (P) was dissolved in 25 ml of decalin to prepare the sample. The specific viscosity of the cyclic olefin (co)polymer was measured at 135°C according to ASTM J1601, and the intrinsic viscosity [η] of the cyclic olefin (co)polymer was determined by extrapolating the ratio of this specific viscosity to the concentration to a concentration of 0.

[0103] [Table 1]

[0104] <Medical containers> [Manufacturing of medical containers] (Examples 1-6 and Comparative Examples 1-6) The resin pellets obtained above were injection molded using Niigata Machine Techno's "MD-30SIV, screw diameter 14 mm" to obtain a syringe-like container with a thickness of 1 mm compliant with ISO 11040.

[0105] (Comparative Examples 7-10) A syringe-like container was obtained in the same manner as in Example 1, except that pellets of a propylene homopolymer (with a melt flow rate of 20 g / 10 min according to JIS K 7210 standards (230°C, 2.16 kg load)) were used instead of the resin pellets obtained above.

[0106] [Water contact angle and diiodomethane contact angle] (Examples 1-6 and Comparative Examples 9-10) A syringe-like container was irradiated with 50 kGy of gamma rays and then left to stand at 25°C ± 2°C for 12 days. Next, a test specimen was cut from the center of the syringe-like container in the longitudinal direction, and the water contact angle and diiodomethane contact angle were measured by the droplet method and analyzed by the 2θ method. The results are shown in Table 2.

[0107] (Comparative Examples 1-8) Under sterile conditions, the syringe-like container was washed with sterile water for injection and air-dried. Next, a test specimen was cut from the center of the syringe-like container in the longitudinal direction, and the water contact angle and diiodomethane contact angle were measured and analyzed using the same method as in Example 1. The results are shown in Table 2.

[0108] <Packaged protein preparations> [Preparation of protein preparations] First, protein preparations (rituximab solution and adalimumab solution) were prepared using the method described below.

[0109] [Rituximab solution] After removing polysorbate 80 from rituximab intravenous infusion (manufactured by Zenyaku Kogyo Co., Ltd.) using a cation exchange column, a 1 mg / mL rituximab solution (20 mM phosphate, 150 mM sodium chloride, pH 7.0) was prepared. The prepared rituximab solution was sterilized in a sterile environment using a 0.22 μm filter. In Table 2, this is indicated as RTX.

[0110] [Adalimumab solution] Polysorbate 80 was removed from a 0.8 mg Humira subcutaneous injection 80 mg syringe (manufactured by Eisai Co., Ltd.) by purification using a cation exchange column, and then a 1 mg / mL adalimumab solution (20 mM phosphate, 150 mM sodium chloride, pH 7.0) was prepared. The prepared adalimumab solution was sterilized in a sterile environment using a 0.22 μm filter. In Table 2, this is denoted as ADA.

[0111] [Evaluation of protein adsorption capacity] (Examples 1-6 and Comparative Examples 9-10) The syringe-like containers obtained by the above method were irradiated with gamma rays under the above conditions, and then left to stand at 25°C ± 2°C for 12 days. Three syringe-like containers were prepared in this manner. Using a prepared syringe, 0.5 mL of the protein preparation was drawn up, the opening was sealed with a rubber stopper, and then wrapped with Parafilm to create a tight seal. The syringe was then left to stand undisturbed in a dark place at 5±2°C for 3 days. Next, the Parafilm and rubber stopper were removed, and the protein preparation was dispensed from the syringe-like container. Then, 1 mL of solvent (20 mM phosphoric acid, 150 mM sodium chloride, pH 7.0) was drawn into the empty syringe-like container and dispensed. The process of drawing in and dispensing 1 mL of solvent was repeated a total of three times. The syringe-like container was then washed in this manner. Next, 0.5 mL of 5% SDS solution was filled into a syringe-like container and placed in an ultrasonic water bath, where it was subjected to ultrasonic treatment at 25°C ± 2°C for 15 minutes. In this way, proteins that remained adsorbed on the inner wall of the syringe-like container even after washing with the solvent were dissolved in the SDS solution.

[0112] After sonication, the amount of protein in the SDS solution, i.e., the amount of protein adsorbed onto the inner wall of the syringe-like container, was quantified by UPLC under the following conditions. The arithmetic mean of the protein adsorption amounts quantified from the three samples was then defined as the total protein adsorption amount. Mobile phase A: 0.1 vol% trifluoroacetic acid (TFA) aqueous solution Mobile phase B: 0.1 vol% TFA-containing acetonitrile • Column: ACQUITY UPLC Protein BEH C4 Column, 300 Å, 1.7 μm, 1 mm × 100 mm (manufactured by Waters Co., Ltd.) (Measurement conditions for ULC) Column temperature: 80°C ·Injection volume: 100μL ·Flow rate: 0.1mL / min. ·Measurement wavelength: 210nm

[0113] The amount of protein adsorption was evaluated according to the following criteria. The results are shown in Table 2. Acceptable: Protein adsorption capacity is 2.0 mg / m² 2 below Not suitable: Protein adsorption capacity is 2.0 mg / m². 2 bigger

[0114] (Comparative Examples 1-8) The evaluation was performed in the same manner as in Example 1, except that the syringe-like containers were prepared by washing them with sterile water for injection and air-drying them in a sterile environment. The results are shown in Table 2.

[0115] [Table 2]

[0116] The containerized formulation of this embodiment was able to suppress the adsorption of the formulation onto the container. This indicates that the containerized formulation according to this embodiment can suppress the adsorption of the formulation onto the container.

Claims

1. A packaged preparation in which the preparation is contained within a medical container, The aforementioned medical container contains a cyclic olefin-based (co)polymer (P), The cyclic olefin-based (co)polymer (P) comprises one or more selected from the group consisting of [X-1], [X-2], [X-3], [X-4] and [X-5] below, A containerized preparation wherein the water contact angle of the medical container is 60.0° or more and 90.0° or less. [X-1] A random copolymer comprising a structural unit (A) derived from an α-olefin having 2 to 20 carbon atoms, and a structural unit (B) derived from a cyclic olefin that does not have an aromatic ring; [X-2] A copolymer comprising the constituent unit (A), the constituent unit (B), and a constituent unit (C) derived from a cyclic olefin having an aromatic ring; [X-3] One or two ring-opening polymers or ring-opening copolymers selected from the group consisting of cyclic olefins without the aromatic ring and cyclic olefins having the aromatic ring; [X-4] The hydride of [X-3]; [X-5] A graft-modified product of [X-1], [X-2], [X-3], or [X-4].

2. The containerized preparation according to claim 1, wherein the medical container is radiation-sterilized.

3. The containerized formulation according to claim 1 or 2, wherein the cyclic olefin-based (co)polymer (P) comprises one or more selected from the group consisting of [X-1], [X-2], and [X-3].

4. The containerized formulation according to claim 3, wherein the cyclic olefin-based (co)polymer (P) comprises [X-2].

5. The containerized formulation according to any one of claims 1 to 4, wherein when the total content of the constituent units (A), (B), and (C) in the cyclic olefin-based (co)polymer (P) is 100 mol%, the content of the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 0.1 mol% or more and 50 mol% or less.

6. A containerized formulation according to any one of claims 1 to 5, wherein when the total content of the constituent unit (B) and the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 100 mol%, the content of the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 5.0 mol% or more and 95.0 mol% or less.

7. A containerized formulation according to any one of claims 1 to 6, wherein when the total content of the constituent unit (A), the constituent unit (B), and the constituent unit (C) in the cyclic olefin-based (co)polymer (P) is 100 mol%, the content of the constituent unit (A) in the cyclic olefin-based (co)polymer (P) is 10.0 mol% or more and 80.0 mol% or less.

8. The containerized formulation according to any one of claims 1 to 7, wherein the cyclic olefin lacking the aromatic ring comprises a compound represented by the following formula (B-1). 【Chemistry 1】 In the formula (B-1), n is 0 or 1, m is 0 or a positive integer, q is 0 or 1, and R １ ~R １８ as well as R ａ and R ｂ are each independently a hydrogen atom, a halogen atom or a hydrocarbon group which may be substituted with a halogen atom, and R １５ ~R １８ may be bonded to each other to form a monocyclic or polycyclic ring, and the monocyclic or polycyclic ring may have a double bond, and R １５ and R １６ or R １７ and R １８ may form an alkylidene group. However, it does not contain an aromatic ring.

9. The containerized formulation according to any one of claims 1 to 8, wherein the cyclic olefin having an aromatic ring comprises one or more compounds selected from the group consisting of a compound represented by the following formula (C-1), a compound represented by the following formula (C-2), and a compound represented by the following formula (C-3). 【Chemistry 2】 In the above formula (C-1), n ​​and q are each independently 0, 1, or 2, and R １ ~R １７ Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms which may be substituted with a halogen atom other than a fluorine atom, and R １０ ~R １７ One of them is a bond, and when q = 0, R １０ and R １１ , R １１ and R １２ , R １２ and R １３ , R １３ and R １４ , R １４ and R １５ , R １５ and R １０ They may be bonded to each other to form a monocycle or polycycle, and when q = 1 or 2, R １０ and R １１ , R １１ and R １７ , R １７ and R １７ , R １７ and R １２ , R １２ and R １３ , R １３ and R １４ , R １４ and R １５ , R １５ and R １６ , R １６ and R １６ , R １６ and R １０ These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring. 【Transformation 3】 In the above formula (C-2), n and m are each independently 0, 1, or 2, and q is 1, 2, or 3, R １８ ~R ３１ Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms which may be substituted with a halogen atom other than a fluorine atom, and when q = 1, R ２８ and R ２９ , R ２９ and R ３０ , R ３０ and R ３１ They may be bonded to each other to form a monocycle or polycycle, and when q = 2 or 3, R ２８ and R ２８ , R ２８ and R ２９ , R ２９ and R ３０ , R ３０ and R ３１ , R ３１ and R ３１ These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring. 【Chemistry 4】 In the above formula (C-3), q is 1, 2, or 3, and R ３２ ~R ３９ Each of these is independently a hydrogen atom, a halogen atom other than a fluorine atom, or a hydrocarbon group having 1 to 20 carbon atoms which may be substituted with a halogen atom other than a fluorine atom, and when q = 1, R ３６ and R ３７ , R ３７ and R ３８ , R ３８ and R ３９ They may be bonded to each other to form a monocycle or polycycle, and when q = 2 or 3, R ３６ and R ３６ , R ３６ and R ３７ , R ３７ and R ３８ , R ３８ and R ３９ , R ３９ and R ３９ These elements may be bonded to each other to form a monocycle or polycycle, and the monocycle or polycycle may have a double bond, and the monocycle or polycycle may be an aromatic ring.

10. A containerized formulation according to any one of claims 1 to 9, wherein the glass transition temperature (Tg) of the cyclic olefin-based (co)polymer (P), as measured by differential scanning calorimeter (DSC), is 70°C or higher and 180°C or lower.

11. The containerized formulation according to any one of claims 1 to 10, wherein the intrinsic viscosity [η] of the cyclic olefin (co)polymer (P), as measured in decalin at 135°C, is 0.05 dl / g or more and 5.00 dl / g or less.

12. The containerized formulation according to any one of claims 1 to 11, wherein the cyclic olefin having the aromatic ring comprises one or more selected from the group consisting of benzonorbornane, indenenorbornene, and methylphenylnorbornene.

13. The containerized formulation according to any one of claims 1 to 12, wherein the medical container is a syringe, vial, infusion bag, cartridge, ampoule, bottle, pouch or blister pack.

14. The containerized formulation according to any one of claims 1 to 13, wherein the formulation is a nucleic acid formulation or a protein formulation.

15. The aforementioned preparation is a protein preparation, The containerized formulation according to claim 14, wherein the protein formulation comprises one or more selected from the group consisting of antibodies, blood coagulation factors, peptide hormones, protein hormones, interferon, enzymes, cytokines, insulin, erythropoietin, receptor Fc fusion proteins, and albumin.

16. The containerized formulation according to claim 15, wherein the antibody comprises one or more selected from the group consisting of chimeric antibodies, human antibodies, humanized antibodies, and domain antibodies thereof.

17. A containerized formulation according to any one of claims 1 to 16, which is a pre-filled syringe or a pre-filled cartridge.

18. A containerized formulation according to any one of claims 1 to 17, which can suppress the adsorption of the active ingredient in the formulation onto the medical container.

19. The containerized formulation according to any one of claims 1 to 18, wherein the diiodomethane contact angle of the medical container is 25.0° or more and 50.0° or less.

20. A package containing a containerized preparation according to any one of claims 1 to 19, sealed in an oxygen-impermeable packaging material.

21. The packaging according to claim 20, which is in the form of blister packaging.

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