Prefilled medication package and method for manufacturing the prefilled medication package

Abstract

The purpose of the present invention is to provide a prefilled drug package capable of inhibiting aggregation of proteins after long-term preservation even when a protein solution preparation in which the concentration of a nonionic surfactant is low is contained. The prefilled drug package according to the present invention comprises a protein solution preparation, and a container that contains the protein solution preparation. The concentration of a nonionic surfactant in the protein solution preparation is 0 mg / mL or more but less than 0.05 mg / mL. At least a portion of the container into contact with the protein solution preparation is made of a resin containing a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a chain olefin.

Description

[Technical Field]

[0001] The present invention relates to pre-filled medication packages and methods for making pre-filled medication packages. [Background technology]

[0002] In recent years, the use of prefilled medicine packages, which are filled with medicine in advance, has been expanding from the viewpoints of ease of use and the ability to prevent medical accidents.

[0003] Here, the drug filled in the prefilled drug package is, for example, a preparation containing a protein in an aqueous solution (protein solution preparation). However, in the prefilled drug package filled with such a protein solution preparation, there is a problem that the protein aggregates when stored for a long period of time.

[0004] In order to inhibit such protein aggregation, it has been conventional to add nonionic surfactants such as polysorbate 80 and polysorbate 20 to protein solution formulations (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2018-537170 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have focused on the disadvantages of nonionic surfactants such as polysorbate 80 and polysorbate 20, which are presumably caused by degradation products resulting from the decomposition of the nonionic surfactants. When administered to the human body, these surfactants may cause problems such as hypersensitivity and chromosomal abnormalities, and may be carcinogenic. Based on this, the present inventors attempted to reduce the concentration of nonionic surfactants in protein solution formulations when manufacturing prefilled drug packages using the above-mentioned conventional technology. However, according to the inventors' investigations, when the concentration of nonionic surfactants in protein solution formulations was reduced in the above-mentioned conventional prefilled drug packages, protein aggregation could not be suppressed during long-term storage of the prefilled drug packages.

[0007] Therefore, an object of the present invention is to provide a prefilled pharmaceutical package that can suppress protein aggregation after long-term storage, even when it contains a protein solution formulation with a low concentration of nonionic surfactant. Another object of the present invention is to provide a method for producing a prefilled pharmaceutical package that can suppress protein aggregation after long-term storage, even when the package contains a protein solution formulation with a low concentration of nonionic surfactant. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and have found that, by forming at least a portion of the portion of a container of a prefilled drug package containing a protein solution formulation that comes into contact with the protein solution formulation from a specific resin, protein aggregation can be made less likely to occur after long-term storage, even when the concentration of nonionic surfactant in the protein solution formulation is significantly reduced, and have completed the present invention.

[0009] That is, the present invention aims to advantageously solve the above-mentioned problems, and the prefilled drug package of the present invention is a prefilled drug package comprising a protein solution formulation and a container containing the protein solution formulation, wherein the concentration of the nonionic surfactant in the protein solution formulation is 0 mg / mL or more and less than 0.05 mg / mL, and at least a portion of the container that comes into contact with the protein solution formulation is made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin. Thus, even when the concentration of the nonionic surfactant in the protein solution formulation is low, 0 mg / mL or more and less than 0.05 mg / mL, a prefilled drug package having a container in which at least a portion of the portion that comes into contact with the protein solution formulation (hereinafter sometimes referred to as the "formulation contact portion") is made of the above-mentioned resin can suppress aggregation of the protein in the protein solution formulation even when the prefilled drug package is stored for a long period of time.

[0010] In the prefilled drug package of the present invention, the container preferably has a water contact angle of 90° or more at the portion that comes into contact with the protein solution formulation. If the water contact angle of the formulation contact portion is 90° or more, aggregation of proteins in the protein solution formulation can be further suppressed when the prefilled drug package is stored for a long period of time. In the present invention, the "water contact angle" of the preparation contact portion can be measured by the method described in the examples of this specification.

[0011] Furthermore, the prefilled medicine package of the present invention may be configured, for example, to further include a sealing member, and the container may have an opening that is sealed by the sealing member.

[0012] In the prefilled drug package of the present invention, the protein solution formulation can contain at least one of an antibody and an antigen-binding fragment thereof.

[0013] In the prefilled drug package of the present invention, the antibody can be at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody thereof.

[0014] Furthermore, in the prefilled medicine package of the present invention, the protein solution formulation may comprise at least one selected from the group consisting of ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumab, mogamulizumab, rituximab, ranibizumab, infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.

[0015] Here, the prefilled medicine package of the present invention is, for example, a vial, an infusion bag, a prefilled cartridge, an ampoule, a bottle, a pouch, or a blister pack.

[0016] The present invention also aims to advantageously solve the above-mentioned problems. The method for producing a prefilled drug package of the present invention comprises a protein solution formulation and a container containing the protein solution formulation, and includes a step of filling the container with the protein solution formulation, wherein the protein solution formulation has a nonionic surfactant concentration of 0 mg / mL or more and less than 0.05 mg / mL, to obtain the prefilled drug package, wherein at least a portion of the container that comes into contact with the protein solution formulation is made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a linear olefin. Thus, even when the concentration of the nonionic surfactant in the protein solution formulation is low, ie, 0 mg / mL or more and less than 0.05 mg / mL, by filling the protein solution formulation into a container where at least a portion of the portion that comes into contact with the protein solution formulation is made of the above-mentioned resin, a prefilled drug package that can suppress aggregation of the protein in the protein solution formulation can be obtained, even when stored for a long period of time.

[0017] Here, the method for producing a prefilled drug package of the present invention preferably further comprises, prior to the step of obtaining the prefilled drug package, a step of pre-drying the resin and a step of molding the pre-dried resin to obtain the container. If a container obtained by molding the pre-dried resin is used, aggregation of proteins in the protein solution formulation can be further suppressed when the obtained prefilled drug package is stored for a long period of time.

[0018] In the method for producing a prefilled drug package of the present invention, the oxygen concentration in the resin after the pre-drying is preferably 10 ppm by mass or less. If the oxygen concentration in the pre-dried resin is 10 ppm by mass or less, aggregation of the protein in the protein solution formulation can be more sufficiently suppressed when the resulting prefilled drug package is stored for a long period of time. In the present invention, the "oxygen concentration" in the resin can be measured by the method described in the examples of this specification.

[0019] Furthermore, in the method for producing a prefilled drug package of the present invention, the pre-drying is preferably carried out under an inert gas atmosphere, which can more effectively suppress aggregation of the protein in the protein solution formulation when the resulting prefilled drug package is stored for a long period of time.

[0020] Furthermore, in the method for producing a prefilled drug package of the present invention, the drying temperature for the pre-drying is preferably 80° C. or higher and 120° C. or lower. If the resin is pre-dried at a temperature within the above range, aggregation of the protein in the protein solution formulation can be more sufficiently suppressed when the resulting prefilled drug package is stored for a long period of time.

[0021] Here, in the method for producing a prefilled drug package of the present invention, the protein solution formulation may contain at least one of an antibody and an antigen-binding fragment thereof.

[0022] In the method for manufacturing a prefilled drug package of the present invention, the antibody can be at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and domain antibodies thereof.

[0023] Furthermore, in the method for producing a prefilled medicine package of the present invention, the protein solution formulation may contain at least one selected from the group consisting of ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumab, mogamulizumab, rituximab, ranibizumab, infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.

[0024] The method for producing a prefilled medicine package of the present invention is a method for producing, for example, a vial, an infusion bag, a prefilled cartridge, an ampule, a bottle, a pouch, or a blister pack. [Effects of the Invention]

[0025] According to the present invention, a prefilled drug package can be provided that can suppress protein aggregation after long-term storage, even when containing a protein solution formulation with a low concentration of nonionic surfactant. Furthermore, the present invention can provide a method for producing a prefilled pharmaceutical package that can suppress protein aggregation after long-term storage, even when the package contains a protein solution formulation with a low concentration of nonionic surfactant. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a diagram showing a schematic configuration of an example of a vial that is a prefilled medicine package according to the present invention. FIG. [Figure 2] 1 is a diagram showing a schematic configuration of an example of an infusion bag that is a prefilled medicine package according to the present invention. FIG. DETAILED DESCRIPTION OF THE INVENTION

[0027] Hereinafter, embodiments of the present invention will be described in detail. The prefilled drug package of the present invention contains a protein solution formulation in a container. The prefilled drug package of the present invention can be manufactured, for example, using the manufacturing method of the prefilled drug package of the present invention.

[0028] (prefilled medication packaging) The prefilled drug package of the present invention comprises at least a container having an internal space capable of containing a liquid such as a protein solution formulation, and a protein solution formulation contained in the internal space of the container. The prefilled drug package of the present invention may also comprise components other than the container and the protein solution formulation described above. For example, the prefilled drug package of the present invention may comprise a member (sealing member) capable of sealing the internal space of the container. When the container has an opening communicating the internal space with the outside, sealing this opening with the sealing member allows the protein solution formulation to be contained (sealed) in the internal space defined by the sealing member and the container, shielded from the outside air, while allowing the protein solution formulation to be easily removed.

[0029] Here, the prefilled drug package of the present invention is not particularly limited as long as it is a container, package, etc. that can accommodate the protein solution formulation and is filled with the protein solution formulation prior to use, such as administration of the protein solution formulation to the human body. Specific examples of the prefilled drug package of the present invention include vials, infusion bags, prefilled cartridges, ampoules, bottles, pouches, blister packs, and prefilled syringes. In one embodiment of the present invention, the term "prefilled drug package" may exclude "prefilled syringes." In such an embodiment, the term "prefilled drug package" may be written as, for example, "prefilled drug package (excluding prefilled syringes)."

[0030] An example of the structure of the prefilled medicine package of the present invention will be further described below with reference to Figures 1 and 2. Figure 1 uses a vial as an example of a prefilled medicine package, and Figure 2 uses an infusion bag as an example of a prefilled medicine package, and then explains their structures, but the prefilled medicine package of the present invention is not limited to these.

[0031] <Vial> An example of a vial as a prefilled drug package of the present invention is shown in Figure 1. The vial 10 shown in Figure 1 comprises a container 11 as a container, a cap 12 as a sealing member, and a protein solution formulation 13. The container 11 is approximately cylindrical and has an opening at one end of the cylinder (the upper end in Figure 1), which is sealed by the cap 12. The protein solution formulation 13 is contained in an internal space defined by the container 11 and the cap 12. The protein solution formulation 13 can be removed to the outside by, for example, piercing the cap 12 with a syringe needle.

[0032] <Infusion bag> An example of an infusion bag as a prefilled drug package of the present invention is shown in Figure 2. The infusion bag 20 shown in Figure 2 includes a packaging body 21 as a container, a port 22 as a sealing member, and a protein solution preparation 23. The packaging body 21 is generally rectangular in plan view and has an opening on one side of the rectangle (the lower side in Figure 2), which is sealed by the port 22. The packaging body 21 has a hole 24 formed therein, allowing the infusion bag 20 to be hung using a hook or the like. Here, the protein solution preparation 23 is contained in an internal space defined by the package 21 and the port 22. The protein solution preparation 23 can be removed to the outside by, for example, piercing the port 22 with an injection needle.

[0033] The prefilled drug package of the present invention illustrated in Figures 1 and 2 above is characterized in that the concentration of the nonionic surfactant in the protein solution formulation contained in the container is 0 mg / mL or more and less than 0.05 g / mL, and at least a portion of the portion of the container that comes into contact with the protein solution formulation is formed from a resin containing a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a chain olefin.

[0034] The prefilled drug package of the present invention uses the above-mentioned specific resin to form at least a portion of the container, and the surface of the portion formed by the specific resin is in contact with the protein solution formulation. Therefore, even if the concentration of nonionic surfactant in the protein solution formulation is 0 mg / mL or more but less than 0.05 mg / mL, protein aggregation can be suppressed after long-term storage. The reason for this effect is unclear, but it is presumed to be as follows. That is, according to the present inventors, protein aggregation in the prefilled drug package is thought to occur when the protein adsorbs to the inner wall surface of the container of the prefilled drug package and the adsorbed protein aggregates. Here, if the portion of the container of the prefilled drug package that contacts the protein solution formulation is formed from a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a linear olefin, the affinity between the inner wall surface of the container and the protein can be reduced, thereby preventing protein adsorption. It is presumed that suppressing protein adsorption to the inner wall surface in this way can suppress protein aggregation inside the prefilled drug package.

[0035] The protein solution formulation contained in the prefilled drug package of the present invention, as well as the container and optional sealing member provided in the prefilled drug package of the present invention, will be further described below.

[0036] <Protein solution formulation> The protein solution formulation contains at least a protein and water, and the concentration of the nonionic surfactant is equal to or greater than 0 mg / mL and less than 0.05 mg / mL.

[0037] <<Protein>> Proteins contained in the protein solution formulation include, but are not limited to, antibodies (chimeric antibodies, human antibodies, humanized antibodies, and domain antibodies thereof) and antigen-binding fragments thereof.

[0038] More specific examples of proteins include ofatumumab (trade name "Arzera (registered trademark)"), cetuximab (trade name "Erbitux (registered trademark)"), tocilizumab (trade name "Actemra (registered trademark)"), bevacizumab (trade name "Avastin (registered trademark)"), canakinumab (trade name "Ilaris (registered trademark)"), golimumab (trade name "Simponi (registered trademark)"), ustekinumab (trade name "Stelara (registered trademark)"), eculizumab (trade name "Soliris (registered trademark)"), omalizumab (trade name "Xolair (registered trademark)"), trastuzumab (trade name "Herceptin (registered trademark)"), pertuzumab (trade name "Perjeta (registered trademark)"), adalimumab (trade name "Humira (registered trademark)"), and the like. )"), denosumab (trade name "Pralia (registered trademark)", "Ranmark (registered trademark)"), mogamulizumab (trade name "Potelizio (registered trademark)"), rituximab (trade name "Rituxan (registered trademark)"), ranibizumab (trade name "Lucentis (registered trademark)"), infliximab (trade name "Remicade (registered trademark)"), aflibercept (trade name "Eylea (registered trademark)"), abatacept (trade name "Orencia (registered trademark)"), etanercept (trade name "Enbrel (registered trademark)"), gemtuzumab ozogamicin (trade name "Mylotarg (registered trademark)"), panitumumab (trade name "Vectibix (registered trademark)"), basiliximab (trade name "Simulect (registered trademark)"), certolizumab Examples include pegol (trade name Cimzia®) and palivizumab (trade name Synagis®).

[0039] The protein solution formulation may contain one type of protein or two or more types of proteins. That is, the protein solution formulation may contain, for example, both an antibody and an antigen-binding fragment, or may contain two or more types of antibodies, or may contain two or more types of antigen-binding fragments.

[0040] Here, the protein concentration in the protein solution formulation is preferably 0.005 mg / mL or more, more preferably 0.01 mg / mL or more, even more preferably 0.05 mg / mL or more, and preferably 500 mg / mL or less, more preferably 300 mg / mL or less, and even more preferably 200 mg / mL or less. If the protein concentration in the protein solution formulation is 0.005 mg / mL or more, the intended effect of the protein can be sufficiently obtained when the protein solution formulation is administered to the human body, etc., and if it is 500 mg / mL or less, protein aggregation in the protein solution formulation can be sufficiently suppressed when the prefilled drug package is stored for a long period of time.

[0041] <<Nonionic surfactants>> The nonionic surfactant optionally contained in the protein solution formulation is a component that can function as a stabilizer to stabilize the above-mentioned protein. Examples of such nonionic surfactants include, but are not limited to, 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 sorbit 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. The nonionic surfactants may be used singly or in combination of two or more.

[0042] As described above, in the prefilled drug package of the present invention, a protein solution formulation having a nonionic surfactant concentration of 0 mg / mL or more but less than 0.05 mg / mL is used to reduce the risk of hypersensitivity and other reactions. For example, nonionic surfactants having polyoxyethylene chains (such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbit 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) may undergo autoxidation at the polyoxyethylene chain end to produce degradation products during long-term storage. However, as described above, in the present invention, since the concentration of the nonionic surfactant in the protein solution formulation is 0 mg / mL or more but less than 0.05 mg / mL, even if degradation products are produced, the amount produced is minimal, thereby sufficiently reducing the risks of hypersensitivity, chromosomal abnormalities, and carcinogenicity. From the viewpoint of reducing the above-mentioned risks, the concentration of the nonionic surfactant in the protein solution formulation is preferably 0.04 mg / mL or less, more preferably 0.01 mg / mL or less, even more preferably 0.005 mg / mL or less, and particularly preferably 0 mg / mL (below the detection limit).

[0043] <<Other ingredients>> Here, the protein solution formulation may contain components (other components) other than the protein, water, and nonionic surfactant. Other components optionally contained in the protein solution formulation include known components used in the preparation of protein solution formulations. Examples of such known components include stabilizers (excluding the nonionic surfactants described above), diluents, solubilizers, isotonicity agents, excipients, pH adjusters, soothing agents, buffers, sulfur-containing reducing agents, and antioxidants. Other components also 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. The concentration of inorganic salts in the protein solution formulation is preferably 300 mM or less. The concentration of organic salts in the protein solution formulation is preferably 300 mM or less.

[0044] <<Preparation method>> The method for preparing the protein solution formulation is not particularly limited as long as it can provide a protein solution formulation in which at least the protein is dissolved and the concentration of the nonionic surfactant is within a predetermined range. For example, the protein solution formulation can be obtained by dissolving the protein and an optional surfactant in an aqueous buffer such as acetate buffer, phosphate buffer, or citrate buffer. The pH of the resulting protein solution formulation is not particularly limited, but can be set to 3.0 or higher and 8.0 or lower.

[0045] <Containment Unit> The container provided in the prefilled drug package of the present invention is not particularly limited as long as it is a member having a space (internal space) formed therein capable of containing a protein solution formulation, and may be a member having an internal space partitioned only by the container itself. However, as described above, from the viewpoint of facilitating removal of the protein solution formulation, it is preferable that the container has an opening communicating the internal space with the outside, as shown in Figures 1 and 2 above, and that the opening is sealed with a sealing member.

[0046] As described above, at least a portion of the formulation contact portion of the container must be made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin. That is, in the prefilled drug package of the present invention, the above-mentioned molded product of the specified resin (resin molded product) is located on at least the inner wall surface of the container that forms the internal space, and the resin molded product and the protein solution formulation must be in direct contact without any other member (for example, a coating composed of a material other than the specified resin molded product) in between. In order to bring the molded resin product into contact with the protein solution formulation, the container may be entirely or partially made of a molded resin product. For example, the wall forming the internal space of the container may have a structure formed by laminating multiple layers (multilayer structure), with at least the innermost layer being a molded resin product.

[0047] From the viewpoint of further suppressing aggregation of proteins in a protein solution formulation during long-term storage of a prefilled drug package, it is preferable that the entire formulation-contacting portion of the container be made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin.

[0048] The resin used to form the container will be described below. The resin used to form the container may contain components (other components) other than the above-mentioned hydrogenated cyclic olefin ring-opening polymer and the copolymer of cyclic olefin and chain olefin.

[0049] <<Hydrogenated Cyclic Olefin Ring-Opening Polymer>> The hydrogenated cyclic olefin ring-opening polymer is a polymer obtained by subjecting a cyclic olefin ring-opening polymer obtained by ring-opening polymerization of a cyclic olefin monomer to a hydrogenation reaction.

[0050] [Cyclic olefin ring-opening polymer] Here, the cyclic olefin monomer used to prepare the cyclic olefin ring-opening polymer can be a compound having a cyclic structure formed by carbon atoms and having a polymerizable carbon-carbon double bond in the cyclic structure. Specific examples of the cyclic olefin monomer include norbornene-based monomers (monomers containing a norbornene ring) and monocyclic olefin monomers. The "norbornene ring" contained in the norbornene-based monomer may have one or more carbon atoms interposed between the carbon-carbon single bonds constituting the ring structure, and these intervening carbon atoms may further form single bonds to form a new ring structure within the norbornene ring.

[0051] Examples of norbornene-based monomers include: Bicyclic monomers such as bicyclo[2.2.1]hept-2-ene (trivial name: norbornene) and its derivatives (those having a substituent on the ring; the same applies below), 5-ethylidene-bicyclo[2.2.1]hept-2-ene (trivial name: ethylidenenorbornene) and its derivatives; Tricyclo[4.3.0.1 2,5 ] Tricyclic monomers such as deca-3,7-diene (common name: dicyclopentadiene) and its derivatives; 7,8-benzotricyclo[4.3.0.1 2,5 ]dec-3-ene (trivial name: methanotetrahydrofluorene and its derivatives, tetracyclo[7.4.0.0 2,7 .1 10,13 ]trideca-2,4,6,11-tetraene) and its derivatives, tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene (trivial name: tetracyclododecene) and its derivatives (e.g., 8-methyl-tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene, 8-ethyl-tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene), 8-ethylidenetetracyclo[4.4.0.1 2,5 .1 7,10 tetracyclic monomers such as ]-3-dodecene and its derivatives; Examples include:

[0052] Here, examples of the substituents possessed by the above-mentioned derivatives include alkyl groups such as a methyl group and an ethyl group; alkenyl groups such as a vinyl group; alkylidene groups such as an ethylidene group and a propan-2-ylidene group; aryl groups such as a phenyl group; a hydroxy group; an acid anhydride group; a carboxyl group; and alkoxycarbonyl groups such as a methoxycarbonyl group.

[0053] Furthermore, examples of monocyclic olefin monomers include cyclic monoolefins such as cyclobutene, cyclopentene, methylcyclopentene, cyclohexene, methylcyclohexene, cycloheptene, and cyclooctene; and cyclic diolefins such as cyclohexadiene, methylcyclohexadiene, cyclooctadiene, methylcyclooctadiene, and phenylcyclooctadiene.

[0054] The above-mentioned cyclic olefins can be used alone or in combination of two or more. When two or more cyclic olefins are used, the cyclic olefin ring-opening polymer may be a block copolymer or a random copolymer. Among these, norbornene-based monomers are preferred as cyclic olefins, and tricyclo[4.3.0.1 2,5 ]deca-3,7-diene and its derivatives, tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene and its derivatives, 7,8-benzotricyclo[4.3.0.1 2,5 ]dec-3-ene and its derivatives are more preferred, and tricyclo[4.3.0.1 2,5 ]deca-3,7-diene, tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene, 7,8-benzotricyclo[4.3.0.1 2,5 ]Deca-3-ene is more preferred.

[0055] Here, the amount of norbornene-based monomer used in preparing the cyclic olefin ring-opening polymer is not particularly limited, but is preferably 80% by mass or more, more preferably 90% by mass or more, and even more preferably 100% by mass, relative to 100% by mass of the total amount of cyclic olefin used in preparing the cyclic olefin ring-opening polymer (i.e., the cyclic olefin ring-opening polymer is a polymer obtained by using only one or more types of norbornene-based monomers as monomers).

[0056] The method for preparing the cyclic olefin ring-opening polymer is not particularly limited, and for example, a known method of ring-opening polymerizing the above-mentioned cyclic olefin as a monomer using a metathesis polymerization catalyst can be employed. Examples of such a method include the method described in JP 2016-155327 A.

[0057] The weight-average molecular weight (Mw) of the cyclic olefin ring-opening polymer obtained as described above is not particularly limited, but is preferably 10,000 or more, more preferably 15,000 or more, and preferably 100,000 or less, more preferably 50,000 or less. If the weight-average molecular weight of the cyclic olefin ring-opening polymer is 10,000 or more, the strength of the container obtained using a resin containing a hydrogenated cyclic olefin ring-opening polymer can be sufficiently ensured. On the other hand, if the weight-average molecular weight of the cyclic olefin ring-opening polymer is 100,000 or less, the moldability of the resin containing a hydrogenated cyclic olefin ring-opening polymer can be sufficiently ensured. Furthermore, the molecular weight distribution (Mw / Mn) of the cyclic olefin ring-opening polymer is not particularly limited, but is preferably from 1 to 5, more preferably from 1 to 4. When the molecular weight distribution of the cyclic olefin ring-opening polymer is within the above range, a container having sufficient mechanical strength can be obtained. In the present invention, the weight average molecular weight (Mw) and number average molecular weight (Mn) of polymers such as cyclic olefin ring-opening polymers are values ​​calculated in terms of standard polyisoprene by gel permeation chromatography (GPC) using cyclohexane as an eluent.

[0058] [Hydrogenation reaction] The cyclic olefin ring-opening polymer can be subjected to a hydrogenation reaction to obtain a hydrogenated cyclic olefin ring-opening polymer. The method for hydrogenating the cyclic olefin ring-opening polymer is not particularly limited, and for example, a known method of supplying hydrogen to a reaction system in the presence of a hydrogenation catalyst can be used. Examples of such methods include the method described in JP 2016-155327 A. The hydrogenation rate (proportion of hydrogenated main chain carbon-carbon double bonds) in the hydrogenation reaction is not particularly limited, but from the viewpoint of suppressing discoloration and oxidative deterioration when molding the hydrogenated cyclic olefin ring-opening polymer to produce a container, it is preferably 70% or more, more preferably 80% or more, even more preferably 90% or more, and particularly preferably 99% or more. In the present invention, the "hydrogenation rate" in the hydrogenation reaction can be measured by nuclear magnetic resonance (NMR) spectroscopy.

[0059] The weight-average molecular weight (Mw) of the hydrogenated cyclic olefin ring-opening polymer obtained after the hydrogenation reaction is not particularly limited, but is preferably 10,000 or more, more preferably 15,000 or more, and preferably 100,000 or less, more preferably 50,000 or less. If the weight-average molecular weight of the hydrogenated cyclic olefin ring-opening polymer is 10,000 or more, the strength of the container obtained using a resin containing the hydrogenated cyclic olefin ring-opening polymer can be sufficiently ensured. On the other hand, if the weight-average molecular weight of the hydrogenated cyclic olefin ring-opening polymer is 100,000 or less, the moldability of the resin containing the hydrogenated cyclic olefin ring-opening polymer can be sufficiently ensured. Furthermore, the molecular weight distribution (Mw / Mn) of the hydrogenated cyclic olefin ring-opening polymer is not particularly limited, but is preferably from 1 to 5, more preferably from 1 to 4. When the molecular weight distribution of the hydrogenated cyclic olefin ring-opening polymer is within the above range, a container having sufficient mechanical strength can be obtained.

[0060] <<Cyclic olefin and chain olefin copolymer>> A copolymer of a cyclic olefin and a chain olefin (hereinafter sometimes simply referred to as "copolymer") is a polymer obtained by copolymerizing a cyclic olefin monomer and a chain olefin monomer.

[0061] [Cyclic Olefins] The cyclic olefin monomer used to prepare the copolymer can be the same as those mentioned above in the section "Hydrogenated Cyclic Olefin Ring-Opening Polymer." The cyclic olefin can be used alone or in combination of two or more. Among these, bicyclo[2.2.1]hept-2-ene (common name: norbornene) and its derivatives, tetracyclo[4.4.0 ... 2,5 .1 7,10 ]dodec-3-ene (trivial name: tetracyclododecene) and its derivatives are preferred, and bicyclo[2.2.1]hept-2-ene is more preferred.

[0062] [Chain olefin] The chain olefin monomer used to prepare the copolymer may be a compound having a chain structure formed of carbon atoms and having a polymerizable carbon-carbon double bond in the chain structure. In the present invention, compounds that fall under the category of cyclic olefins are not included in the chain olefins.

[0063] Examples of the chain olefin include α-olefins such as ethylene, propylene, 1-butene, 1-pentene, and 1-hexene; aromatic vinyl compounds such as styrene and α-methylstyrene; and non-conjugated dienes such as 1,4-hexadiene, 4-methyl-1,4-hexadiene, 5-methyl-1,4-hexadiene, and 1,7-octadiene.

[0064] The chain olefins may be used alone or in combination of two or more. Among these, the chain olefins are preferably α-olefins, more preferably α-olefins having 1 to 20 carbon atoms, and even more preferably ethylene.

[0065] [Copolymerization] The method for preparing the copolymer is not particularly limited, and for example, a known method of addition polymerization of the above-mentioned cyclic olefin and chain olefin using a polymerization catalyst can be used. Examples of such a method include the method described in JP 2016-155327 A. Here, the ratio of the amount of the cyclic olefin to the amount of the chain olefin used in preparing the copolymer is not particularly limited, but the amount of the cyclic olefin is preferably 30% by mass or more, more preferably 50% by mass or more, and even more preferably 70% by mass or more, and is preferably 99% by mass or less, more preferably 97% by mass or less, and even more preferably 95% by mass or less, relative to 100% by mass of the total amount of the cyclic olefin and the chain olefin used in preparing the copolymer. The copolymer of a cyclic olefin and a chain olefin may be a block copolymer or a random copolymer.

[0066] The weight-average molecular weight (Mw) of the copolymer of cyclic olefin and chain olefin is not particularly limited, but is preferably 20,000 or more, more preferably 25,000 or more, and preferably 100,000 or less. If the weight-average molecular weight of the copolymer is 20,000 or more, the strength of the container obtained using a resin containing the copolymer can be sufficiently ensured. On the other hand, if the weight-average molecular weight of the copolymer is 100,000 or less, the moldability of the resin containing the copolymer can be sufficiently ensured. Furthermore, the molecular weight distribution (Mw / Mn) of the copolymer is not particularly limited, but is preferably from 1 to 5, more preferably from 1 to 4. When the molecular weight distribution of the copolymer is within the above range, a container having sufficient mechanical strength can be obtained.

[0067] <<Suitable polymers>> As described above, the resin used to form the container may contain at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin, but the resin preferably contains at least a hydrogenated cyclic olefin ring-opening polymer. If a container obtained using a resin containing at least a hydrogenated cyclic olefin ring-opening polymer is used, aggregation of proteins in a protein solution formulation can be sufficiently suppressed when the prefilled drug package is stored for a long period of time.

[0068] <<Other ingredients>> Other components that may be optionally contained in the resin used to form the container include polymer components other than the above-mentioned polymers (such as thermoplastic elastomers) and known additives. Examples of known additives include antioxidants, ultraviolet absorbers, light stabilizers, near-infrared absorbers, plasticizers, antistatic agents, and acid scavengers, as described in JP 2016-155327 A. These may be used alone or in combination of two or more. The content of these other components in the resin can be determined appropriately depending on the purpose of adding the component. For example, when a thermoplastic elastomer is used, the content thereof is preferably 0.01 to 0.5 parts by mass, based on 100 parts by mass of the total amount of the hydrogenated cyclic olefin ring-opening polymer and the copolymer of cyclic olefin and chain olefin (when each is used alone, the amount of either one is 100 parts by mass). Furthermore, from the viewpoint of further suppressing aggregation of proteins in the protein solution formulation, it is preferable to use at least one of an antioxidant and a light stabilizer as the additive. Preferred examples of the antioxidant include phenolic antioxidants such as pentaerythritol tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]; and phosphorus-based antioxidants such as 6-[3-(3-t-butyl-4-hydroxy-5-methylphenyl)propoxy]-2,4,8,10-tetrakis-t-butyldibenzo[d,f][1.3.2]dioxaphosphepin and 3,9-bis(2,6-di-tert-butyl-4-methylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane. Preferred examples of the light stabilizer include hindered amine light stabilizers such as dibutylamine, 2,4,6-trichloro-1,3,5-triazine, N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl-1,6-hexamethylenediamine, and polycondensates of N-(2,2,6,6-tetramethyl-4-piperidyl)butylamine. The antioxidants and light stabilizers may be used alone or in combination of two or more kinds. Also, an antioxidant and a light stabilizer may be used in combination. From the viewpoint of further suppressing aggregation of proteins in protein solution formulations, the content of the antioxidant in the resin is preferably 0.01 parts by mass or more and 0.2 parts by mass or less, relative to 100 parts by mass of the total amount of the hydrogenated cyclic olefin ring-opening polymer and the copolymer of cyclic olefin and chain olefin (when each is used alone, the amount of either is 100 parts by mass). Furthermore, the content of the light stabilizer in the resin is preferably 0.02 parts by mass or more and 0.5 parts by mass or less, based on 100 parts by mass of the total amount of the hydrogenated cyclic olefin ring-opening polymer and the copolymer of cyclic olefin and chain olefin (when each is used alone, the amount of either is 100 parts by mass), from the viewpoint of further suppressing aggregation of proteins in protein solution formulations. The mixing method for obtaining a resin containing the above-mentioned polymer and, optionally, other components is not particularly limited, and can be carried out using, for example, a known melt kneader such as a single-screw extruder, a twin-screw extruder, a Banbury mixer, a kneader, or a feeder ruder. After mixing, the mixture can be extruded into a rod shape in the usual way and cut to an appropriate length with a strand cutter to form pellets.

[0069] <<How to make the container>> The method for molding a resin containing the above-mentioned components to obtain a container in which at least a portion of the inner wall surface is made of a resin molding is not particularly limited, and for example, the method described in the section below titled "Method for manufacturing a prefilled drug package" can be adopted.

[0070] <<Water contact angle>> In the container obtained as described above, the water contact angle of the formulation contact portion is preferably 90° or more, more preferably 91° or more, from the viewpoint of further suppressing aggregation of proteins in the protein solution formulation. The water contact angle of the formulation contact portion is not particularly limited, but can be, for example, 110° or less, 100° or less, or 94° or less. The water contact angle of the formulation-contacting portion can be adjusted by changing the types of polymers and additives contained in the resin used to form the container or the manufacturing method of the container. For example, the water contact angle of the formulation-contacting portion can be improved by using hydrophobic polymers or additives (those without hydrophilic groups, etc.). Furthermore, the water contact angle of the formulation-contacting portion can be improved by, for example, performing pre-drying as described in the section "Manufacturing Method of Prefilled Drug Packages" below prior to molding the resin.

[0071] <Sealing member> The prefilled drug package of the present invention may optionally include a sealing member. The sealing member is not particularly limited as long as it can seal the opening of the container and prevent leakage of the protein solution formulation contained in the internal space when the container has an opening, and known sealing members such as caps and ports can be used. The material of the sealing member is not particularly limited and may be, for example, a known resin material such as rubber. From the viewpoint of further suppressing aggregation of proteins in the protein solution formulation, the sealing member may be made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin.

[0072] (Manufacturing method for prefilled medicine packages) The above-described prefilled medicine package of the present invention can be suitably manufactured, for example, by the manufacturing method of the prefilled medicine package of the present invention. The method for producing a prefilled drug package of the present invention is a method for producing a prefilled drug package comprising a protein solution formulation and a container containing the protein solution formulation. Here, the method for producing a prefilled drug package of the present invention includes at least a step (filling step) of filling a container with a protein solution formulation having a nonionic surfactant concentration of 0 mg / mL or more and less than 0.05 mg / mL to obtain a prefilled drug package containing the protein solution formulation. Here, at least a portion of the container that comes into contact with the formulation is formed using a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a linear olefin. A prefilled drug package obtained by filling a protein solution formulation having a nonionic surfactant concentration of 0 mg / mL or more and less than 0.05 mg / mL using the above-mentioned filling process can suppress aggregation of proteins in the protein solution formulation even when stored for a long period of time, for the same reasons as those described above in the section on "Prefilled drug packages."

[0073] In the following description, the terms "container," "hydrogenated cyclic olefin ring-opening polymer," "copolymer of cyclic olefin and chain olefin," "resin," "sealing member," and "protein solution preparation" are the same as those described above in the "prefilled drug package" section. Specifically, specific examples and preferred examples of the "container," "hydrogenated cyclic olefin ring-opening polymer," "copolymer of cyclic olefin and chain olefin," "resin," "sealing member," and "protein solution preparation" in the manufacturing method for the prefilled drug package of the present invention are the same as the specific examples and preferred examples of the "container," "hydrogenated cyclic olefin ring-opening polymer," "copolymer of cyclic olefin and chain olefin," "resin," "sealing member," and "protein solution preparation" in the prefilled drug package of the present invention described above, and therefore will not be described in this section.

[0074] <Filling process> The method for filling the internal space of the container with the protein solution formulation is not particularly limited, and any known method can be used. For example, if the container has an opening, the protein solution formulation can be injected through the opening and the opening can be sealed with a sealing member. Furthermore, the filling step is preferably performed under sterilization.

[0075] <Other processes> The method for producing the prefilled drug package of the present invention may optionally include steps other than the filling step described above (other steps). Here, in the manufacturing method of the prefilled medicine package of the present invention, it is preferable to include a step of pre-drying the resin, which is the molding material, (pre-drying step) prior to the above-mentioned filling step, and a step of molding the pre-dried resin to form a container (molding step).

[0076] <<Pre-drying process>> By drying the resin used to form the container prior to molding, the water contact angle of the container surface (particularly the surface of the formulation contact portion) can be maintained, and aggregation of the protein in the protein solution formulation can be sufficiently suppressed. Note that the reason why drying the resin before molding allows the water contact angle of the container surface obtained after molding to be maintained is not clear, but it is presumed that this is because drying can reduce the oxygen concentration in the resin, thereby suppressing oxidation of the container surface due to heat during molding and making it hydrophilic. The shape of the resin during pre-drying is not particularly limited, and can be any shape such as a sheet or pellet. From the viewpoints of drying efficiency and ease of molding, however, a pellet shape is preferred.

[0077] Here, the oxygen concentration in the resin after pre-drying is preferably 10 mass ppm or less, more preferably 5 mass ppm or less, even more preferably 4 mass ppm or less, and particularly preferably 1.5 mass ppm or less. If the oxygen concentration in the resin after pre-drying is 10 mass ppm or less, the value of the water contact angle of the formulation contact portion of the container formed using the resin can be maintained, and aggregation of the protein in the protein solution formulation can be further suppressed in a pre-filled drug package including the container.

[0078] Furthermore, pre-drying is preferably performed under an inert gas atmosphere. By performing pre-drying under an inert gas atmosphere, oxygen can be efficiently removed from the resin while preventing oxidation of the resin due to external oxygen, and as a result, aggregation of the protein in the protein solution formulation can be further suppressed in a pre-filled drug package equipped with the resulting container. Note that the inert gas can be helium, argon, nitrogen, neon, krypton, or a mixture thereof.

[0079] In the pre-drying, the drying temperature (ambient temperature) is preferably 80°C or higher, more preferably 90°C or higher, even more preferably 100°C or higher, and preferably 120°C or lower, more preferably 110°C or lower. If the drying temperature in the pre-drying is 80°C or higher, oxygen in the resin can be efficiently removed, and as a result, aggregation of the protein in the protein solution formulation can be further suppressed in a pre-filled pharmaceutical package equipped with the resulting container. On the other hand, if the drying temperature in the pre-drying is 120°C or lower, hardening of the resin prior to molding can be prevented.

[0080] Furthermore, the drying time in the pre-drying is preferably 1 hour or more, more preferably 2 hours or more, even more preferably 4 hours or more, and preferably 24 hours or less, more preferably 12 hours or less. If the drying time in the pre-drying is 1 hour or more, oxygen in the resin can be efficiently removed, and as a result, aggregation of the protein in the protein solution formulation can be further suppressed in a pre-filled pharmaceutical package including the obtained container. On the other hand, if the drying time in the pre-drying is 24 hours or less, oxidation degradation of the resin prior to molding can be prevented.

[0081] <<Forming process>> The method for molding the resin after the pre-drying is not particularly limited, and can be appropriately selected from known molding methods depending on the type of pre-filled medicine package and the desired shape of the container. Such known molding methods include, for example, extrusion molding, injection molding, inflation molding, blow molding, extrusion blow molding, injection blow molding, press molding, vacuum molding, powder slush molding, calendar molding, foam molding, thermoforming, etc. The molding conditions for such known molding methods can be appropriately set. Furthermore, if the wall forming the internal space of the container has a multilayer structure, a container having an internal space can be obtained, for example, by producing a multilayer film having the multilayer structure and then bonding the edges of a pair of multilayer films.

[0082] In addition, the manufacturing method of the prefilled drug package of the present invention may include, in addition to the above-mentioned preliminary drying process and molding process, other processes, for example, a process of sterilizing the container and / or sealing member before the filling process. [Example]

[0083] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In the following description, "%" and "parts" representing amounts are based on mass unless otherwise specified. In the examples and comparative examples, the molecular weight of the polymer (weight average molecular weight, number average molecular weight, and molecular weight distribution), the hydrogenation rate when the polymer was hydrogenated, the glass transition temperature of the polymer, the oxygen concentration in the resin, the water contact angle of the formulation contact portion of the container, the concentration of the nonionic surfactant in the protein solution formulation after long-term storage of the prefilled drug package (concentration after storage), whether or not decomposition products of the nonionic surfactant were generated in the protein solution formulation after long-term storage of the prefilled drug package, and the inhibition of protein aggregation in the protein solution formulation after long-term storage of the prefilled drug package were measured and evaluated using the following methods.

[0084] <Molecular weight etc.> The weight-average molecular weight (Mw) and number-average molecular weight (Mn) of the polymer were measured as values ​​converted to standard polyisoprene by gel permeation chromatography (GPC) using cyclohexane as a solvent. The molecular weight distribution (Mw / Mn) was calculated from the obtained Mw and Mn. The measurement device used was an "HLC8320GPC" (manufactured by Tosoh Corporation). The standard polyisoprenes used were 10 standard polyisoprenes (monodisperse) manufactured by Tosoh Corporation with Mw = 602, 1390, 3920, 8050, 13800, 22700, 58800, 71300, 109000, and 280000. The measurements were performed using three columns connected in series: "TSKgel G5000HXL," "TSKgel G4000HXL," and "TSKgel G2000HXL" (all manufactured by Tosoh Corporation), at a flow rate of 1.0 ml / min, a sample injection volume of 100 μml, and a column temperature of 40°C. <Hydrogenation rate> Using deuterated chloroform as the solvent, 1 H-NMR measurement was carried out, and the hydrogenation rate in the hydrogenation reaction was calculated. <Glass transition temperature (Tg)> Measurement was carried out in accordance with JIS K 6911 using a differential scanning calorimeter (manufactured by Nanotechnology Co., Ltd., product name "DSC6220S11"). <Oxygen concentration in resin> The resin pellets were heated at 130°C for 60 minutes using a thermal desorption analyzer (manufactured by Denshi Kagaku Co., Ltd., product name "WA1000S / W type"), and the amount of oxygen released during this heating was measured to calculate the oxygen concentration in the resin. <Water contact angle> The container or multilayer film was cut with nippers to extract the formulation contact portion, and the static contact angle was measured at any 10 points on the formulation contact portion using a Kyowa Contact Angle Meter (manufactured by Kyowa Interface Science Co., Ltd., product name "Drop Master 300") by the curve fitting method, and the average value of these was used as the water contact angle of the formulation contact portion. <Concentration of nonionic surfactant after storage> The prefilled drug package was left standing for 1 week in a dark place at 4° C. After being left standing for 1 week, the protein solution formulation in the prefilled drug package was collected. The concentration of the nonionic surfactant in the protein solution formulation after long-term storage (concentration after storage) was calculated using the following formula. Concentration after storage (mg / mL) = Concentration of nonionic surfactant before long-term storage (mg / mL, initial concentration) × (A1 / A0) In the above formula, A0 and A1 are the area intensities of the peaks attributable to the nonionic surfactant obtained from the data obtained by analyzing the protein solution formulation by high performance liquid chromatography (HPLC) before and after long-term storage, respectively. The HPLC conditions are as follows: Equipment: Product name "HP-1100" (Agilent Technologies) Column: Product name "ZORBAX (registered trademark) Eclipse Plus C18HT" (2.1 mm id x 150 mm, 1.8 μm, manufactured by Agilent Technologies) Solvent: acetonitrile / water = 70 / 30 Injection volume: 16μL Flow rate: 0.4mL / min Detection method: UV 198 nm <Whether or not decomposition products of nonionic surfactants are produced> The prefilled drug package was left standing for 1 week in a dark place at 4° C. After being left standing for 1 week, the protein solution formulation in the prefilled drug package was collected. Then, the protein solution formulation after long-term storage was analyzed by HPLC under the same conditions as for "post-storage concentration of nonionic surfactant" to confirm the presence or absence of a peak attributable to a degradation product. If this peak was confirmed, it was determined that degradation products had been generated after storage "yes," and if this peak was not confirmed, it was determined that degradation products had not been generated after storage (the amount generated was below the detection limit). <Prevention of protein aggregation> The prefilled drug packages were left standing in the dark at 4°C for one week. The protein solution formulations in the prefilled drug packages were then recovered. The number of aggregates with particle diameters of 1 μm or greater contained in the recovered protein solution formulations was visually counted using a FlowCam8100 (Fluid Imaging Technologies, Scarborough, ME). The sample volume was 0.15 mL, and analysis was performed at a flow rate of 0.05 mL / min. Visual Spreadsheet software (Fluid Imaging Technologies) was used for data analysis. This procedure was repeated four times. The number of aggregates per unit volume (particles / mL) was calculated for each run, and the average value was used as the post-storage aggregate concentration (particles / mL). The smaller the post-storage aggregate concentration, the more suppressed protein aggregation in the protein solution formulations was during long-term storage of the prefilled drug packages.

[0085] (Example 1-1) <Preparation of protein solution formulation> Purified Humira (adalimumab) was adjusted to a concentration of 0.1 mg / mL using phosphate buffered saline (pH: 7.0, NaCl: 200 mM, phosphate: 100 mM) to obtain a protein solution formulation. <Containment Creation> <<Preparation of Hydrogenated Cyclic Olefin Ring-Opening Polymer (Hydrogenated Product A)>> Under a nitrogen atmosphere, 500 parts of dehydrated cyclohexane, 0.82 parts of 1-hexene, 0.15 parts of dibutyl ether, and 0.30 parts of triisobutylaluminum were placed in a reactor at room temperature and mixed. The mixture was then heated to 45°C and added to the reactor in the presence of tricyclo[4.3.0.1 2,5 ]deca-3,7-diene (trivial name: dicyclopentadiene, hereinafter abbreviated as "DCP") 76 parts, tetracyclo[4.4.0.1 2,5 .1 7,10 ]dodec-3-ene (hereinafter abbreviated as "TCD"), 70 parts, and tetracyclo[7.4.0.0 2,7 .1 10,1354 parts of trideca-2,4,6,11-tetraene (hereinafter abbreviated as "MTF") and 80 parts of tungsten hexachloride (0.7% toluene solution) were added in parallel over a period of 2 hours to polymerize the mixture. Next, 1.06 parts of butyl glycidyl ether and 0.52 parts of isopropyl alcohol were added to the polymerization solution to inactivate the polymerization catalyst and terminate the polymerization reaction. Gas chromatography analysis of the reaction solution containing the resulting ring-opened polymer revealed that the polymerization conversion of each monomer was 99.5%. Next, 270 parts of cyclohexane was added to 100 parts of the reaction solution containing the obtained ring-opened polymer, and further, a nickel catalyst supported on diatomaceous earth (nickel support rate: 58 wt %, pore volume: 0.25 ml / g, specific surface area: 180 m) was added as a hydrogenation catalyst. 2 The mixture was pressurized to 5 MPa with hydrogen and heated to 200°C with stirring, followed by an 8-hour reaction, yielding a reaction solution containing a hydrogenated DCP / TCD / MTF ring-opening copolymer. The hydrogenation catalyst was removed by filtration, and the solution was then heated to 270°C and a pressure of 1 kPa or less using a cylindrical concentrating dryer (Hitachi). The cyclohexane solvent and other volatile components were then removed from the solution. The molten hydrogenated product was then extruded in a strand-like fashion from an extruder, cooled, and pelletized to yield pellets. The pelletized hydrogenated cyclic olefin ring-opening polymer (hydrogenated product A) had an Mw of 34,000, a molecular weight distribution (Mw / Mn) of 2.3, a hydrogenation rate of 99.7%, and a Tg of 137°C. <<Preparation of resin pellets containing hydride A>> 100 parts of the hydrogenated product A obtained as described above and 0.024 parts of pentaerythritol tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate] (hereinafter abbreviated as "antioxidant X") as an antioxidant were mixed in a blender, and the mixture was kneaded and extruded at a cylinder temperature of 285°C using a twin-screw kneader whose pump was substituted with nitrogen, to obtain resin pellets. <<Pre-drying and molding>> The resin pellets obtained as described above were dried (pre-dried) using a hot air dryer under a nitrogen atmosphere at an atmospheric temperature of 100°C for 6 hours. The oxygen concentration of the resin after pre-drying was measured. The results are shown in Table 1. The pre-dried resin was then injection-molded using an injection molding machine (manufactured by Fanuc Corporation, product name "FANUC ROBOSHOT (registered trademark) α100B") at a resin temperature of 290°C and a mold temperature of 100°C to produce a preform with a total length of 34.5 mm, a maximum outer diameter of 11.0 mm, and a wall thickness of 3.0 mm. This preform was stretched 1.1 times vertically and 2.0 times horizontally using a blow molding machine (manufactured by Frontier Corporation, product name "FMB-1") under conditions of a preform heating temperature of 185°C, a blow time of 1.10 seconds, and a mold temperature of 137°C to produce a roughly cylindrical container with an opening. The water contact angle of the portion of the resulting container that came into contact with the formulation was measured. The results are shown in Table 1. <Prefilled drug package (vial) production> Using the above-described container and protein solution formulation, a prefilled drug package having the configuration shown in Figure 1 was produced in the following procedure. The prefilled drug package was produced in a sterile environment. 10.0 mL of the protein solution formulation was filled into the internal space of the container through the opening. The opening of the container was then sealed with a rubber stopper (made by laminating a PTFE film) as a sealing member to obtain a prefilled drug package filled with the protein solution formulation. Using the obtained prefilled drug package, the post-storage concentration of the nonionic surfactant, the presence or absence of generation of degradation products of the nonionic surfactant, and the inhibition of protein aggregation were evaluated. The results are shown in Table 1.

[0086] (Example 1-2) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that 0.04 parts of 6-[3-(3-t-butyl-4-hydroxy-5-methylphenyl)propoxy]-2,4,8,10-tetrakis-t-butyldibenzo[d,f][1.3.2]dioxaphosphepine (hereinafter referred to as "antioxidant Y") was used instead of antioxidant X, and various evaluations were carried out. The results are shown in Table 1.

[0087] (Examples 1-3) A prefilled drug package was prepared in the same manner as in Example 1-1, except that, in place of antioxidant X, 0.15 parts of a polycondensate of dibutylamine, 2,4,6-trichloro-1,3,5-triazine, N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl-1,6-hexamethylenediamine, and N-(2,2,6,6-tetramethyl-4-piperidyl)butylamine (hereinafter abbreviated as "light stabilizer Z") was used, and various evaluations were performed. The results are shown in Table 1.

[0088] (Examples 1-4) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that 0.04 parts of antioxidant Y and 0.15 parts of light stabilizer Z were used instead of antioxidant X, and various evaluations were carried out. The results are shown in Table 1.

[0089] (Examples 1-5) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that 0.2 parts of 3,9-bis(2,6-di-tert-butyl-4-methylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane (hereinafter referred to as "antioxidant W") was used instead of antioxidant X, and various evaluations were performed. The results are shown in Table 1.

[0090] (Examples 1 to 6) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that 0.5 parts of antioxidant W was used instead of antioxidant X, and various evaluations were carried out. The results are shown in Table 1.

[0091] (Examples 1-7) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that 0.05 parts of antioxidant W and 0.15 parts of light stabilizer Z were used instead of antioxidant X, and various evaluations were performed. The results are shown in Table 1.

[0092] (Examples 1-8) A prefilled drug package was prepared in the same manner as in Example 1-1, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.04 mg / mL, and various evaluations were carried out. The results are shown in Table 1.

[0093] Examples 1-9 In the preparation of the container, a prefilled medicine package was prepared in the same manner as in Example 1-1, except that the copolymer of cyclic olefin and chain olefin prepared as follows (copolymer B) was used instead of the hydrogenated product of the cyclic olefin ring-opening polymer (hydrogenated product A). The results are shown in Table 1. <<Preparation of copolymer of cyclic olefin and chain olefin (copolymer B)>> Norbornene (120 kg) was added to a reaction vessel charged with 258 L of cyclohexane under a nitrogen stream at room temperature, and the mixture was stirred for 5 minutes. Furthermore, triisobutylaluminum was added so that the concentration in the system became 1.0 ml / L. Subsequently, ethylene was passed through the system at normal pressure while stirring to create an ethylene atmosphere. The internal temperature of the autoclave was kept at 70°C, and the internal pressure was increased to 6 kg / cm (gauge pressure) with ethylene. 2The system was pressurized to a pressure of 0.4 L. After stirring for 10 minutes, 0.4 L of a toluene solution containing isopropylidene(cyclopentadienyl)(indenyl)zirconium dichloride and methylalumoxane, which had been prepared in advance, was added to the system to initiate the copolymerization reaction of ethylene and norbornene. The catalyst concentrations at this time were 0.018 mmol / L of isopropylidene(cyclopentadienyl)(indenyl)zirconium dichloride and 8.0 mmol / L of methylalumoxane relative to the total system. During this copolymerization reaction, ethylene was continuously supplied into the system, maintaining the temperature at 70°C and the internal pressure at 6 kg / cm (gauge pressure). 2 After 60 minutes, the copolymerization reaction was stopped by adding isopropyl alcohol. After depressurization, the polymer solution was taken out, and then 1 ml of water was added. 3 The resulting mixture was contacted with an aqueous solution of 5 liters of concentrated hydrochloric acid in a ratio of 1:1 under strong stirring, and the catalyst residue was transferred to the aqueous phase. After allowing the contact mixture to stand, the aqueous phase was separated and removed, and the mixture was further washed with water twice to purify and separate the polymerized liquid phase. The purified and separated polymerized liquid phase was then contacted with three times the amount of acetone under strong stirring to precipitate the copolymer, and the solid portion (copolymer) was collected by filtration and thoroughly washed with acetone. Furthermore, to extract the unreacted monomer, this solid portion was filtered with 40 kg / m 3 The mixture was poured into acetone so that the temperature became 0.5°C, and then extracted for 2 hours at 60°C. After the extraction, the solid portion was collected by filtration and dried for 12 hours at 130°C and 350 mmHg under a nitrogen flow to obtain ethylene-norbornene copolymer (copolymer B). Ethylene-norbornene copolymer (copolymer B) was pelletized in the same manner as for hydrogenated product A in Production Example 1. The pelletized ethylene-norbornene copolymer (copolymer B) had a weight-average molecular weight (Mw) of 96,000, a molecular weight distribution (Mw / Mn) of 2.4, and a Tg of 138°C.

[0094] Examples 1-10 Prefilled drug packages were prepared in the same manner as in Examples 1-9, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.04 mg / mL, and various evaluations were carried out. The results are shown in Table 1.

[0095] (Examples 1-11) A prefilled medicine package was prepared in the same manner as in Example 1-1, except that pre-drying was not performed when preparing the container, and various evaluations were carried out. The results are shown in Table 1.

[0096] (Examples 1-12) Prefilled medicine packages were prepared in the same manner as in Examples 1-8, except that pre-drying was not performed when preparing the container, and various evaluations were carried out. The results are shown in Table 1.

[0097] (Examples 1-13) <Preparation of protein solution formulation> A protein solution preparation was obtained in the same manner as in Example 1-1. <Production of container (package)> <<Preparation of hydride A and resin pellets containing hydride A>> In the same manner as in Example 1-1, a hydrogenated cyclic olefin ring-opening polymer (hydrogenated product A) and resin pellets containing the hydrogenated product A were obtained. <<Pre-drying>> The resin pellets obtained as described above were dried (pre-dried) using a hot air dryer under a nitrogen atmosphere at an atmospheric temperature of 100°C for 6 hours. The oxygen concentration of the resin after pre-drying was measured. The results are shown in Table 1. <<Molding>> Low-density polyethylene (manufactured by Japan Polyethylene Corporation, product name "Novatec (registered trademark) LD LF640MA"), modified polyolefin adhesive resin (manufactured by Mitsubishi Chemical, product name "MC719"), and the pre-dried resin pellets (hydride A) obtained as described above were used as molding materials. A film melt extrusion molding machine was used to mold a multilayer film consisting of a layer of low-density polyethylene (thickness: 105 μm), a layer of modified polyolefin adhesive resin (thickness: 15 μm), and a layer of resin containing hydride A (thickness: 30 μm) laminated in this order. Using this multilayer film, the water contact angle of the formulation-contacting portion (the surface on the side of the layer of resin containing hydride A) was measured. The results are shown in Table 1. Separately, a sealing member was prepared, which included a roughly cylindrical plug and a roughly cylindrical outer cylinder member (outer diameter: 5 mm, inner diameter: 3 mm, length: 10 mm) fitted onto the plug. The liquid-contacting surface of the plug included in this sealing member was laminated with an ETFE (tetrafluoroethylene-ethylene copolymer) film. Two roughly rectangular multilayer film pieces were cut from the above-mentioned multilayer film. These multilayer film pieces were overlapped with the outer cylindrical member of the above-mentioned sealing member sandwiched between them so that the layers made of the resin containing hydrogenated A faced each other, and the peripheral edges were heat-sealed to obtain a package (width: 115 mm, length: 170 mm). The welding width was 5 mm on both side edges and 3 mm at the narrowest point, and the heat-sealing was performed for 4 seconds. A hanging hole was also provided on the package at a position opposite the sealing member in the longitudinal direction. <Prefilled drug package (infusion bag) production> Using the above-described container and protein solution formulation, a prefilled drug package having the configuration shown in Figure 2 was produced in the following procedure. The prefilled drug package was produced in a sterile environment. 100 mL of protein solution formulation was filled into the internal space of the container through the internal passage of the outer cylindrical member of the sealing member. The above-mentioned stopper was then inserted into the internal passage of the outer cylindrical member (i.e., the opening of the container was sealed with the sealing member) to obtain a prefilled drug package filled with the protein solution formulation. Using the obtained prefilled drug package, the post-storage concentration of the nonionic surfactant, the presence or absence of decomposition products of the nonionic surfactant, and the inhibition of protein aggregation were evaluated. The results are shown in Table 1.

[0098] (Examples 1-14) Prefilled drug packages were prepared in the same manner as in Examples 1-13, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.04 mg / mL, and various evaluations were carried out. The results are shown in Table 1.

[0099] (Examples 1-15) Prefilled medicine packages were prepared in the same manner as in Example 1-13, except that pre-drying was not performed when preparing the container, and various evaluations were carried out. The results are shown in Table 1.

[0100] Example 2-1 Prefilled drug packages were prepared in the same manner as in Example 1-1, except that the protein solution formulation prepared as follows was used, and various evaluations were carried out. The results are shown in Table 2. <Preparation of protein solution formulation> Purified Orencia (abatacept) was adjusted to a concentration of 0.1 mg / mL using phosphate buffered saline (pH: 7.2, NaCl: 200 mM, phosphate: 10 mM) to obtain a protein solution formulation.

[0101] (Examples 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-9, 2-11, 2-13, and 2-15) Prefilled drug packages were prepared in the same manner as in Examples 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-9, 1-11, 1-13, and 1-15, respectively, except that the protein solution formulation prepared in the same manner as in Example 2-1 was used, and various evaluations were performed. The results are shown in Table 2.

[0102] (Examples 2-8, 2-10, 2-12, and 2-14) A protein solution formulation was prepared in the same manner as in Example 2-1, except that polysorbate 80 was added as a nonionic surfactant to a concentration of 0.04 mg / mL. Then, prefilled drug packages were prepared in the same manner as in Examples 1-8, 1-10, 1-12, and 1-14, respectively, except that this protein solution formulation was used, and various evaluations were performed. The results are shown in Table 2.

[0103] (Comparative Example 1-1) A prefilled drug package was prepared in the same manner as in Example 1-1, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.5 mg / mL, and various evaluations were carried out. The results are shown in Table 3.

[0104] (Comparative Example 1-2) Prefilled medicine packages were prepared in the same manner as in Example 1-1, except that the container prepared as follows was used, and various evaluations were carried out. The results are shown in Table 3. <Preparation of container (vial)> The surface of the container (unprocessed container) obtained in the same manner as in Example 1-1 was coated with a silicon oxide thin film (surface coating) by a PECVD process using a plasma CVD apparatus (manufactured by Simco, product name "PD-2201LC") Note that the PECVD process was carried out by supplying a gas containing a linear siloxane precursor, optionally oxygen, and optionally an inert gas diluent while maintaining the unprocessed container in a partial vacuum uninterrupted in a vacuum cassette chamber.

[0105] (Comparative Examples 1-3, 1-4, and 1-5) Prefilled medicine packages were prepared in the same manner as in Example 1-1, Example 1-8, and Comparative Example 1-1, except that glass vials were used as containers, and various evaluations were carried out. The results are shown in Table 3.

[0106] (Comparative Examples 1-6) Prefilled drug packages were prepared in the same manner as in Examples 1-13, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.5 mg / mL, and various evaluations were carried out. The results are shown in Table 3.

[0107] (Comparative Example 2-1) Prefilled drug packages were prepared in the same manner as in Example 2-1, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.5 mg / mL, and various evaluations were carried out. The results are shown in Table 4.

[0108] (Comparative Example 2-2) A prefilled medicine package was prepared in the same manner as in Example 2-1, except that a container prepared in the same manner as in Comparative Example 1-2 was used, and various evaluations were carried out. The results are shown in Table 4.

[0109] (Comparative Examples 2-3, 2-4, and 2-5) Prefilled medicine packages were prepared in the same manner as in Example 2-1, Example 2-8, and Comparative Example 2-1, except that glass vials were used as containers, and various evaluations were carried out. The results are shown in Table 4.

[0110] (Comparative Example 2-6) Prefilled drug packages were prepared in the same manner as in Example 2-13, except that polysorbate 80 was added as a nonionic surfactant to the protein solution formulation at a concentration of 0.5 mg / mL, and various evaluations were performed. The results are shown in Table 4.

[0111] [Table 1]

[0112] [Table 2]

[0113] [Table 3]

[0114] [Table 4]

[0115] Tables 1 to 2 show that the prefilled drug packages of Examples 1-1 to 1-15 and Examples 2-1 to 2-15 can suppress protein aggregation after long-term storage even when the concentration of the nonionic surfactant in the protein solution formulation is low, at least 0 mg / mL and less than 0.05 mg / mL. On the other hand, Table 3 shows that in Comparative Examples 1-1, 1-5, and 1-6, in which the protein solution formulation had a high concentration of nonionic surfactant (0.50 mg / mL), decomposition products of the nonionic surfactant were generated after long-term storage. Furthermore, Table 3 shows that Comparative Example 1-2, in which the formulation contact part is not made of a specified resin due to the surface coating, and Comparative Examples 1-3 and 1-4, in which a glass container is used, are unable to suppress protein aggregation after long-term storage compared to Examples 1-1 to 1-15, which use the same protein. Furthermore, Table 4 shows that in Comparative Examples 2-1, 2-5, and 2-6, in which the protein solution formulations had a high concentration of nonionic surfactant (0.50 mg / mL), decomposition products of the nonionic surfactant were generated after long-term storage. Furthermore, Table 4 shows that in Comparative Example 2-2, in which the surface coating was applied and the formulation contact part was not made of a specified resin, and Comparative Examples 2-3 and 2-4, in which a glass container was used, protein aggregation after long-term storage was not suppressed compared to Examples 2-1 to 2-15, which used the same protein. [Industrial Applicability]

[0116] According to the present invention, a prefilled drug package can be provided that can suppress protein aggregation after long-term storage, even when containing a protein solution formulation with a low concentration of nonionic surfactant. Furthermore, the present invention can provide a method for producing a prefilled pharmaceutical package that can suppress protein aggregation after long-term storage, even when the package contains a protein solution formulation with a low concentration of nonionic surfactant. [Explanation of symbols]

[0117] 10 vials (prefilled medication packaging) 11 Container (container) 12 Cap (sealing member) 13,23 Protein solution formulations 20 infusion bags (prefilled medication packages) 21 Packaging (container) 22 Port (sealing member) 24 holes

Claims

1. A method for producing a prefilled drug package comprising a protein solution formulation and a container containing the protein solution formulation, the method comprising: a step of filling the container with the protein solution formulation having a nonionic surfactant concentration of 0 mg / mL or more and less than 0.05 mg / mL to obtain the prefilled drug package; at least a part of the container that comes into contact with the protein solution formulation is made of a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin; The method may further comprise, prior to obtaining the prefilled medication package, pre-drying the resin; a step of molding the pre-dried resin to obtain the container; Equipped with The method for producing a prefilled medicine package, wherein the oxygen concentration in the resin after the pre-drying is 10 ppm by mass or less.

2. The method for producing a prefilled medicine package according to claim 1, wherein the pre-drying is carried out under an inert gas atmosphere.

3. The method for producing a prefilled medicine package according to claim 1 or 2, wherein the drying temperature of the preliminary drying is 80°C or higher and 120°C or lower.

4. The method for producing a prefilled pharmaceutical package according to any one of claims 1 to 3, wherein the protein solution formulation contains at least one of an antibody and an antigen-binding fragment thereof.

5. The method for producing a prefilled drug package according to claim 4, wherein the antibody is at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody thereof.

6. The method for producing a prefilled medicine package according to any one of claims 1 to 3, wherein the protein solution formulation comprises at least one selected from the group consisting of ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumab, mogamulizumab, rituximab, ranibizumab, infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.

7. The method for producing a prefilled medicine package according to any one of claims 1 to 6, which is a method for producing a vial, an infusion bag, a prefilled cartridge, an ampoule, a bottle, a pouch, or a blister pack.

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