Syringe with built-in filter for pharmaceutical preparation

Abstract

The purpose of the present invention is to remove particles in a solution preparation filled in a syringe prior to administration. The present invention provides an injection preparation in which a solution is filled in a syringe, the syringe being provided with a cylindrical body having a distal end portion and a base end portion, the distal end portion being provided with a discharge hole for discharging the solution accommodated therein to the outside, and a filter disposed inside the cylindrical body, the filter being disposed inside the cylindrical body, the filter being disposed inside the cylindrical body, the filter being disposed inside the cylindrical body, and the filter being disposed inside the cylindrical body. And a filter provided so that the solution passes through the filter and flows from the base end side of the filter to the tip end side of the filter, the filter being a filter membrane, the material of the filter being one or more materials selected from the group consisting of polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS), and acrylic acid copolymers, the filter being provided so that the solution passes through the filter and flows from the base end side of the filter to the tip end side of the filter, and the material being one or more materials selected from the group consisting of PES, PVDF, polysulfone (PS), and acrylic acid copolymers.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation in which a solution containing an active ingredient is filled in a container. Background Art

[0002] In recent years, various antibody-containing preparations have been developed and put into practical use, but most of them are used as preparations for intravenous injection. On the other hand, due to the needs of medical sites, there is a high demand for preparations containing antibodies as self-injectable subcutaneous injection preparations. In particular, there is a high demand for the development of prefilled syringe preparations in which a solution is sealed in a syringe because of its convenience.

[0003] When designing a formulation containing an antibody suitable for subcutaneous injection, the maximum amount of antibody administered per time is large (about 80-200 mg). Since subcutaneous injection generally has a limit on the amount of injection solution, the antibody in the administration solution must be at a high concentration.

[0004] In recent years, among the preparations used in medical fields as prefilled syringe preparations for self-injection, a syringe having a cylindrical syringe body filled with a medicine, an injection needle mounted on the front end of the syringe body, a detachable syringe cap covering the mounted injection needle, and a piston inserted into the syringe body and slidable in the axial direction of the syringe body has been used.

[0005] When using a prefilled syringe preparation, remove the syringe cap, insert the needle into the application site, and then use the plunger rod to move the plunger forward to discharge and administer the drug solution. Generally, in order to ensure the sliding properties of the plunger, a lubricant such as silicone is applied to the inner wall of the prefilled syringe and the plunger.

[0006] For preparations containing antibodies, the formation of particles in aqueous solutions is a problem. The particles formed are larger aggregates than multimers called dimers and trimers. It is known that there are sub-visible particles (SVP) with a particle size of 1.5μm to less than 50μm, which are generally difficult to see with the eye, and visible particles (visible particles: VP, larger than 100μm) that can be visually detected under standard illumination (about 2,000-3,000lx). Although the visual detection rate of visible particles in pharmaceutical preparations varies greatly depending on the implementer, it is reported that the detection sensitivity of particles with a particle size of 100μm is about 40%, the detection sensitivity of particles with a particle size of 150μm is about 70%, and the detection sensitivity of particles with a particle size of 200μm is about 100% under the standard illumination (about 2,000-3,000lx) specified in the Japanese Pharmacopoeia (Non-Patent Document 1). In addition, by increasing the illumination for observing the pharmaceutical preparation and extending the observation time, particles with a particle size smaller than about 40 μm can actually be visually detected. In this specification, particles with a particle size of 40 μm or more to 100 μm are specifically referred to as particles that can be visually detected only under high illumination. In addition, particles with a particle size of 40 μm or more are particles that can be visually detected under high illumination, and are referred to as visually detectable particles.

[0007] Generally speaking, antibodies have the property of condensing on the interface called gas-liquid interface and solid-liquid interface. The presence of these interfaces contributes to the possibility of the formation of particles that can be visually detected. It is reported that the mechanical stress given to the syringe filled with antibody solution causes a significant increase in the microparticles produced due to the presence of the interface (non-patent literature 2). In the antibody solution filled in the syringe, a gas-liquid interface is produced due to the presence of bubbles, and a solid-liquid interface is formed due to contact with the plug and the syringe barrel. In addition, when the plug and barrel of the pre-filled syringe are coated with silicone, the antibody solution contacts the silicone on the solid phase surface to produce a new solid-liquid interface. In addition, it is reported that the protein adsorbed and condensed at the solid-liquid interface is peeled off from the liquid with the movement of air in the solution of the pre-filled syringe preparation, and appears as visible particles (non-patent literature 3).

[0008] Proteinaceous particles formed in such aqueous solutions are preferably not administered in vivo because the risk of immunogenicity cannot be ruled out.

[0009] Furthermore, particles of endogenous and exogenous foreign matter may become a problem not only in antibody preparations but also in prefilled syringe preparations containing low-molecular-weight compounds or medium-molecular-weight compounds as active ingredients.

[0010] As a method for removing particles in the preparation filled in the sample bottle before administration, a filter needle with a filter having a pore size of 5 μm in a transfer needle and a series filter in an infusion set can be cited. The filter needle is a commercially available product named BD blunt filter needle (Becton Dickinson, Japan) and Sterifix (registered trademark) (BBraun). In addition, for a syringe to be mixed with a variety of contents, it is known to have a syringe with a sealing structure and a filter that separates the space in the cavity into a wet part and a dry part (patent documents 1-3), and in the case of using an injection needle injection in which the liquid of an ampoule is sucked through an injection needle, a syringe equipped with a filter (patent document 4) is provided in order to filter foreign matter in the syringe. On the other hand, a method for removing particles in a prefilled syringe preparation before administration has not yet been established.

[0011] Prior art literature

[0012] Patent Literature

[0013] Patent Document 1: Japanese Patent Application Publication No. 2007-508898

[0014] Patent Document 2: Japanese Patent Application Publication No. 2019-051338

[0015] Patent Document 3: Japanese Patent Application No. 2005-537106

[0016] Patent Document 4: Japanese Patent Application No. 2015-536213

[0017] Non-patent literature

[0018] Non-patent literature 1: James A. Melchore, AAPS Pharm Sci Tech; 2011; 12(1):215-221.

[0019] Non-patent literature 2: Torisu et al., J. Pharm. Sci. 106 (2017) 2966-2978.

[0020] Non-patent literature 3: Gerhardt et al., J. Pharm. Sci. 103 (2014) 1601-1612. Summary of the invention

[0021] Problems to be solved by the invention

[0022] Although methods for removing particles from a formulation filled in a sample vial just before administration are known, methods for removing particles from a solution formulation filled in a syringe just before administration have not been established and are technically difficult.

[0023] Means for solving problems

[0024] Therefore, the inventors conducted intensive research on a novel syringe with a built-in filter and completed the present invention. This specification includes the following disclosed inventions.

[0025] [1-1] An injectable preparation in which a solution is filled in a syringe, wherein:

[0026] The syringe has:

[0027] a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and

[0028] a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole,

[0029] The filter is configured so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0030] The filter is a filter membrane, and its material includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0031] [1-2] The injection preparation according to [1-1], wherein the material of the filter membrane is an acrylic copolymer.

[0032] [1-3] The injection preparation according to [1-2], wherein the acrylic copolymer is hydrophobic.

[0033] [1-4] The injection preparation according to any one of [1-1] to [1-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0034] [1-5] An injectable preparation according to any one of [1-1] to [1-4], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0035] [1-6] The injection preparation according to any one of [1-1] to [1-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0036] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0037] The housing has an engaging member when closed,

[0038] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0039] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0040] The filter is held at a front end side portion of the housing.

[0041] [1-7] The injection preparation according to [1-6], wherein one of the sealing engaging member and the sealing engaged member is arranged at the distal end side and the proximal end side relative to the other of the sealing engaging member and the sealing engaged member.

[0042] [1-8] The injection preparation according to [1-6] or [1-7], wherein the material of the inner plug member is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0043] [1-9] The injection preparation according to any one of [1-1] to [1-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0044] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0045] The filter is held at the front end side portion of the housing.

[0046] [1-10] The injection preparation according to any one of [1-6] to [1-9], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0047] [1-11] The injectable preparation according to any one of [1-6] to [1-10], wherein the material of the shell is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0048] [1-12] The injection preparation according to any one of [1-1] to [1-11], wherein the compound contained in the solution as an active ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

[0049] [1-13] The injection preparation according to [1-12], wherein the compound comprises an antibody or a binding fragment thereof or a cyclic peptide.

[0050] [1-14] The preparation for syringe according to [1-12], wherein the low molecular weight compound has a molecular weight of less than 500.

[0051] [1-15] The preparation for syringe according to [1-12], wherein the middle molecular compound has a molecular weight of 500 to 15,000.

[0052] [1-16] The preparation for syringe according to [1-12], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0053] [1-17] The injection preparation according to any one of [1-1] to [1-16], wherein the solution is kept in a non-contact state with the filter before use.

[0054] [1-18] The injection preparation according to any one of [1-1] to [1-16], wherein the solution is in contact with the filter before use.

[0055] [1-19] The injection preparation according to [1-17], wherein when the injection preparation is prepared by filling a syringe with a solution, the solution is kept in a non-contact state with a filter before use during or after preparation.

[0056] [1-20] The injection preparation according to any one of [1-1] to [1-19], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0057] [1-21] An injectable preparation according to any one of [1-1] to [1-20], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0058] [1-22] An injectable preparation according to any one of [1-1] to [1-21], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0059] [1-23] The injectable preparation according to [1-1] or [1-22], comprising an injection needle connectable to a syringe.

[0060] [1-24] The injection preparation according to any one of [1-1] to [1-23], wherein the solution is an aqueous solution.

[0061] [1-25] The injection preparation according to any one of [1-1] to [1-24], wherein the solution contains emicizumab as an active ingredient.

[0062] [2-1] An injectable preparation in which a solution is filled in a syringe, wherein:

[0063] The syringe has:

[0064] a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and

[0065] a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole,

[0066] The filter is configured so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0067] The filter is a filter membrane, and its material includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0068] During the discharge of the solution, particles that can be visually detected can be removed from the discharged solution.

[0069] [2-2] The injection preparation according to [2-1], wherein the material of the filter membrane is an acrylic copolymer.

[0070] [2-3] The injection preparation according to [2-2], wherein the acrylic copolymer is hydrophobic.

[0071] [2-4] The injection preparation according to any one of [2-1] to [2-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0072] [2-5] An injectable preparation according to any one of [2-1] to [2-4], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0073] [2-6] The injection preparation according to any one of [2-1] to [2-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0074] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0075] The housing has an engaging member when closed,

[0076] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0077] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0078] The filter is held at the front end side portion of the housing.

[0079] [2-7] The injection preparation according to [2-6], wherein one of the sealing engaging member and the sealing engaged member is arranged at the distal end side and the proximal end side relative to the other of the sealing engaging member and the sealing engaged member.

[0080] [2-8] The injection preparation according to any one of [2-1] to [2-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0081] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0082] The filter is held at the front end side portion of the housing.

[0083] [2-9] The injection preparation according to any one of [2-6] to [2-8], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0084] [2-10] The injection preparation according to any one of [2-1] to [2-9], wherein the particles have a particle size greater than 40 μm.

[0085] [2-11] The injection preparation according to any one of [2-1] to [2-10], wherein the particles include particles derived from a component of the solution or particles other than a component derived from the solution.

[0086] [2-12] The injection preparation according to [2-11], wherein the particles are components derived from a solution.

[0087] [2-13] The injection preparation according to [2-11], wherein the particles are derived from components other than the solution.

[0088] [2-14] The injection preparation according to any one of [2-1] to [2-13], wherein the compound contained in the solution as an active ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

[0089] [2-15] The injection preparation according to [2-14], wherein the compound comprises an antibody or a binding fragment thereof or a cyclic peptide.

[0090] [2-16] The preparation for syringe according to [2-14], wherein the low molecular weight compound has a molecular weight of less than 500.

[0091] [2-17] The preparation for syringe according to [2-14], wherein the middle molecular compound has a molecular weight of 500 to 15,000.

[0092] [2-18] The preparation for syringe according to [2-14], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0093] [2-19] The injection preparation according to any one of [2-1] to [2-18], wherein the solution is kept in a non-contact state with the filter before use.

[0094] [2-20] The injection preparation according to any one of [2-1] to [2-18], wherein the solution is in contact with the filter before use.

[0095] [2-21] The injection preparation according to [2-19], wherein the solution is kept in a non-contact state with the filter during or after the injection preparation in which the solution is filled in the syringe.

[0096] [2-22] The injection preparation according to any one of [2-1] to [2-21], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0097] [2-23] An injectable preparation according to any one of [2-1] to [2-22], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0098] [2-24] An injectable preparation according to any one of [2-1] to [2-23], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0099] [2-25] The injection preparation according to any one of [2-1] to [2-24], wherein the solution is an aqueous solution.

[0100] [2-26] The injection preparation according to any one of [2-1] to [2-25], wherein the solution contains emicizumab as an active ingredient.

[0101] [3-1] A method for removing visually detectable particles contained in an injectable preparation, wherein:

[0102] The injection preparation is a solution filled in a syringe.

[0103] The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0104] The method comprises the step of discharging the solution filled in the syringe through a filter, wherein the filter is a filter membrane whose material comprises at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0105] [3-2] The method according to [3-1], wherein the material of the filter membrane is an acrylic copolymer.

[0106] [3-3] The method according to [3-2], wherein the acrylic copolymer is hydrophobic.

[0107] [3-4] The method according to any one of [3-1] to [3-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0108] [3-5] A method according to any one of [3-1] to [3-4], wherein a front end side subspace is provided at the front end side of the filter, and a base end side subspace is provided at the base end of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end side subspace and smaller than the area of ​​the front end side subspace.

[0109] [3-6] The method according to any one of [3-1] to [3-5], wherein the syringe includes a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0110] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0111] The housing has an engaging member when closed,

[0112] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0113] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0114] The filter is held at the front end side portion of the housing.

[0115] [3-7] The method according to [3-6], wherein one of the closing engaging member and the closing engaged member is arranged on the front end side and the base end side relative to the other of the closing engaging member and the closing engaged member.

[0116] [3-8] The method according to any one of [3-1] to [3-5], wherein the syringe includes a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0117] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0118] The filter is held at the front end side portion of the housing.

[0119] [3-9] The method according to any one of [3-6] to [3-8], wherein the volume of the space on the front end side of the cylinder is 150 mm. 3 Configure in the following way.

[0120] [3-10] The method according to any one of [3-1] to [3-9], wherein the particles have a particle size greater than 40 μm.

[0121] [3-11] The method according to any one of [3-1] to [3-10], wherein the particles include particles derived from components of the solution or particles other than components derived from the solution.

[0122] [3-12] The method according to [3-11], wherein the particles are components derived from a solution.

[0123] [3-13] The method according to [3-11], wherein the particles are derived from components other than the solution.

[0124] [3-14] The method according to any one of [3-1] to [3-13], wherein the compound contained in the solution as an active ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

[0125] [3-15] The method according to [3-14], wherein the compound comprises an antibody or a binding fragment thereof or a cyclic peptide.

[0126] [3-16] The method according to [3-14], wherein the low molecular weight compound has a molecular weight of less than 500.

[0127] [3-17] The method according to [3-14], wherein the medium molecular weight compound has a molecular weight of 500-15000.

[0128] [3-18] The method according to [3-14], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0129] [3-19] The method according to any one of [3-1] to [3-18], wherein the solution is kept in a non-contact state with the filter before use.

[0130] [3-20] The method according to any one of [3-1] to [3-18], wherein the solution is in contact with the filter before use.

[0131] [3-21] The method according to [3-19], wherein when the injectable preparation is prepared by filling a solution in a syringe, or after preparation, the solution is kept in a non-contact state with a filter before use.

[0132] [3-22] A method according to any one of [3-1] to [3-21], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0133] [3-23] A method according to any one of [3-1] to [3-22], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0134] [3-24] The method according to any one of [3-1] to [3-23], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0135] [3-25] The method according to any one of [3-1] to [3-24], wherein the solution is an aqueous solution.

[0136] [3-26] The method according to any one of [3-1] to [3-25], wherein the solution contains emicizumab as an active ingredient.

[0137] [4-1] A syringe filled with a solution,

[0138] The syringe comprises a barrel and a filter, wherein the barrel is formed into a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0139] The filter is a filter membrane, and its material includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer; even if a solution with a viscosity of less than 95 cP is discharged through the filter at a discharge speed of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0140] [4-2] A syringe filled with a solution,

[0141] The syringe comprises a barrel and a filter, wherein the barrel is formed into a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0142] The filter is a filter membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer. When a solution with a viscosity of 95 cP or less is discharged through the filter at a discharge speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times or within 1.5 times compared with a syringe without a built-in filter.

[0143] [4-3] The syringe according to [4-1] or [4-2], wherein the material of the filter membrane is an acrylic copolymer.

[0144] [4-4] The syringe according to [4-3], wherein the acrylic copolymer is hydrophobic.

[0145] [4-5] The syringe according to any one of [4-1] to [4-4], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0146] [4-6] An injection syringe according to any one of [4-1] to [4-5], wherein a front end side subspace is provided at the front end side of the filter, and a base end side subspace is provided at the base end of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end side subspace and smaller than the area of ​​the front end side subspace.

[0147] [4-7] The syringe according to any one of [4-1] to [4-6], wherein the syringe has a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0148] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0149] The housing has an engaging member when closed,

[0150] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0151] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0152] The filter is held at the front end side portion of the housing.

[0153] [4-8] The syringe according to [4-7], wherein one of the closing engaging member and the closing engaged member is arranged on the front end side and the base end side relative to the other of the closing engaging member and the closing engaged member.

[0154] [4-9] The syringe according to [4-7] or [4-8], wherein the material of the inner plug member is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0155] [4-10] The syringe according to any one of [4-1] to [4-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0156] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0157] The filter is held at the front end side portion of the housing.

[0158] [4-11] The syringe according to any one of [4-7] to [4-10], wherein the volume of the space on the front end side of the barrel of the partition device is 150mm 3Configure in the following way.

[0159] [4-12] The syringe according to any one of [4-7] to [4-11], wherein the material of the shell is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0160] [4-13] The syringe according to any one of [4-1] to [4-12], wherein the compound contained in the solution as an active ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

[0161] [4-14] The syringe according to [4-13], wherein the compound comprises an antibody or a binding fragment thereof or a cyclic peptide.

[0162] [4-15] The syringe according to [4-13], wherein the low molecular weight compound has a molecular weight of less than 500.

[0163] [4-16] The syringe according to [4-13], wherein the middle molecular compound has a molecular weight of 500-15000.

[0164] [4-17] The syringe according to [4-13], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0165] [4-18] The syringe according to any one of [4-1] to [4-17], wherein the solution is kept in a non-contact state with the filter before use.

[0166] [4-19] The syringe according to any one of [4-1] to [4-17], wherein the solution is in contact with the filter before use.

[0167] [4-20] The syringe according to [4-18], wherein when the injectable preparation is filled with a solution in the syringe, the solution is kept in a non-contact state with the filter before use during or after the manufacture of the injectable preparation.

[0168] [4-21] A syringe according to any one of [4-1] to [4-20], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0169] [4-22] The syringe according to any one of [4-1] to [4-21], wherein the solution is an aqueous solution.

[0170] [4-23] The syringe according to any one of [4-1] to [4-22], wherein the solution contains emicizumab as an active ingredient.

[0171] [5-1] An injectable preparation, which is a solution filled in a syringe and can be stored for more than 10 days for use as a medicine, wherein:

[0172] The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0173] The filter is a filter membrane, and its material includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0174] [5-2] The injection preparation according to [5-1], wherein even after storage at 5°C, 25°C, or 40°C, changes in physical properties of the preparation are less than those of a preparation filled in a prefilled syringe without a built-in filter.

[0175] [5-3] The injection preparation according to [5-1] or [5-2], wherein the material of the filter membrane is an acrylic copolymer.

[0176] [5-4] The injection preparation according to [5-3], wherein the acrylic copolymer is hydrophobic.

[0177] [5-5] The injection preparation according to any one of [5-1] to [5-4], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0178] [5-6] An injectable preparation according to any one of [5-1] to [5-5], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0179] [5-7] The injectable preparation according to any one of [5-1] to [5-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0180] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0181] The housing has an engaging member when closed,

[0182] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0183] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0184] The filter is held at the front end side portion of the housing.

[0185] [5-8] The injection preparation according to [5-7], wherein one of the sealing engaging member and the sealing engaged member is arranged at the distal end side and the proximal end side relative to the other of the sealing engaging member and the sealing engaged member.

[0186] [5-9] The injection preparation according to any one of [5-1] to [5-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0187] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0188] The filter is held at a front end side portion of the housing.

[0189] [5-10] The injection preparation according to any one of [5-7] to [5-9], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0190] [5-11] The injection preparation according to any one of [5-1] to [5-10], wherein the compound contained in the solution as an active ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

[0191] [5-12] The injection preparation according to [5-11], wherein the compound comprises an antibody or a binding fragment thereof or a cyclic peptide.

[0192] [5-13] The preparation for syringe according to [5-11], wherein the low molecular weight compound has a molecular weight of less than 500.

[0193] [5-14] The preparation for syringe according to [5-11], wherein the middle molecular compound has a molecular weight of 500 to 15,000.

[0194] [5-15] The preparation for syringe according to [5-11], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0195] [5-16] The injection preparation according to any one of [5-1] to [5-15], wherein the injection preparation is kept in a non-contact state with the filter before use.

[0196] [5-17] The injection preparation according to any one of [5-1] to [5-15], wherein the injection preparation is in contact with a filter before use.

[0197] [5-18] The injection preparation according to [5-16], wherein when the injection preparation is filled with a solution in a syringe, the solution remains in a non-contact state with the filter even if stress is applied during or after the production of the injection preparation.

[0198] [5-19] The injection preparation according to any one of [5-1] to [5-18], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0199] [5-20] An injectable preparation according to any one of [5-1] to [5-19], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0200] [5-21] An injectable preparation according to any one of [5-1] to [5-20], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0201] [5-22] The injection preparation according to any one of [5-1] to [5-21], wherein the solution is an aqueous solution.

[0202] [5-23] The injection preparation according to any one of [5-1] to [5-22], wherein the solution contains emicizumab as an active ingredient.

[0203] [6-1] An injectable preparation, which is an injectable preparation in which a solution containing a protein as an active ingredient is filled in a syringe, wherein:

[0204] The syringe has:

[0205] a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and

[0206] a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole,

[0207] The filter is configured so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0208] The filter is a filter membrane, and its material includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0209] [6-2] The injection preparation according to [6-1], wherein the material of the filter membrane is an acrylic copolymer.

[0210] [6-3] The injection preparation according to [6-2], wherein the acrylic copolymer is hydrophobic.

[0211] [6-4] The injection preparation according to any one of [6-1] to [6-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0212] [6-5] An injectable preparation according to any one of [6-1] to [6-4], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0213] [6-6] The injection preparation according to any one of [6-1] to [6-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0214] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0215] The housing has an engaging member when closed,

[0216] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0217] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0218] The filter is held at a front end side portion of the housing.

[0219] [6-7] The injection preparation according to [6-6], wherein one of the sealing engaging member and the sealing engaged member is arranged on the front end side and the base end side relative to the other of the sealing engaging member and the sealing engaged member.

[0220] [6-8] The injection preparation according to [6-6] or [6-7], wherein the material of the inner plug member is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0221] [6-9] The injection preparation according to any one of [6-1] to [6-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0222] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0223] The filter is held at the front end side portion of the housing.

[0224] [6-10] The injection preparation according to any one of [6-6] to [6-9], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0225] [6-11] The injectable preparation according to any one of [6-6] to [6-10], wherein the material of the shell is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0226] [6-12] The injection preparation according to any one of [6-1] to [6-11], wherein the protein is a monoclonal antibody.

[0227] [6-13] The injection preparation according to any one of [6-1] to [6-12], wherein the solution is kept in a non-contact state with the filter before use.

[0228] [6-14] The injection preparation according to any one of [6-1] to [6-12], wherein the solution is in contact with the filter before use.

[0229] [6-15] The injection preparation according to [6-13], wherein when the injection preparation is prepared by filling a syringe with a solution containing a protein as an active ingredient, the solution is kept in a non-contact state with a filter before use during or after preparation.

[0230] [6-16] The injection preparation according to any one of [6-1] to [6-15], wherein the concentration of the protein in the solution is 0.1 mg / mL or more.

[0231] [6-17] The injection preparation according to any one of [6-1] to [6-16], wherein the protein concentration in the solution is in the range of 0.1 to 300 mg / mL.

[0232] [6-18] The injection preparation according to any one of [6-1] to [6-17], wherein the concentration of the protein in the solution is in the range of 1-200 mg / mL, 50-200 mg / mL, or 80-200 mg / mL.

[0233] [6-19] The injection preparation according to any one of [6-1] to [6-18], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0234] [6-20] An injectable preparation according to any one of [6-1] to [6-19], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0235] [6-21] An injectable preparation according to any one of [6-1] to [6-20], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0236] [6-22] The injectable preparation according to any one of [6-1] to [6-21], comprising an injection needle that can be connected to a syringe.

[0237] [6-23] The injection preparation according to any one of [6-1] to [6-22], wherein the solution is an aqueous solution.

[0238] [6-24] The injection preparation according to any one of [6-1] to [6-23], wherein the protein is emicizumab.

[0239] [7-1] An injectable preparation, which is an injectable preparation in which a solution containing a protein as an active ingredient is filled in a syringe, wherein:

[0240] The syringe has:

[0241] a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and

[0242] a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole,

[0243] The filter is configured so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0244] The filter is a filter membrane, and its material includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0245] During the discharge of the solution, particles that can be visually detected can be removed from the discharged solution.

[0246] [7-2] The injection preparation according to [7-1], wherein the material of the filter membrane is an acrylic copolymer.

[0247] [7-3] The injection preparation according to [7-2], wherein the acrylic copolymer is hydrophobic.

[0248] [7-4] The injection preparation according to any one of [7-1] to [7-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0249] [7-5] An injectable preparation according to any one of [7-1] to [7-4], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0250] [7-6] The injection preparation according to any one of [7-1] to [7-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0251] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0252] The housing has an engaging member when closed,

[0253] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0254] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0255] The filter is held at the front end side portion of the housing.

[0256] [7-7] The injection preparation according to [7-6], wherein one of the sealing engaging member and the sealing engaged member is arranged on the front end side and the base end side relative to the other of the sealing engaging member and the sealing engaged member.

[0257] [7-8] The injection preparation according to any one of [7-1] to [7-5], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0258] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0259] The filter is held at the front end side portion of the housing.

[0260] [7-9] The injection preparation according to any one of [7-6] to [7-8], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0261] [7-10] The injection preparation according to any one of [7-1] to [7-9], wherein the particles have a particle size greater than 40 μm.

[0262] [7-11] The injection preparation according to any one of [7-1] to [7-10], wherein the particles include particles derived from a component of the solution or particles other than a component derived from the solution.

[0263] [7-12] The injection preparation according to [7-11], wherein the particles are components derived from a solution.

[0264] [7-13] The injection preparation according to [7-11], wherein the particles are derived from components other than the solution.

[0265] [7-14] The injection preparation according to any one of [7-1] to [7-13], wherein the protein is a monoclonal antibody.

[0266] [7-15] The injection preparation according to any one of [7-1] to [7-14], wherein the solution is kept in a non-contact state with the filter before use.

[0267] [7-16] The injection preparation according to any one of [7-1] to [7-14], wherein the solution is in contact with the filter before use.

[0268] [7-17] The injection preparation according to [7-15], wherein when the injection preparation is filled with a solution containing a protein as an active ingredient in a syringe, the solution is kept in a non-contact state with the filter during or after the production of the injection preparation.

[0269] [7-18] The injection preparation according to any one of [7-1] to [7-17], wherein the concentration of the protein in the solution is 0.1 mg / mL or more.

[0270] [7-19] The injection preparation according to any one of [7-1] to [7-18], wherein the concentration of the protein in the solution is in the range of 0.1 to 300 mg / mL.

[0271] [7-20] The injection preparation according to any one of [7-1] to [7-19], wherein the concentration of the protein in the solution is in the range of 1-200 mg / mL, 50-200 mg / mL or 80-200 mg / mL.

[0272] [7-21] The injection preparation according to any one of [7-1] to [7-20], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0273] [7-22] An injectable preparation according to any one of [7-1] to [7-21], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0274] [7-23] An injectable preparation according to any one of [7-1] to [7-22], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0275] [7-24] The injection preparation according to any one of [7-1] to [7-23], wherein the solution is an aqueous solution.

[0276] [7-25] The injection preparation according to any one of [7-1] to [7-24], wherein the protein is emicizumab.

[0277] [8-1] A method for removing visually detectable particles contained in an injectable preparation, wherein:

[0278] Injectable preparations are solutions containing protein as an active ingredient and are filled in syringes.

[0279] The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0280] The method comprises the step of discharging the solution filled in the syringe through a filter, wherein the filter is a filter membrane whose material comprises at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0281] [8-2] The method according to [8-1], wherein the material of the filter membrane is an acrylic copolymer.

[0282] [8-3] The method according to [8-2], wherein the acrylic copolymer is hydrophobic.

[0283] [8-4] The method according to any one of [8-1] to [8-3], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0284] [8-5] A method according to any one of [8-1] to [8-4], wherein a front end side subspace is set at the front end side of the filter, and a base end side subspace is set at the base end of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end side subspace and smaller than the area of ​​the front end side subspace.

[0285] [8-6] The method according to any one of [8-1] to [8-5], wherein the syringe has a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0286] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0287] The housing has an engaging member when closed,

[0288] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0289] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0290] The filter is held at the front end side portion of the housing.

[0291] [8-7] The method according to [8-6], wherein one of the closing engaging member and the closing engaged member is arranged on the front end side and the base end side relative to the other of the closing engaging member and the closing engaged member.

[0292] [8-8] The method according to any one of [8-1] to [8-5], wherein the syringe has a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0293] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0294] The filter is held at the front end side portion of the housing.

[0295] [8-9] The method according to any one of [8-6] to [8-8], wherein the volume of the space on the front end side of the cylinder is 150 mm. 3 Configure in the following way.

[0296] [8-10] The method according to any one of [8-1] to [8-9], wherein the particles have a particle size greater than 40 μm.

[0297] [8-11] The method according to any one of [8-1] to [8-10], wherein the particles include particles derived from components of the solution or particles other than components derived from the solution.

[0298] [8-12] The method according to [8-11], wherein the particles are components derived from a solution.

[0299] [8-13] The method according to [8-11], wherein the particles are derived from components other than the solution.

[0300] [8-14] The method according to any one of [8-1] to [8-13], wherein the protein is a monoclonal antibody.

[0301] [8-15] The method according to any one of [8-1] to [8-14], wherein the solution is kept in a non-contact state with the filter before use.

[0302] [8-16] The method according to any one of [8-1] to [8-14], wherein the solution is in contact with the filter before use.

[0303] [8-17] The method according to [8-15], wherein when the injectable preparation containing a solution containing a protein as an active ingredient is filled in a syringe, the solution is kept in a non-contact state with the filter during or after the production.

[0304] [8-18] The method according to any one of [8-1] to [8-17], wherein the concentration of the protein in the solution is 0.1 mg / mL or more.

[0305] [8-19] The method according to any one of [8-1] to [8-18], wherein the concentration of the protein in the solution is in the range of 0.1 to 300 mg / mL.

[0306] [8-20] The method according to any one of [8-1] to [8-19], wherein the concentration of the protein in the solution is in the range of 1-200 mg / mL, 50-200 mg / mL or 80-200 mg / mL.

[0307] [8-21] A method according to any one of [8-1] to [8-20], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0308] [8-22] A method according to any one of [8-1] to [8-21], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times, or within 1.5 times that of a syringe without a built-in filter.

[0309] [8-23] The method according to any one of [8-1] to [8-22], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0310] [8-24] The method according to any one of [8-1] to [8-23], wherein the solution is an aqueous solution.

[0311] [8-25] The method according to any one of [8-1] to [8-24], wherein the protein is emicizumab.

[0312] [9-1] A syringe filled with a solution containing a protein as an active ingredient,

[0313] The invention comprises a barrel and a filter, wherein the barrel is formed into a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0314] The filter is a filter membrane, and its material includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer; even if a solution with a viscosity of less than 95 cP is discharged through the filter at a discharge speed of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0315] [9-2] A syringe filled with a solution containing a protein as an active ingredient,

[0316] The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0317] The filter is a filter membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer. When a solution with a viscosity of 95 cP or less is discharged through the filter at a discharge speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, within 1.4 times or within 1.5 times compared with a syringe without a built-in filter.

[0318] [9-3] The syringe according to [9-1] or [9-2], wherein the material of the filter membrane is an acrylic copolymer.

[0319] [9-4] The syringe according to [9-3], wherein the acrylic copolymer is hydrophobic.

[0320] [9-5] The syringe according to any one of [9-1] to [9-4], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0321] [9-6] An injection syringe according to any one of [9-1] to [9-5], wherein a front end side subspace is provided at the front end side of the filter, and a base end side subspace is provided at the base end of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end side subspace and smaller than the area of ​​the front end side subspace.

[0322] [9-7] The syringe according to any one of [9-1] to [9-6], wherein the syringe has a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space,

[0323] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0324] The housing has an engaging member when closed,

[0325] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0326] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0327] The filter is held at the front end side portion of the housing.

[0328] [9-8] The syringe according to [9-7], wherein one of the sealing engaging member and the sealing engaged member is arranged on the front end side and the base end side relative to the other of the sealing engaging member and the sealing engaged member.

[0329] [9-9] The injection preparation according to [9-7] or [9-8], wherein the material of the inner plug member is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0330] [9-10] The syringe according to any one of [9-1] to [9-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0331] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0332] The filter is held at the front end side portion of the housing.

[0333] [9-11] The syringe according to any one of [9-7] to [9-10], wherein the volume of the space on the front end side of the barrel of the partition device is 150mm 3 Configure in the following way.

[0334] [9-12] The syringe according to any one of [9-7] to [9-11], wherein the material of the shell is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0335] [9-13] The syringe according to any one of [9-1] to [9-12], wherein the protein is a monoclonal antibody.

[0336] [9-14] The syringe according to any one of [9-1] to [9-13], wherein the solution is kept in a non-contact state with the filter before use.

[0337] [9-15] The syringe according to any one of [9-1] to [9-13], wherein the solution is in contact with the filter before use.

[0338] [9-16] The syringe according to [9-14], wherein when the injectable preparation containing a solution containing a protein as an active ingredient is filled in the syringe, the solution is kept in a non-contact state with the filter during or after the production.

[0339] [9-17] The syringe according to any one of [9-1] to [9-16], wherein the concentration of the protein in the solution is 0.1 mg / mL or more.

[0340] [9-18] The syringe according to any one of [9-1] to [9-17], wherein the concentration of the protein in the solution is in the range of 0.1 to 300 mg / mL.

[0341] [9-19] The syringe according to any one of [9-1] to [9-18], wherein the concentration of the protein in the solution is in the range of 1-200 mg / mL, 50-200 mg / mL or 80-200 mg / mL.

[0342] [9-20] A syringe according to any one of [9-1] to [9-19], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0343] [9-21] The syringe according to any one of [9-1] to [9-20], wherein the solution is an aqueous solution.

[0344] [9-22] The syringe according to any one of [9-1] to [9-21], wherein the protein is emicizumab.

[0345] [10-1] An injectable preparation, which is a solution filled in a syringe and can be stored for more than 10 days for use as a medicine, wherein:

[0346] The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side.

[0347] The filter is a filter membrane, and its material includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0348] [10-2] The injection preparation according to [10-1], wherein even after storage at 5°C, 25°C, or 40°C, changes in physical properties of the preparation are less than those of a preparation filled in a prefilled syringe without a built-in filter.

[0349] [10-3] The injection preparation according to [10-1] or [10-2], wherein the material of the filter membrane is an acrylic copolymer.

[0350] [10-4] The injection preparation according to [10-3], wherein the acrylic copolymer is hydrophobic.

[0351] [10-5] The injection preparation according to any one of [10-1] to [10-4], wherein the filter has a pore size of 5 μm or less, preferably 5 μm.

[0352] [10-6] An injectable preparation according to any one of [10-1] to [10-5], wherein a front end subspace is provided on the front end side of the filter, and a base end subspace is provided on the base end side of the filter, and when viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

[0353] [10-7] The injection preparation according to any one of [10-1] to [10-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0354] The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell,

[0355] The housing has an engaging member when closed,

[0356] The inner plug member has a closed-time engaged member that engages with the base end side of the engaging member.

[0357] The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space,

[0358] The filter is held at the front end side portion of the housing.

[0359] [10-8] The injection preparation according to [10-7], wherein one of the sealing engaging member and the sealing engaged member is arranged on the front end side and the base end side relative to the other of the sealing engaging member and the sealing engaged member.

[0360] [10-9] The injection preparation according to any one of [10-1] to [10-6], wherein the syringe has a partitioning device that partitions the space inside the barrel into a base end side space and a front end side space,

[0361] The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body.

[0362] The filter is held at the front end side portion of the housing.

[0363] [10-10] The injection preparation according to any one of [10-7] to [10-9], wherein the volume of the space on the front end side of the cylinder of the partition device is 150 mm 3 Configure in the following way.

[0364] [10-11] The injection preparation according to any one of [10-1] to [10-10], wherein the protein is a monoclonal antibody.

[0365] [10-12] The injection preparation according to any one of [10-1] to [10-11], wherein the injection preparation is kept in a non-contact state with the filter before use.

[0366] [10-13] The injection preparation according to any one of [10-1] to [10-11], wherein the injection preparation is in contact with a filter before use.

[0367] [10-14] The injection preparation according to [10-12], wherein when the injection preparation is filled with a solution containing a protein as an active ingredient in a syringe, the solution remains in a non-contact state with the filter even when stress is applied during or after production.

[0368] [10-15] The injection preparation according to any one of [10-1] to [10-14], wherein the concentration of protein in the solution is 0.1 mg / mL or more.

[0369] [10-16] The injection preparation according to any one of [10-1] to [10-15], wherein the concentration of the protein in the solution is in the range of 0.1 to 300 mg / mL.

[0370] [10-17] The injection preparation according to any one of [10-1] to [10-16], wherein the concentration of the protein in the solution is in the range of 1-200 mg / mL, 50-200 mg / mL or 80-200 mg / mL.

[0371] [10-18] An injectable preparation according to any one of [10-1] to [10-17], wherein even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge rate of 300 mm / min, there is no damage to the filter and no peeling of the contact surface between the filter and the shell.

[0372] [10-19] An injectable preparation according to any one of [10-1] to [10-18], wherein when a solution having a viscosity of 95 cP or less is discharged through a filter at a discharge rate of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times or 1.5 times that of a syringe without a built-in filter.

[0373] [10-20] An injectable preparation according to any one of [10-1] to [10-19], wherein the solution comprises one or more pharmaceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents and stabilizers.

[0374] [10-21] The injection preparation according to any one of [10-1] to [10-20], wherein the solution is an aqueous solution.

[0375] [10-22] The injection preparation according to any one of [10-1] to [10-21], wherein the solution contains emicizumab as an active ingredient.

[0376] Effects of the Invention

[0377] According to the present invention, even if visible particles are present in the solution of the injection preparation filled in the syringe, the solution filled in the syringe is filtered by the filter when the entire amount is discharged, so that a high-quality preparation free of particles can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0378] [ Figure 1 ] Figure 1 It is a cross-sectional view for explaining the closed state of the inner plug member in the syringe of the prefilled syringe according to the present embodiment.

[0379] [ Figure 2 ] Figure 2 It is a cross-sectional view for explaining the opened state of the inner plug component in the prefilled syringe.

[0380] [ Figure 3 ] Figure 3 for Figure 1 An enlarged cross-sectional view of the area shown in III.

[0381] [ Figure 4 ] Figure 4 for Figure 2 An enlarged cross-sectional view of the area indicated by IV.

[0382] [ Figure 5 ] Figure 5 is a perspective view of the inner plug component in the syringe.

[0383] [ Figure 6 ] Figure 6 A perspective view of the inner plug component.

[0384] [ Figure 7 ] Figure 7 It is a side view for explaining the closed state of the inner plug member in the syringe of the prefilled syringe according to the modification.

[0385] [ Figure 8 ] Figure 8 It is a cross-sectional view for explaining the opened state of the inner plug component in the prefilled syringe.

[0386] [ Fig. 9 ] Fig. 9 for Figure 7 An enlarged cross-sectional view of the area indicated in IX.

[0387] [ Fig.10 ] Fig.10 for Figure 8 An enlarged cross-sectional view of the area indicated by X.

[0388] [ Fig.11 ] Fig.11 is a perspective view of the inner plug component in the syringe.

[0389] [ Fig.12 ] Fig.12 It is a perspective view of the inner plug component.

[0390] [ Fig.13 ] Fig.13 These are schematic cross-sectional views of the prefilled syringe involved in the modified example when in use, (a) shows the closed state of the inner plug component, (b) shows the state immediately after the inner plug component is opened, (c) shows the open state of the inner plug component, and (d) shows the state after the drug is administered.

[0391] [ Fig.14 ] Fig.14 These are schematic cross-sectional views of the prefilled syringe involved in the modified example when in use, (a) shows the closed state of the inner plug component, (b) shows the state immediately after the inner plug component is opened, (c) shows the open state of the inner plug component, and (d) shows the state after the drug is administered.

[0392] [ Fig.15 ] Fig.15 Cross-sectional view of a syringe showing a prefilled syringe with a retaining device.

[0393] [ Fig.16 ] Fig.16 for Fig.15 An enlarged cross-sectional view of the area shown in III.

[0394] [ Fig.17 ] Fig.17 This is a schematic diagram for explaining the installation of the filter in the holding device.

[0395] [ Fig.18 ] Fig.18 This is a side view of a syringe of a prefilled syringe according to a modified example.

[0396] [ Fig.19 ] Fig.19 for Fig.18 An enlarged cross-sectional view of the area indicated by VI.

[0397] [ Fig. 20 ] Fig. 20 It is a side view of a syringe involved in a modification.

[0398] [ Fig.21 ] Fig.21 for Fig. 20 An enlarged cross-sectional view of the area indicated by VIII.

[0399] [ Fig. 22 ] Fig. 22 The following are photos of (a) a normal filter without damage and (b) an abnormal filter with damage after the solution is discharged. DETAILED DESCRIPTION

[0400] (1) Prefilled syringe

[0401] Hereinafter, with respect to the prefilled syringe having the syringe according to the embodiment of the present invention, reference will be made to Figure 1-Figure 6 Provide explanation.

[0402] Prefilled syringe 1 Figure 1 and Figure 2As described above, a syringe 2 for administering a drug is provided. In addition, the prefilled syringe 1 is provided with a piston 3 inserted into the syringe 2. Further, the prefilled syringe 1 is provided with an injection needle 4 connected to the syringe 2. The prefilled syringe 1 is provided with a protective cap 5 for sealing the injection needle 4. The drug is a liquid drug, for example, a protein preparation.

[0403] The syringe 2 includes a cylindrical body 6 having a distal end portion 60 and a proximal end portion 61 and a partitioning device 7 that partitions a space S inside the cylindrical body 6 into a proximal end space S1 and a distal end space S2. The syringe 2 is substantially cylindrical.

[0404] Next, in the prefilled syringe 1 and the syringe 2, one side of the front end portion 60 is configured ( Figure 1-Figure 4 The lower middle side) is referred to as the "front end side", and the side of the front end portion 61 ( Figure 1-Figure 4 The upper middle side) is simply referred to as the "base end side." In addition, the barrel axis direction of the syringe 2 is also simply referred to as the "barrel axis direction."

[0405] The barrel 6 is a component for storing medicine inside. In addition, the barrel 6 is provided with an outlet hole for injecting the medicine contained inside to the outside on the front end portion 60. In the present embodiment, the barrel 6 has a cylindrical portion 62 connecting the front end portion 60 and the base end portion 61 in addition to the front end portion 60 and the base end portion 61. The barrel 6 has a flange portion 63, which extends outward from the entire outer circumference of the other end of the barrel axial direction of the cylindrical portion 62 (in the radial outward direction of the cylindrical portion 62).

[0406] The barrel 6 is formed of a material that is transparent and can withstand the internal pressure applied by applying a drug. Specifically, the material of the barrel 6 is a resin containing a cyclic olefin such as norbornene as a repeating unit. More specifically, the material of the barrel 6 is a transparent resin formed by forming a copolymer such as COC (cyclic olefin copolymer) by a cyclic olefin single polymer COP (cyclic olefin polymer) and a cyclic olefin with ethylene, etc. The material of the barrel 6 can be pp (polypropylene) and glass.

[0407] In order to reduce the sliding resistance of the piston 3 with respect to the inner peripheral surface of the cylinder 6, silicone may be applied to the inner surface of the cylinder 6 (for example, the inner surface of the cylindrical portion 62).

[0408] The front end portion 60 of the barrel 6 is disposed at one end (specifically, the end portion on the front end side) of the barrel portion 62 in the barrel axial direction. Figure 3 and Figure 4 As shown, an injection hole 64 for injecting the medicine stored inside to the outside is provided. In the barrel 6 of this embodiment, the injection hole 64 is a needle hole through which the injection needle 4 is inserted.

[0409] When the needle inserted into the injection hole 64 is, for example, a 27G needle, the inner diameter of the injection hole 64 is 0.27 mm, and the area of ​​the injection hole 64 when viewed from the cylinder axis direction is 0.057 mm. 2 In addition, when the needle inserted into the injection hole 64 is 29G, the inner diameter of the injection hole 64 is 0.21mm, and the area of ​​the injection hole 64 when viewed from the cylinder axis direction is 0.035mm. 2 .

[0410] The proximal end surface 600 of the distal end portion 60 is configured to close a portion of the distal edge of the tubular portion 62 other than the injection hole 64. The proximal end surface 600 extends, for example, in a state of being inclined toward the distal end as it approaches the radially inner side.

[0411] The area of ​​the cylindrical portion 62 when viewed from the cylindrical axis direction is, for example, substantially constant, specifically, 12.56 mm. 2 Above and 314mm 2 The inner diameter of the cylindrical portion 62 is, for example, substantially constant, and specifically, is 4 mm or more and 20 mm or less.

[0412] The interior of the barrel 6 contains a partitioning device 7, and the partitioning device 7 divides the space S inside the barrel 6 into a base end side space S1 on the base end side in the barrel axis direction and a front end side space S2 on the front end side in the barrel axis direction. Figure 2-Figure 5 As shown, the base side space S1 which is the space closer to the base side than the partition device 7 contains the liquid preparation, and the front side space S2 which is the space closer to the front side than the partition device 7 is in an empty state without containing any medicine. Specifically, the front side space S2 includes a first front side space S21 which is a space closer to the front side than the filter 80 and does not contain any medicine, and a second front side space S22 which is a space closer to the base side than the filter 80 and does not contain any medicine.

[0413] Either the first distal space S21 or the second distal space S22 can contain a solid medicine. Alternatively, the base end space S1 and the distal space S2 can each contain a liquid medicine.

[0414] The partition device 7 includes a cylindrical housing 8 and an inner plug member 9 that can be opened and closed inside the housing 8. In this embodiment, the partition device 7 includes one housing 8 and one inner plug member 9. In addition, the partition device 7 is arranged at the front end portion 60 of the cylinder 6 (see Figure 3 and Figure 4 ). Furthermore, the partition device 7 includes a filter 80 installed in the housing 8 inside the cylinder 6. The partition device 7 includes one filter 80, or may include a plurality of filters 80 stacked on top of each other.

[0415] The partition device 7 may not include the filter 80. In this case, the partition device 7 is composed of, for example, a housing 8 and an inner plug member 9 that can open and close the interior of the housing 8.

[0416] The housing 8 is a component configured to be in liquid-tight contact with the inner side surface of the cylinder 6 (for example, the inner side surface of the cylindrical portion 62). In addition, the housing 8 is accommodated in the cylinder 6 in a state of being in pressure contact with the cylinder 6. Specifically, at least a portion of the outer peripheral surface 800 of the housing 8 is in close contact with the inner side surface of the housing.

[0417] In this embodiment, the outer peripheral surface 800 of the housing 8 includes a base end outer peripheral surface portion 801 disposed on the base end side, and a front end outer peripheral surface portion 802 disposed on the front end side, wherein the front end outer peripheral surface portion 802 is formed with a smaller diameter than the base end outer peripheral surface portion 801. Thus, the base end outer peripheral surface portion 801 is in liquid-tight close contact with the inner peripheral surface of the barrel 6. The front end outer peripheral surface 802 faces the inner peripheral surface of the barrel 6 through a gap.

[0418] In addition, the shell 8 is made of a flexible material. The shell 8 of this embodiment is more flexible than the barrel 6. Specifically, the material of the shell 8 is, for example, a resin, rubber, elastomer, etc. that is softer than the material of the barrel 6. The flexibility of the barrel 6 and the shell 8 can be determined, for example, by measuring the durometer hardness. The shell 8 is made of such a material, which ensures the flexibility of the shell 8 relative to the barrel 6 and prevents the barrel 6 from cracking.

[0419] The cylindrical body 8 has a cylindrical shape. In the present embodiment, the housing 8 is arranged on the proximal side of the filter 80. In other words, the housing 8 is composed only of the proximal side portion arranged on the proximal side of the filter 80.

[0420] In addition, although the housing 8 of the present embodiment is composed of only the proximal portion, the distal portion disposed on the distal side of the filter 80 may be composed integrally with or separately from the proximal portion.

[0421] The housing 8 has a closed engagement member 81. Specifically, the housing 8 has a closed engagement member 81. The closed engagement member 81 is when the inner plug member 9 is in the closed state (refer to Figure 3 ), which engages with the inner plug component 9.

[0422] When closed, the meshing component 81 protrudes radially inward from the inner circumferential surface 82 of the shell 8, is connected to all surrounding areas, or is formed in multiple numbers at intervals in all directions around. In the present embodiment, when closed, the meshing component 81 is a rib protruding from the inner circumferential surface 82 of the shell 8 toward the cylinder axis side (radial inner side). Specifically, when closed, the meshing component 81 is a rib that is continuous in the surrounding direction. In addition, when closed, the meshing component 81 is arranged in the central part of the inner circumferential surface 82 in the cylinder axis direction. When closed, the base end side end face of the meshing component 81 is a flat surface extending radially.

[0423] In addition, in the present embodiment, the inner circumferential surface 82 of the housing 8 includes a base end inner circumferential surface portion 821 arranged on the base end side and a distal end inner circumferential surface portion 822 arranged on the distal end side, and the base end inner circumferential surface portion 821 is configured with a larger diameter than the distal end inner circumferential surface portion 822 .

[0424] The above shell 8 has a small diameter inner circumferential surface on the front end side (specifically, the front end inner circumferential surface portion 822), a large diameter inner circumferential surface on the base end side (specifically, the base end inner circumferential surface portion 821), and a closed meshing part 81 between the small diameter inner circumferential surface and the large diameter inner circumferential surface.

[0425] In addition, the housing 8 has a stepped surface 810 extending radially inward from the inner peripheral surface 82 toward the base end side. Although the housing 8 has a stepped surface 810 at the base end side of the engagement member 81 when closed, the stepped surface 810 may be formed on other parts of the engagement member 81 when closed. Furthermore, the stepped surface 810 may be located on either side closer to the front end side or the base end side than the engagement member 81 when closed.

[0426] In the present embodiment, the housing 8 includes a mounting portion 83 for mounting the filter 80, a main body portion 84 where the engaging member 81 is located when closed, and an extension portion 85 extending from the main body portion 84. The mounting portion 83, the main body portion 84, and the extension portion 85 are arranged in this housing 8 in the order from the front end side to the base end side. In addition, in this housing 8, any of the mounting portion 83, the main body portion 84, and the extension portion 85 are cylindrical. The thickness of the housing 8 (the distance between the inner peripheral surface and the outer peripheral surface of the housing 8 in the radial direction of the cylindrical axis direction and the perpendicular direction) is not uniform. Specifically, the thickness of the mounting portion 83 is thicker than the thickness of the extension portion 85.

[0427] The outer circumference of the mounting portion 83 is slightly separated from the inner circumference of the barrel 6 (specifically, the inner circumference of the cylindrical portion 62 of the barrel 6). Furthermore, the mounting portion 83 has a tapered shape with a smaller outer diameter as it approaches the front end side. The inner circumference of the mounting portion 83 has a tapered shape with a larger inner diameter as it approaches the front end side.

[0428] The main body portion 84 is a connecting portion between the mounting portion 83 and the extension portion 85. The outer peripheral surface of the main body portion 84 is slightly separated from the inner peripheral surface of the cylinder 6 (specifically, the inner peripheral surface of the cylindrical portion 62 of the cylinder 6). Furthermore, the main body portion 84 has a tapered shape with a smaller outer diameter as it approaches the front end side. The inner peripheral surface of the main body portion 84 is composed of a protruding surface of the meshing member 81 when closed. In addition, the inner peripheral surface of the main body portion 84 is located closest to the radial inner side of the inner peripheral surface of the housing 8.

[0429] The outer peripheral surface of the extension portion 85 is in contact with the inner peripheral surface of the barrel 6 (specifically, the inner peripheral surface of the cylindrical portion 62 of the barrel 6). In this way, since the outer peripheral surface of the extension portion 85 is in close contact with the inner peripheral surface of the barrel 6, it is possible to prevent the medicine from leaking from the front end side through the outer peripheral surface of the housing 8 and the inner peripheral surface of the barrel 6. The inner peripheral surface of the extension portion 85 is located closer to the radial outside than the inner peripheral surface of the mounting portion 83. That is, the inner diameter of the extension portion 85 becomes larger than the inner diameter of the mounting portion 83.

[0430] In the above-described housing 8, the radially inner side of the meshing member 81 forms a liquid flow path C8 (see FIG. 1 ) which is a passage for the drug solution from the base end side space S1 to the front end side space S2 when the housing 8 is closed. Figure 4 ). That is, the liquid flow path C8 is formed inside the inner peripheral surface of the main body portion 84.

[0431] The inner plug member 9 is a member that can be opened and closed for the interior of the housing 8 in such a manner that the base end side space S1 and the front end side space S2 become connected or disconnected through the interior of the housing 8. In the present embodiment, the inner plug member 9 is a plug disposed inside the housing 8, but may also be a cover covering the front end side of the housing 8.

[0432] In addition, when the inner plug member 9 is in the closed state, the inner plug member 9 has a closed-time engaged member 90 (see Figure 3 ). The closed-time engaged component 90 is arranged on the front end side and the base end side of the closed-time engaged component 81. Specifically, the closed-time engaged component 90 includes a base end side closed-time engaged component 901 located on the base end side and a front end side closed-time engaged component 902 located on the front end side. That is, the inner plug component 9 has a plurality of (for example, two) closed-time engaged components 90.

[0433] The inner plug member 9 has a limiting device 91, which is used to release the engagement between the engagement member 81 when closed and the engaged member 90 when closed, and to limit the movement of the inner plug member 9 in the state where the base end side space S1 and the front end side space S2 are in a connected state toward the front end side. The inner plug member 9 has the limiting device 91, so that the base end side space S1 and the front end side space S2 are in a connected state, and the inner plug member 9 is prevented from blocking the flow path of the injection hole 64 and the like.

[0434] In this embodiment, the restricting device 91 restricts the movement of the inner plugging member 9 toward the distal end side at a position where the inner plugging member 9 is separated from the proximal end side of the filter 80. In this way, the inner plugging member 9 can be prevented from clogging the hole of the filter 80.

[0435] In addition, the inner plug member 9 has a cover portion 92 which has an outer peripheral surface of the meshed member 90 when closed and is capable of opening and closing the liquid flow path C8 of the housing 8. Further, the inner plug member 9 has a stepped meshing member 93 which is arranged closer to the base end side than the cover portion 92 and protrudes radially outward than the cover portion 92, and a piston flow path C9 (see FIG. 1 ) which is arranged radially inward of the stepped meshing member 93 and is formed between the cover portion 92 and the stepped meshing member 93 in the cylinder axial direction. Figure 4 Thus, when the inner plug member 9 is in the open state, the liquid contained in the base end side space S1 flows from the base end side to the front end side (according to the pressure drop) through the piston flow path C9 radially inward of the step meshing member 93 and the liquid flow path C8 radially inward of the meshing member 81 when closed. Figure 4 The liquid medicine flows smoothly into the front side space S2 through the cover portion 92 and the closed engagement member 81. In addition, since the outer peripheral portion 920 of the cover portion 92 and the front end inner peripheral surface portion 822 of the housing 8 are configured so that there is no contact throughout the entire periphery, the liquid medicine can flow evenly throughout the entire periphery.

[0436] In this embodiment, the inner plug member 9 has a step surface 810 as a limiting device 91, and a step engagement member 93 protruding radially outward and capable of engaging with the step surface 810 from the base end side. The limiting device 91 includes the step surface 810 and the step engagement member 93, and since the step engagement member 93 engages with the step surface 810 from the base end side, the movement of the inner plug member 9 can be effectively limited.

[0437] The step engagement member 93 is provided, for example, in a continuous or discontinuous manner in all directions around the periphery, and is provided in a continuous manner in the present embodiment. With such a configuration, the engagement between the engagement member 81 and the engaged member 90 during closing is released, and the inner plug member 9 moves toward the front end side. At the time point when the base end side space S1 and the front end side space S2 are completely connected, the step engagement member 93 provided in a continuous or discontinuous manner in all directions around the periphery engages with the step surface 810 from the base end side, and the movement of the inner plug member 9 toward the front end side is restricted. Since the step engagement member 93, the step surface 810, and the cover portion 92 are all configured in a manner that the entire outer periphery is in all directions on the radially outer side, the inner plug member 9 is restricted from moving in a stable posture.

[0438] The inner plug member 9, in addition to the cover portion 92, also includes a foot portion 94 extending from the cover portion 92. In this embodiment, the inner plug member 9 is as shown in FIG. Figure 5 and Figure 6As shown in FIG. 1 , the inner plug member 9 includes a plurality of foot portions 94 (specifically, four foot portions 94). In addition, the inner plug member 9 includes a plurality of protruding portions 95 (specifically, four protruding portions 95) protruding from each foot portion 94 toward the housing 8 side (radially outward). Furthermore, the inner plug member 9 includes an annular portion 96 connecting the plurality of protruding portions 95.

[0439] The inner plug member 9 has a protruding portion 95 as the step engagement member 93 , and more specifically, the inner plug member 9 has an annular portion 96 other than the protruding portion 95 as the step engagement member 93 .

[0440] The cover portion 92 is an embedded portion inside the housing 8 (see Figure 3 and Figure 4 ). In addition, the cover portion 92 has a part 90 to be engaged when closed on the outer peripheral surface, which is a part that can be opened and closed to the inside of the shell 8. Furthermore, the cover portion 92 is a partition between the base end side space S1 and the front end side space S2. For example, the cover portion 92 is roughly disc-shaped. The part 90 to be engaged when closed is set in the outer peripheral portion 920 of the cover portion 92. The inner peripheral portion 921 of the cover portion 92 (located at a position closer to the radial inner side than the outer peripheral portion 920 of the cover portion 92) has a cover foot member 922 extending from a position on the disc to the base end side. In the present embodiment, the base end side end face of the cover foot member 922 is located closer to the front end side than the base end side end face of the foot portion 94. In addition, the base end side end face of the cover foot member 922 is located closer to the front end side than the base end side end face of the protruding portion 95. Furthermore, the base end side end face of the cover foot member 922 is located closer to the front end side than the base end side end face of the annular portion 96.

[0441] The foot cover member 922 protrudes from the radial center of the cover portion 92 toward the base end. The outer diameter of the foot cover member 922 is smaller than the outer diameter of the cover portion 92. The foot cover member 922 is disposed at the radial center of the area surrounded by the plurality of foot portions 94 (plural protruding portions) in the outer peripheral direction. In addition, the foot cover member 922 is disposed at the radial center of the area surrounded by the annular portion 96.

[0442] The engaged part 90 when closed is, for example, a convex portion protruding from the side of the housing 8. Specifically, the engaged part 90 when closed is a rib protruding from the side of the housing 8. In the present embodiment, the engaged part 90 when closed is a rib continuously arranged in the peripheral direction, but may also be a plurality of ribs spaced apart over the entire periphery in the peripheral direction.

[0443] When the base end side is closed, the engaged member 901 is provided at the top of the base end side of the cover portion 92. When the front end side is closed, the engaged member 902 is provided at the top of the front end side of the cover portion 92.

[0444] The engaged component 901 when the base end side is closed and the engaged component 902 when the front end side is closed are arranged in a separated manner in the cylindrical axis direction. The engaged component 901 when the base end side is closed and the engaged component 902 when the front end side is closed constitute a cover recessed portion 97. The cover recessed portion 97 is engaged with the engaged component 81 when the shell 8 is closed from the radial outer direction. In this engaged state, the engaged component 901 when the base end side is closed engages with the engaged component 81 when the closed state, restricting the movement of the plug component 9 in the shell 8 toward the front end side. In addition, in the engaged state, the engaged component 902 when the front end side is closed engages with the engaged component 81 when the closed state, restricting the movement of the plug component 9 in the shell 8 toward the base end side.

[0445] The leg portion 94 is a portion extending toward the proximal side from the top portion of the proximal side of the outer peripheral portion 920 of the cover portion 92. The plurality of leg portions 94 (specifically, four leg portions 94) are arranged at equal intervals in the circumferential direction.

[0446] The piston flow path C9 is formed on the radially inner side of the foot portion 94. The piston flow path C9 includes an axial flow path C91 formed on the radially inner side of the foot portion 94 in the cylinder axis direction, and a connecting flow path C92 connecting the axial flow path C91 and the space on the radially outer side of the foot portion 94 (see Figure 4 The axial flow path C91 is arranged radially inside the protruding portion 95 and is formed along the cylinder axis direction between the protruding portion 95 and the cover portion 92. The connecting flow path C92 is formed between the plurality of leg portions 94 and is open radially outward, and is connected to the axial flow path C91 radially outside the axial flow path C91.

[0447] The protruding portion 95 is a portion extending from the distal end of the base end side of the leg portion 94 toward the housing 8. The plurality of protruding portions 95 (specifically, four protruding portions 95) are arranged at equal intervals in the peripheral direction.

[0448] The annular portion 96 is a portion connected to the top end (radially outer top end) of the protruding portion 95 on the housing 8 side. The annular portion 96 has, for example, an annular shape. The annular portion 96 may also have an annular shape other than an annular shape, such as a prism shape.

[0449] In the above inner plug component 9, when the inner plug component 9 is in an open state, since the stepped engaging part 93 (specifically, the protruding portion 95, in the present embodiment, the protruding portion 95 and the annular portion 96) of the inner plug component 9 is engaged with the stepped surface 810 (the base end side end surface of the engaging part 81 when closed) of the shell 8, the further movement of the inner plug component 9 toward the front end side (the detachment of the inner plug component 9 from the engaging part 81 when closed) is restricted.

[0450] In addition, the inner plug member 9 can contact the piston 3 inserted from the base end side in the cylinder 6. That is, the inner plug member 9 includes a contact surface 98 that can contact the inserted piston 3.

[0451] The contact surface 98 is a surface on the base end side of the inner plug member 9. Specifically, the contact surface 98 is formed by the surface on the lower end side of the cover portion 92. More specifically, the contact surface 98 is formed by the base end side end surface of the cover foot member 922 and the base end side end surface of the foot portion 94.

[0452] The inner plug member 9 is made of a flexible material. In the present embodiment, the inner plug member 9 is more flexible than the cylinder 6. Specifically, the material of the inner plug member 9 is, for example, a resin, rubber, or elastomer that is softer than the material of the cylinder 6. The flexibility of the inner plug member 9 can be determined, for example, by measuring the durometer hardness. The material of the inner plug member 9 can be, for example, the same as the material of the housing 8, or it can be different.

[0453] The filter 80 is a filter for filtering medicine. In addition, the filter 80 is arranged at the front end side portion of the housing 8 (in the present embodiment, the front end surface 830 of the mounting portion 83 of the housing 8), and is arranged inside the barrel 6 closer to the base end side than the injection hole 64.

[0454] In this embodiment, the filter 80 is mounted on the front end side portion of the housing 8, and specifically, contacts the front end surface 830. The contact is ultrasonic welding, but other welding methods including thermal welding may also be used. The filter 80 may also contact the front end surface 830.

[0455] In the above syringe 2, the partition device 7 is configured as follows: when pressure is applied by the piston 3 inserted from the base end side of the barrel 6, one of the closed engaging member 81 and the closed engaged member 90 passes over the other, and the engagement between the closed engaging member 81 and the closed engaging member 90 is released, thereby opening the inner plug member 9 to the inside of the housing 8, so that the base end side space S1 and the front end side space S2 are connected. In other words, the partition device 7 is configured to open the inner plug member 9 from the closed state (see Figure 3 ) becomes open (refer to Figure 4 ). Specifically, it is constructed in the following manner: when the piston 3 applies a pressing force from the base end side, at least one of the closed engaging member 81 and the closed engaged member 90 is elastically deformed, the closed engaged member 90 passes over the closed engaging member 81, and the inner plug member 9 moves toward the front end side, thereby releasing the engagement between the closed engaging member 81 and the closed engaged member 90, and the inner plug member 9 is opened to the inside of the housing 8, so that the base end side space S1 is connected to the front end side space S2.

[0456] Furthermore, in the syringe 2, the filter 80 is sandwiched between the barrel 6 and the mounting portion 83 of the housing 8. Specifically, the filter 80 is sandwiched in the barrel axial direction by the base end surface 600 of the front end portion 60 of the barrel 6 and the front end surface 830 of the mounting portion 83. Thus, when administering the drug solution, even if pressure is applied to the filter 80, the filter 80 is unlikely to be disengaged from the mounting portion 83.

[0457] Furthermore, in the syringe 2, the base end space S1, the front end space S2, and the injection hole 64 are arranged in order from the base end side to the front end side. In the syringe 2 of this embodiment, the central axis of the base end space S1 and the central axis of the front end space S2 are both consistent with the central axis of the injection hole 64. Therefore, when the medicine is administered, the flow of the medicine from the base end space S1 to the injection hole 64 is good.

[0458] The syringe 2 of this embodiment may also be sterilized by radiation such as gamma rays. The sterilization may be performed by using a gas such as ethylene oxide gas or an autoclave.

[0459] The piston 3 is a component that is operated when the medicine in the cylinder 6 is ejected. The piston 3 of this embodiment includes: an axial rod component 30, a washer 31 installed at one end of the rod component 30 in the longitudinal direction and in close contact with the entire inner circumference of the tubular component 62 of the cylinder 6, and an operating portion 32 installed at the other end of the rod component 30 in the longitudinal direction.

[0460] In the piston 3 of the present embodiment, the front end surface 33 is constituted by the front end surface of the gasket 31. Specifically, when the administration of the drug is completed, the front end surface 33 contacts the end surface of the inner plug member 9 on the proximal end side.

[0461] In addition, the piston 3 is operated by a doctor or a nurse etc., but can also be operated by a patient. In this case, the prefilled syringe 1 can also be installed in an automatic syringe.

[0462] The injection needle 4 is a member for administering the medicine in the cylinder 6 to the patient. The front end of the injection needle 4 is covered with a protective cap 5 .

[0463] According to the above syringe 2, from the state where the closed engagement member 81 is engaged with the closed engagement member 90, one passes over the other by the extrusion force of the piston 3 (in the present embodiment, from the state where the closed engagement member 81 is engaged with the closed engagement member 901 on the base end side, the closed engagement member 901 on the base end side passes over the closed engagement member 81 by the extrusion force), thereby the engagement is released at once. Therefore, the partitioning device 7 in the partition cylinder 6 is reliably opened, the base end side space S1 is communicated with the front end side space S2, and the liquid medicine can be smoothly injected.

[0464] In the syringe 2 of the present embodiment, since there is another one between the closed engaging part 81 and the closed engaged part 90 arranged at the front end side and the base end side (in the present embodiment, the closed engaging part 81 is located between the closed engaged part 901 on the base end side and the closed engaged part 902 on the front end side), the movement of the inner plug part 9 in the closed state toward the front end side and the base end side in the direction of the cylinder axis with respect to the shell 8 can be restricted, and unintentional movement during transportation, etc. can be restricted.

[0465] In addition, in the syringe 2 of the present embodiment, since the filter 80 is arranged at the front end side portion of the shell 8, the partition device 7 separates the inside of the cylinder 6 before the injection of the medicine. Therefore, if the medicine is contained in the base end side space S1, the filter 80 can be prevented from contacting the medicine before injection.

[0466] Furthermore, in the syringe 2 of the present embodiment, since the partition device 7 is arranged at the front end portion of the barrel 6, the filter 80 can be prevented from contacting the medicine contained in the base end side space S1 before the medicine is injected, and after the partition device 7 in the partition barrel 6 is opened, the filter 80 can filter the medicine.

[0467] The structure of the partition device 7 may be different from the above structure. For example, the inner plug member 9 only needs to include the member 90 to be engaged during closing, and may be different from the above structure.

[0468] Specifically, if Figure 7 to Figure 12 As shown, the inner plug member 9 may not have the annular portion 96. That is, it is conceivable that the inner plug member 9 includes the engaged member 90 when closed, the cover portion 92 covering the base end side space S1, the foot portion 94 extending from the cover portion 92, the foot portion 94 (specifically, four foot portions 94), and a plurality of protruding portions 95 (specifically, four protruding portions 95) protruding from each foot portion 94 to the housing 8 side (radially outward side).

[0469] In addition, the inner plug member 9 may include a connection portion connecting the cover portion 92 (specifically, the cover foot portion 922 of the cover portion 92) and the foot portion 94. In this case, when the inner plug member 9 is pressed by the piston 3, the radial deflection of the foot portion 94 generated in the state where the step engagement portion 93 (protruding portion 95) is engaged with the step surface 810 can be restricted by the connection portion.

[0470] Furthermore, the inner plug member 9 may include a bolt extension portion extending in the circumferential direction from the end portion (the end portion on the radially outward side) of the protruding portion 95 on the housing 8 side instead of the annular portion 96. For example, a plurality of bolt extension portions may be provided, extending from each protruding portion 95. A plurality of bolt extension portions may be arranged with gaps therebetween in the circumferential direction.

[0471] In addition, the inner plug member 9 may not include the leg portion 94 or the protruding portion 95, and may be composed of the member to be engaged 90 and the cover portion 92 when closed, for example.

[0472] In addition, in the above-mentioned embodiment, when the squeezing force is applied from the base end side by the piston 3, at least one of the closed engaging part 81 and the closed engaged part 90 is elastically deformed, the closed engaged part 90 passes over the closed engaging part 81, and the inner plug part 9 moves toward the front end side, and the engagement between the closed engaging part 81 and the closed engaged part 90 is released. However, it is also possible that when the squeezing force is applied, at least one of the closed engaging part 81 and the closed engaged part 90 is elastically deformed, the closed engaging part 81 passes over the closed engaged part 90, and the shell 8 moves toward the front end side, and the engagement between the closed engaging part 81 and the closed engaged part 90 is released.

[0473] Even with such a structure, the engagement between the closed engaging member 81 and the closed engaged member 90 can be released at once by one passing over the other by the squeezing force of the piston 3. Therefore, the partitioning device 7 in the partition cylinder 6 is reliably opened, the base end side space S1 is connected to the front end side space S2, and the liquid medicine can be smoothly injected.

[0474] In the above-mentioned embodiment, the partition device 7 has one engagement member 81 when closed and a plurality of (specifically, two) engagement members 90 when closed, but it may also have a plurality of engagement members 81 when closed and one engagement member 90 when closed. Specifically, the engagement member 81 when closed may be arranged at the front end side and the base end side relative to the engagement member 90 when closed. In this case, in the housing 8, a recess may be formed between the engagement members 81 when closed arranged at the front end side and the base end side. In the recess, the engagement member 90 when closed of the inner plug member 9 is engaged from the radial inner direction. In this engaged state, the engagement member 81 when closed arranged at the base end side engages with the engagement member 90 when closed from the base end side, restricting the movement of the inner plug member 9 to the base end side relative to the housing 8. In addition, in the engaged state, the engagement member 81 when closed arranged at the front end side engages with the engagement member 90 when closed from the front end side, restricting the movement of the inner plug member 9 to the front end side relative to the housing 8. In addition, the partitioning device 7 may also have a closed-engaging member 81 and a closed-engaged member 90.

[0475] In the above embodiment, the partitioning device 7 is disposed at the front end portion 60 of the cylinder 6, but it may be disposed at a midway position in the axial direction of the cylinder 6. For example, in a state where the partitioning device 7 is disposed at a midway position in the axial direction of the cylinder 6 and separates the base end side space S1 and the front end side space S2, the liquid dose ML may be contained in the base end side space S1, and the solid dose MS may be contained in the front end side space S2 (specifically, the first front end side space S21) (see Fig.13 (a)). From this state, the piston 3 applies a pressing force from the base end side, as shown in FIG. Fig.13 As shown in (b), when the inner plug member 9 is opened to the inside of the housing 8 and the base end side space S1 is connected to the front end side space S2, the liquid agent ML flows from the base end side space S1 into the front end side space S2. Fig.13 As shown in (c), a mixed medicine MM of a solid medicine MS and a liquid medicine ML is obtained. Fig.13 As shown in (d), a mixed drug MM can be administered.

[0476] As described above, in the present embodiment, the partition device 7 is constructed as follows: it is arranged at the midway position in the axial direction of the cylinder 6, and divides the space inside the cylinder 6 into a base end side space S1 and a front end side space S2, and opens when the extrusion of the piston 3 from the base end side space S1 reaches a specified pressure, and moves to the front end portion 60 of the cylinder 6 in an open state along with the extrusion operation of the piston 3 toward the front end side of the cylinder 6.

[0477] Furthermore, since the partition device 7 that partitions the proximal space S1 and the distal space S2 includes the filter 80 , when the partition device 7 is opened and the liquid ML flows from the proximal space S1 into the distal space S2 , unnecessary solid matter can be captured by the filter 80 .

[0478] In addition, the partition device 7 may also be a structure without the filter 80. For example, it is conceivable that Fig.14 As shown in (a), the partition device 7 includes only the housing 8 and the inner plug member 9, which are arranged midway in the cylinder 6, and the filter member 86 including the filter 80 is arranged separately from each other on the front end side of the partition device 7.

[0479] It is considered that even in this case, the space S inside the cylinder 6 can be divided into a base side space S1 and a front side space S2 by the partition device 7, wherein the base side space S1 is a space closer to the base side than the shell 8 and the inner plug member 9, and the front side space S2 is a space closer to the front side than the shell 8 and the inner plug member 9. In the present embodiment, the front side space S2 includes a third front side space S3 as a space between the shell 8 and the inner plug member 9 and the filter member 86, and a fourth front side space S4 as a space closer to the front side than the filter member 86. It is considered that in this structure, the liquid agent ML is contained in the base side space S1, the liquid agent ML or the solid agent MS is contained in the third front side space S3, and the solid agent MS is contained in the fourth front side space S4 or the space is empty. In the present embodiment, the liquid agent ML is contained in the base side space S1, the solid agent MS is contained in the third front side space S3, and the fourth front side space S4 is empty.

[0480] In addition, in the partition device 7, the housing 8 does not include the filter 80, and the filter member includes the filter 80. In addition, both the housing 8 and the filter member 86 are substantially cylindrical. In addition, in the present embodiment, the inner peripheral surface of the filter member 86 is formed with a smaller diameter than the inner peripheral surface of the housing 8, but the inner peripheral surface of the filter member 86 may be formed with substantially the same diameter as the inner peripheral surface of the housing 8.

[0481] In this structure, in a state where the partitioning device 7 partitions the base end side space S1 and the third front end side space S3, the liquid agent ML contained in the base end side space S1 and the solid agent MS contained in the third front end side space S3 are separated. From this state, the piston 3 applies a pressing force from the base end side, such as Fig.14 As shown in (b), when the inner plug member 9 is opened to the inside of the housing 8 and the base end side space S1 is connected to the third front end side space S3, the liquid ML flows from the base end side space S1 into the third front end side space S3. Fig.14 As shown in (c), a mixed medicine MM of a solid medicine MS and a liquid medicine ML is obtained. Fig.14 As shown in (d), a mixed drug MM can be administered.

[0482] As described above, the partitioning device 7 is formed such that the housing 8 and the inner plug member 9 disposed at the midway position of the cylinder 6 in the axial direction divide the space S in the cylinder 6 into the base end side space S1 and the front end side space S2, and is opened when the extrusion of the piston 3 from the base end side space S1 reaches a predetermined pressure, and moves to the front end portion 60 of the cylinder 6 in an open state along with the extrusion operation of the piston 3 toward the front end side of the cylinder 6. In addition, in this structure, there are provided: a filter member 86 disposed closer to the front end side than the housing 8, and having a flow hole communicating from the base end side to the front end side, and a filter 80 mounted on the filter member 86, and filtering the liquid flowing through the flow hole. Therefore, when the inner plug member 9 is opened to the housing 8, the liquid agent ML flows from the base end side space S1 into the front end side space S2, is mixed with the solid agent MS and is poured out from the front end portion 60 of the cylinder 6, the unnecessary solid matter can be captured by the filter 80. Furthermore, since the filter member 86 is disposed at the front end portion 60 of the cylinder 6 so as not to move toward the front end side, the pressing resistance of the piston 3 when the housing 8 moves toward the front end side can be made uniform.

[0483] Furthermore, for example, it is conceivable that the partition device 7 includes a combination of two housings 8 and inner plug members 9, and is separately arranged in a manner that one combination is arranged on the base end side and the other combination is arranged on the front end side. In this case, it is conceivable that the following configuration is used: the liquid medicine ML is accommodated in a space closer to the base end side than the housing 8 and inner plug member 9 located on the base end side, the liquid medicine ML or the solid medicine MS is accommodated in a space between the housing 8 and inner plug member 9 located on the base end side and the housing 8 and inner plug member 9 located on the front end side, and the solid medicine MS is accommodated in a space closer to the front end side than the housing 8 and inner plug member 9 located on the front end side, or the space is empty.

[0484] In addition, when the multiple meshing parts 81 are arranged at intervals on the entire circumference, the multiple meshing parts 81 can also be arranged at the position on the opposite side of the clamping cylinder shaft. In addition, the multiple meshing parts 81 can also be arranged at equal intervals on the circumference. In the case where the meshed parts 90 are also arranged at intervals on the entire circumference, the multiple meshed parts 90 can also be arranged at the position on the opposite side of the clamping cylinder shaft, or can be arranged at equal intervals on the circumference. In such a structure, since the meshing parts 81 and the meshed parts 90 are stably meshed when sealed, it is difficult for the inner plug part 9 to disengage from the housing 8 during the transportation of the syringe 2.

[0485] In one aspect of the present invention, a retaining member 10 may be disposed in the cylinder instead of the partitioning device. In the present specification, the retaining member 10 is a partitioning device that does not have an inner plug and is only composed of a shell. The retaining member 10 is a member on which a filter 80 is installed. In addition, the retaining member 10 is accommodated in the cylinder 6 in a state of being crimped to the cylinder 6. Specifically, at least a portion of the outer peripheral surface of the retaining member 10 is in close contact with the inner peripheral surface of the cylinder 6.

[0486] In addition, the holding member 10 is formed of a material having flexibility. The holding member 10 of the present embodiment is more flexible than the barrel 6. Specifically, the material of the holding member 10 is, for example, a resin, rubber, elastomer, etc. that is softer than the material of the barrel 6. The flexibility of the barrel 6 and the holding member 10 can be determined, for example, by measuring the durometer hardness. By forming the holding member 10 from such a material, the flexibility of the holding member 10 with respect to the barrel 6 can be ensured, and cracking of the barrel 6 can be prevented.

[0487] The holding member 10 includes a proximal portion 110 disposed closer to the proximal side than the filter 80. The holding member 10 of this embodiment is composed only of the proximal portion 110. The proximal portion 110 of the holding member 10 is provided with a flow path 111 through which the drug flows from the proximal side to the distal side.

[0488] The proximal portion 110 of the holding member 10 has a contact surface 200 as a proximal end surface 200 that can contact the piston 3 inserted into the cylinder 6 from the proximal side. The proximal portion 110 has a cylindrical shape with the distal end side blocked by a disk having a through hole at the center.

[0489] The contact surface 200 of the base end portion 110 has a shape corresponding to the front end surface 33 of the piston 3. The contact surface 200 is configured so as to contact the front end surface 33 of the piston 3 over the entire circumferential surface of the cylinder 6.

[0490] The contact surface 200 of this embodiment is, for example, Fig.16 As shown, it includes: a base end side contact surface 201 located on the base end side, a front end side contact surface 202 located on the front end side, and a connecting contact surface 203 connecting the base end side contact surface 201 and the front end side contact surface 202 .

[0491] The base end side contact surface 201 is, for example, a surface substantially perpendicular to the axial direction. The tip end side contact surface 202 is, for example, a surface substantially perpendicular to the axial direction.

[0492] The connection contact surface 203 is a surface extending in the axial direction. For example, the center portion of the connection contact surface 203 in the axial direction is recessed in the radially outward direction.

[0493] The base end portion 110 of this embodiment includes a mounting portion 112 to which the filter 80 is mounted and a leg portion 113 extending from the mounting portion 112. In the base end portion 110, the mounting portion 112 is provided on the distal end side, and the leg portion 113 is arranged on the base end side.

[0494] The flow path 111 is provided at the mounting portion 112 of the base end portion 80. The area of ​​the flow path 111 when viewed from the axial direction (the cross-sectional area of ​​the flow path 111 in the direction perpendicular to the axial center) of the present embodiment is constant. In addition, the area of ​​the flow path 111 when viewed from the axial direction is 0.64 mm 2 Above and 1.33mm 2 The inner diameter of the flow path 111 of the present embodiment is fixed. The inner diameter of the flow path 111 is, for example, 0.3 mm or more and 0.9 mm or less. The flow path 111 is a through hole, specifically a cylindrical shape, but may also be a square cylindrical shape.

[0495] The mounting part 112 has a shape in which the outer peripheral part protrudes toward the front end side. The outer peripheral surface of the mounting part 112 of the present embodiment is slightly separated from the inner peripheral surface of the barrel 6 (specifically, the inner peripheral surface of the tubular member 62 of the barrel 6). Furthermore, the mounting part 112 has a tapered shape in which the outer diameter is smaller as it approaches the front end side. In addition, the mounting part 112 has a mounting outer peripheral part 220 constituting the outer peripheral part and a mounting inner peripheral part 221 located closer to the inner side of the diameter than the mounting outer peripheral part 220 and defining the flow path 111.

[0496] Furthermore, in the mounting part 112, the outer peripheral front end surface 222, which is the front end surface of the mounting outer peripheral portion 220, is located closer to the front end side than the inner peripheral front end surface 223, which is the front end surface of the mounting inner peripheral portion 221. In other words, the front end surface of the mounting part 112 is recessed at the center portion in the circumferential direction. The mounting outer peripheral portion 220 has a shoulder portion 224 as the outer peripheral portion on the front end side.

[0497] The foot portion 113 has a shape in which the outer peripheral portion protrudes toward the base end side. The base end surface 230 of the foot portion 113 constitutes the contact surface 200 of the base end side portion 110. The outer peripheral surface of the foot portion 113 is in surface contact with the inner peripheral surface of the barrel 6 (specifically, the inner peripheral surface of the tubular member 62 of the barrel 6). In this way, the outer peripheral surface of the foot portion 113 is in close contact with the inner peripheral surface of the barrel 6, and the medicine reliably passes through the flow path 111 of the retaining member 10 and is filtered through the filter 80.

[0498] The filter 80 of this embodiment is mounted on the front end surface 804 of the base end side portion 110 of the holding member 10. Specifically, the filter 80 is bonded to the front end surface 204. More specifically, the filter 80 is bonded to the outer peripheral front end surface 222 of the mounting outer peripheral portion 220. The bonding is ultrasonic welding, but other bonding methods including heat welding and other welding methods may also be used. In addition, the filter 80 may also be bonded to the front end surface 204.

[0499] In addition, if Fig.17 As shown, before the filter 80 is bonded, a protruding portion 225 protruding toward the front end side is provided at the base end side portion 110 (for example, the mounting peripheral portion 220). When the filter 80 is bonded, the protruding portion 225 melts and expands, so that after the filter 80 is bonded, the front end surface 204 of the base end side portion 110 becomes a substantially flat surface.

[0500] The front end side subspace 71 is defined by the inner peripheral surface 65 of the cylinder 6 (specifically, the base end side end surface 600 of the front end portion 60) and the filter 80 (specifically, the front end side surface of the filter 80). In addition, the front end side subspace 71 is connected to the injection hole 64. In this specification, the front end side subspace 71 corresponds to the first front end side space S21.

[0501] Furthermore, the front end side subspace 71 has, for example, a shape in which the area (cross-sectional area in a direction perpendicular to the axis) when viewed from the cylindrical direction decreases from the base end side to the front end side, that is, a tapered shape in which the area (cross-sectional area in a direction perpendicular to the axis) when viewed from the cylindrical direction decreases as it approaches the front end side. The front end side subspace 71 of the present embodiment is roughly cylindrical. The front end side subspace 71 has, for example, a shape in which the inner diameter decreases from the base end side to the front end side, that is, a tapered shape in which the inner diameter decreases as it approaches the front end side. In addition, the front end side subspace 71 has a shape in which the distance between the filter 80 and the base end face 600 of the front end portion 60 of the barrel 6 decreases as it approaches the outer peripheral side. As a result, when the drug is administered, the drug solution is squeezed into the front end side subspace 71 in a state in which it is easy to move from the outer peripheral side to the barrel axis side in the circumferential direction, thereby suppressing the injection resistance. In addition, the front end side subspace 71 may also be a square cylinder.

[0502] The base end side portion of the front end side subspace 71, i.e., the portion with the largest area (e.g., inner diameter) of the front end side subspace 71, is parallel to the shoulder portion 224 in the axial direction of the cylinder 6, and its inner diameter is approximately the same as the outer diameter of the shoulder of the retaining component 10.

[0503] The base end side subspace 72 is defined by the filter 80 (specifically, the base end side surface of the filter 80) and the front end surface 204 of the base end side portion 110 (specifically, the inner peripheral front end surface 223 of the mounting inner peripheral portion 221 and the mounting inner peripheral surface 226 as the inner peripheral surface of the mounting outer peripheral portion 220). In addition, the base end side subspace 72 is formed by the inner peripheral front end surface 223 of the mounting inner peripheral portion 221 being recessed closer to the base end side than the outer peripheral front end surface 222 of the mounting outer peripheral portion 220, that is, by the front end surface of the mounting portion 112 being recessed toward the base end side. In the present specification, the base end side subspace 72 corresponds to the second front end side space S22. In addition, the space combining the front end side subspace 71 and the base end side subspace 72 corresponds to the front end side space S2.

[0504] In addition, the base end side subspace 72 is connected to the flow path 111. Furthermore, the base end side subspace 72, for example, has a shape in which the surface area increases from the base end side to the front end side when viewed from the axial direction, that is, a tapered shape in which the area increases as it approaches the front end side when viewed from the axial direction. The base end side subspace 72 of the present embodiment is roughly cylindrical. The base end side subspace 72, for example, has a shape in which the inner diameter increases from the base end side to the front end side, that is, a tapered shape in which the inner diameter increases as it approaches the front end side. The inclination angle of the mounting inner peripheral surface 226 of the mounting outer peripheral portion 220 that specifies the base end side subspace 72 relative to the axial direction is smaller than the inclination angle of the base end side end surface 600 of the front end portion 60 that specifies the front end side subspace 71 relative to the axial direction. In addition, the base end side subspace 72 may also be a square cylinder.

[0505] In the above syringe 2, the cylinder 6 and the base end portion 110 of the holding member 10 sandwich the filter 80. Specifically, the base end face 600 of the front end portion 60 of the cylinder 6 (specifically, the base end edge 601 of the base end face 600) and the shoulder portion 224 of the base end portion 110 sandwich the filter 80 in the axial direction. Thus, when the drug solution is administered, even if pressure is applied to the filter 80, the filter 80 is difficult to be detached from the base end portion 110.

[0506] The flow path 111, the base end subspace 72, the front end subspace 71, and the injection hole 64 are arranged in order from the base end side to the front end side. In the syringe 2 of this embodiment, the central axis of the flow path 81, the central axis of the base end subspace 72, and the central axis of the front end subspace 71 are all consistent with the central axis of the injection hole 64. Therefore, when the medicine is administered, the flow of the medicine from the flow path 111 to the injection hole 64 is good.

[0507] The dimension L81 of the flow path 111 in the axial direction is larger than the dimension L72 of the proximal subspace 72 in the axial direction. In addition, the dimension L71 of the distal subspace 71 in the axial direction (specifically, the dimension on the central axis of the distal subspace 71) is larger than the dimension L72 of the proximal subspace 72 in the axial direction.

[0508] When viewed from the axial direction, the area of ​​the injection hole 64 is smaller than the area of ​​the base end side subspace 72, smaller than the area of ​​the front end side subspace 71, and smaller than the area of ​​the flow path 111. This means that the area of ​​the injection hole 64 is smaller than the area of ​​any portion in the axial direction of the base end side subspace 72, smaller than the area of ​​any portion in the axial direction of the front end side subspace 71, and smaller than the area of ​​any portion in the axial direction of the flow path 111. Specifically, the area of ​​the injection hole 64 is smaller than the area of ​​the base end side subspace 72, smaller than the maximum area of ​​the front end side subspace 71 (the area of ​​the base end side edge of the front end side subspace 71), and smaller than the area of ​​the flow path 111.

[0509] Furthermore, when viewed from the axial direction, the area of ​​the flow path 111 is smaller than the area of ​​the proximal subspace 72. This means that the area of ​​the flow path 111 is smaller than the area of ​​any portion of the proximal subspace 72 in the axial direction.

[0510] Specifically, the inner diameter R64 of the injection hole 64 is smaller than the inner diameter R72 of the base end side subspace 72, smaller than the maximum inner diameter R71 of the front end side subspace 71 (the inner diameter of the base end side edge of the front end side subspace 71), and smaller than the inner diameter R81 of the flow path 111. In addition, the inner diameter R81 of the flow path 111 is smaller than the inner diameter R72 of the base end side subspace 72.

[0511] Regarding such a dimensional relationship, an experiment was conducted by combining the cylinder 6 with an inner diameter R64 of the injection hole 64 of 0.27 mm and 0.21 mm and the retaining component 10 with an inner diameter R81 of the flow path 111 of 0.3 mm, 0.6 mm, and 0.9 mm and an inner diameter R72 of the base end side subspace 72 of 0.6 mm, 2.1 mm, and 3.6 mm to study the influence on the injection resistance (specifically, the sliding load).

[0512] The results of this experiment are as follows. When the inner diameter R72 of the base end side subspace 72 is 0.6 mm, an increase in the sliding load is confirmed. When the inner diameter R72 of the base end side subspace 72 is 2.1 mm and 3.6 mm, no significant change in the sliding load is found. In addition, when the inner diameter R81 of the flow path 111 is changed within the above range, no significant change in the sliding load is found.

[0513] For example, the inner diameter R81 of the flow path 111 is preferably greater than 1 time and less than 5 times the inner diameter R64 of the outlet hole 64, and is preferably greater than 1.1 times and less than 4.3 times the inner diameter R64 of the outlet hole 64. When the inner diameter R64 of the outlet hole 64 is 0.21 mm or 0.27 mm, the inner diameter R81 of the flow path 111 can be selected from any one of 0.3 mm, 0.6 mm, and 0.9 mm. In addition, for example, the inner diameter R72 of the base end side subspace 72 (the filtering area of ​​the filter 80) is preferably greater than 5 times and less than 20 times the inner diameter R64 of the outlet hole 64, and is preferably greater than 7 times and less than 18 times the inner diameter R64 of the outlet hole 64. When the inner diameter R64 of the outlet hole 64 is 0.21 mm or 0.27 mm, the inner diameter R72 of the base end side subspace 72 can be selected from any one of 2.1 mm and 3.6 mm. If the inner diameters R72 and R71 of the proximal subspace 72 and the distal subspace 71 are within this range, it is possible to ensure a filtering area when administering a drug and suppress injection resistance.

[0514] In addition, the syringe 2 of this embodiment can be sterilized by radiation such as gamma rays. This sterilization can be performed by using a gas such as ethylene oxide gas or an autoclave.

[0515] The piston 3 is a component that is operated when the medicine in the cylinder 6 is ejected. The piston 3 of this embodiment includes: an axial rod component 30, a washer 31 installed at one end of the rod component 30 in the longitudinal direction and in close contact with the entire inner circumference of the tubular component 62 of the cylinder 6, and an operating portion 32 installed at the other end of the rod component 30 in the longitudinal direction.

[0516] In the piston 3 of the present embodiment, the front end surface 33 is constituted by the front end surface of the gasket 31. Specifically, when the drug is administered, the front end surface 33 contacts at least the base end side contact surface 201 of the base end side portion 110 of the retaining member 10, and more specifically, contacts the connection contact surface 203 in addition to the base end side contact surface 201.

[0517] In addition, the piston 3 has a close contact portion 34 that is in close contact with the inner peripheral surface of the cylinder 6, and a protrusion portion 35 that is protruded from the front end surface of the close contact portion 34. The front end surface of the close contact portion 34 is in contact with the base end side contact surface 201, and the front end surface of the protrusion portion 35 is in contact with the front end side contact surface 802. In addition, the outer peripheral surface of the protrusion portion 35 is in close contact with the connection contact surface 203.

[0518] The injection needle 4 is a member for administering the medicine in the cylinder 6 to the patient. The front end of the injection needle 4 is covered with a protective cap 5 .

[0519] According to the above syringe 2, even if particles exist in the medicine contained in the barrel 6, the particles can be captured by the filter 80 when the medicine is administered, and then the medicine flows through the flow path 111, the base end side subspace 72, and the front end side subspace 71, which have an area (for example, inner diameter) larger than the injection hole 64, and is injected from the injection hole 64. Therefore, the resistance when the medicine flows through the flow path 111, the base end side subspace 72, and the front end side subspace 71 can be suppressed, and as a result, the injection resistance of the medicine can be suppressed.

[0520] In the syringe 2 of the present embodiment, since the area (e.g., inner diameter) of the flow path 111 is reduced and the area (e.g., inner diameter) of the base end side subspace 72 is increased, the area contacted by the medicine in the filter 80 (the filtration area of ​​the filter 80) can be ensured and the amount of medicine remaining in the flow path 111 can be reduced, thereby suppressing the injection resistance and the amount of residual liquid.

[0521] In addition, in the syringe 2 of the present embodiment, when the medicine is administered, the front end surface 33 of the piston 3 moves until it contacts the contact surface 200 of the retaining component 10 in the entire circumferential direction, thereby suppressing the residual liquid between the piston 3 and the retaining component 10 and suppressing the amount of residual liquid of the medicine in the cylinder 6.

[0522] In addition, the syringe of the present invention is not limited to the above-mentioned embodiment, and various changes can be made within the scope of the main purpose of the present invention. For example, the structure of other embodiments can be added to the structure of a certain embodiment, and a part of the structure of a certain embodiment can be replaced with the structure of other embodiments. Furthermore, a part of the structure of a certain embodiment can be deleted.

[0523] The structure of the holding member 10 may be different from the above structure. For example, the contact surface 200 of the base end portion 80 may be a different shape as long as it corresponds to the contact surface 33 of the piston 3.

[0524] Specifically, the connection contact surface 203 of the above embodiment extends along the axial direction, but may also include a portion extending in a direction inclined relative to the axial direction. Fig.18 and Fig.19 As shown, the connection contact surface 203 may include: a first connection contact surface 203a which is a surface substantially perpendicular to the axial direction, and second connection contact surfaces 203b and 203c which are a pair of surfaces extending from two edges of the first connection contact surface 203a along the axial direction.

[0525] Specifically, the base end side contact surface 201 in the above embodiment is a surface that is substantially perpendicular to the axial direction, but may also include a portion that is inclined at an angle other than perpendicular to the axial direction. Fig. 20 and Fig.21 As shown, the base side contact surface 201 may include: a first base side contact surface 201a which is a surface substantially perpendicular to the axial direction, and a second base side contact surface 201b which is a surface further extending in the radial direction from the edge in the radial direction of the first base side contact surface 201a and inclined in such a manner that the closer the portion is to the radial direction side, the closer it is to the front end side.

[0526] Even with such a structure, by moving the front end surface 33 of the piston 3 until it contacts the contact surface 200 of the holding member 10 over the entire circumference, residual liquid between the piston 3 and the holding member 10 can be suppressed, and the amount of residual liquid of the medicine in the cylinder 6 can be suppressed.

[0527] The holding member 10 in the above embodiment is composed of the proximal portion 110 , but the distal portion disposed on the distal side of the filter 80 may be integrally included with the proximal portion 110 or may be separately included.

[0528] Furthermore, in the holding member 10 of the above embodiment, the inner diameter of the flow path 111 is smaller than the inner diameter of the proximal side subspace 72 , but may be substantially identical to the inner diameter of the proximal side subspace 72 .

[0529] In the retaining member 10 of the above-described embodiment, the contact surface 200 of the base end portion 110 is configured to be in surface contact with the front end surface 33 of the piston 3 over the entire circumference of the cylinder 6, but it may be configured to be in surface contact with a portion of the circumference of the front end surface 33 of the piston 3. For example, it is conceivable that recessed portions or raised portions are intermittently provided in the circumferential direction with respect to the base end side contact surface 201 of the contact surface 200 of the base end portion 110.

[0530] In the syringe 2 of the above embodiment, the distal subspace 71 is a tapered shape with a decreasing inner diameter toward the distal end, but may also be another shape with a uniform inner diameter. In this case, it is conceivable that the proximal end surface 600 extends in a direction perpendicular to the axial direction, for example.

[0531] The proximal side subspace 72 has a tapered shape in which the inner diameter decreases toward the distal side, but may also have other shapes such as a shape in which the inner diameter is uniform.

[0532] Furthermore, the dimension of the flow channel 111 in the axial direction may be smaller than or equal to the dimension of the proximal end side subspace 72 in the axial direction.

[0533] Furthermore, the dimension of the distal end side subspace 71 in the axial direction may be less than the dimension of the proximal end side subspace 72 in the axial direction. It is conceivable that, in this case, for example, the proximal end side portion 110 of the holding member 10 is arranged at a position in contact with the proximal end side portion 600, or the dimension of the proximal end side portion 110 of the holding member 10 in the axial direction is increased, based on the reduction of the inclination angle of the proximal end face 600 of the distal end portion 60 of the barrel 6 with respect to the barrel axis.

[0534] The partition device 7 or the holding member 10 is configured as follows: the volume of the front end side space of the cylinder 6 is 150mm 3 Below, 110mm 3 Below, 40mm 3 Below, 20mm depending on the situation 3 Below, preferably 18mm 3 The volume of the front end side space (S2) of the cylinder 6 is 15 volume % or less, 7 volume % or less, 5 volume % or less, 2 volume % or less, and preferably 1.8 volume % or less of the volume of the entire cylinder 6.

[0535] In this specification, the sliding resistance of the syringe is the resistance when the piston in the cylinder is slid, and is expressed as a sliding load. In this specification, the term of injection resistance is also used in the same meaning as the sliding resistance.

[0536] (2) Filter

[0537] The filter 80 may be, for example, a membrane, or a mesh, a sintered body, or a foamed body. The material of the filter 80 is resin, ceramic, metal, paper, etc. In the present embodiment, the filter 80 is, for example, a membrane filter. In addition, the filter 80 may also be a pre-filter.

[0538] In one aspect, the filtering area of ​​the filter 80 is the area of ​​the front end side edge of the base end side subspace (72, S22) and the area of ​​the base end side edge of the front end side subspace (71, S21). The area of ​​the front end side edge of the base end side subspace (72, S22) is, for example, equal to the area of ​​the base end side edge of the front end side subspace (71, S21).

[0539] In one aspect, the filter has a film thickness of 100 μm to 400 μm, 125 μm to 350 μm, or 150 μm to 310 μm.

[0540] In one aspect, the filter has a tensile strength of 1000 Psi or more, 2000 Psi or more, 3000 Psi or more when dry or wet, preferably 3500 Psi or more. More preferably, the filter has a tensile strength of 3700 Psi or more when dry, and 3900 Psi or more when wet.

[0541] In one aspect, the filter has an elongation at break of 10% or more, 20% or more, 30% or more, or 40% or more when dry or wet, and preferably has a tensile strength of 45% or more. More preferably, the filter has a tensile strength of 50% or more when dry and a tensile strength of 60% or more when wet.

[0542] In one aspect, the material of the filter includes at least one selected from the group consisting of polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS), and acrylic copolymer.

[0543] Polyethersulfone (PES) has a repeating unit as shown below.

[0544] [Chemical formula 1]

[0545]

[0546] In one aspect, as the polyethersulfone, Supor (registered trademark) (Nihon Pall Ltd.), Millipore Express (Merck Co., Ltd.), and Sartopore (registered trademark) (Sartorius) are preferred, and Supor is particularly preferred.

[0547] Polyvinylidene fluoride (PVDF) has a repeating unit as shown below.

[0548] [Chemical formula 2]

[0549]

[0550] In one aspect, as the polyethersulfone, Durapore (registered trademark) (Merck Co., Ltd.) and Fluorodyne (registered trademark) II (Nihon Pall Ltd.) are preferred, and Durapore is particularly preferred.

[0551] Polysulfone (PS) has a repeating unit as shown below.

[0552] [Chemical formula 3]

[0553]

[0554] In one aspect, as the polysulfone, Asymmetric Super Micron Polysulfone (NihonPall Ltd.) is preferred.

[0555] In one aspect, the acrylic copolymer can be formed on a nonwoven nylon support. In addition, the acrylic copolymer can also be covered by a hydrophilic or hydrophobic coating. In one aspect, as a filter of the acrylic copolymer, a filter of a preferred hydrophobic acrylic copolymer, particularly preferably VERSAPOR (registered trademark) (Nihon Pall Ltd.).

[0556] When a hydrophilic filter is wetted with a solution, air enters and sometimes causes a gas lock phenomenon in which air accumulates inside the thickness of the barrel. The prefilled syringe has a certain amount of space inside, and depending on the direction of use, the possibility of air lock occurring when the air contained in the space passes through after the solution passes cannot be denied. It is known that in the case of gas lock, the filtration performance will be greatly reduced, but this phenomenon generally does not occur in a hydrophobic filter. Therefore, by using a hydrophobic filter, the above risk can be avoided.

[0557] In one aspect, the filter has a pore size of less than 5 μm, preferably 5 μm. In this specification, the pore size of the filter is a property of the filter that is fixed by the diameter of the particles that can be clearly expected to be captured with high efficiency. As the fixed filtration accuracy, "nominal filtration accuracy" and "absolute filtration accuracy" are used. The nominal filtration accuracy refers to the size of the particles that the filter manufacturer uses a range to indicate the size of the particles that can guarantee a certain rate of removal of mixed substances. The absolute filtration accuracy is a value indicating the size of the smallest particle that the filter can completely remove. As a method for measuring the nominal filtration accuracy, ACFTD (AC Fine Test Dust) can be cited. In this method, the particle size that meets the set particle removal rate is used as the filtration accuracy. As a method for measuring the absolute filtration accuracy, a method for measuring the maximum diameter of ACFTD or beads that allows ACFTD or glass beads to pass through the filter once and flow out to the downstream side can be cited. In this specification, the pore size is expressed by absolute filtration accuracy.

[0558] In this specification, the integrity of the filter is a benchmark for the quality of the filter, indicating whether the filter has the desired filtering performance in an important process that requires sterility assurance. As tests for the integrity of the filter, a forward flow test and a bubble point test can be cited. The forward flow test is a quantitative test that applies a certain test pressure to the primary side of the filter when the secondary side of the fully wetted membrane is at atmospheric pressure, and measures the diffusion flow rate through the liquid membrane based on the pressure difference between the primary side of the filter and the stimulated secondary side. In addition, the bubble point test is a quantitative test that applies a certain test pressure to the primary side of the filter when the secondary side of the fully wetted membrane is at atmospheric pressure, and measures the diffusion flow rate through the liquid membrane based on the pressure difference between the primary side of the filter and the stimulated secondary side.

[0559] In this specification, "the solution is kept in a non-contact state with the filter before use" means that the solution is filled into the cylinder in a manner that does not contact the filter in the cylinder, and before use, even if the stress of the expected level of load is usually applied, the non-contact state is maintained. In this case, the use of the injection preparation includes the manufacture of the injection preparation and after manufacture. The stress of the expected level usually refers to the mechanical stress of the drop stress, vibration stress and rotation stress applied in the operation such as transportation during manufacture or after manufacture, but is not limited to this. In one aspect, the injection preparation is usually subjected to 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 25 times or more, 30 times or more or 40 times of drop pressure. The stress applied to the prefilled syringe when falling varies according to the height, direction, etc. in addition to the number of drops. The drop height is, for example, 38.1 cm as described in American Society for Testing and Materials (ASTM) D4169, but is not limited thereto. In one aspect, the non-contact state between the solution and the filter is achieved by separating the cylinder with a partition device, accommodating the drug preparation in the base end side space, and configuring the filter on the front end side of the partition device. "The solution is in contact with the filter before use" means that the solution is in contact with the filter during a certain period or the entire period during the manufacture of the injection preparation or during the storage, transportation, etc. after the manufacture.

[0560] In this specification, "the solution flows from the base end side of the filter to the front end side through the filter" means that the solution filled in the barrel of the syringe, which is closer to the base end side than the filter, moves to the front end side than the filter in the barrel by the piston or the squeezing including the weight. The solution moved to the front end side than the filter in the barrel is injected to the outside through the injection hole.

[0561] (3) Pharmaceutical preparations

[0562] In one aspect of the present invention, the pharmaceutical preparation is a medium molecular compound containing low molecular weight compounds, natural products, polynucleotides, peptides, or a solution containing protein as an effective ingredient. In this specification, low molecular weight compounds refer to compounds with a molecular weight of less than 500, and medium molecular weight compounds refer to compounds with a molecular weight of 500 to 1500. In one aspect of the present invention, medium molecular weight compounds include natural products with a molecular weight of 500 to 2000, polynucleotides with a molecular weight of 3000 to 15000, and peptides with a molecular weight of 600 to 6000. Peptides include cyclic peptides. In addition, polynucleotides include ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and low molecular weight interfering RNAs (siRNAs). The pharmaceutical preparation can be an injection preparation.

[0563] In one aspect of the present invention, the injection preparation is a pharmaceutical preparation filled in an injection container for administration by injection and containing a protein as an active ingredient in a solution. In one aspect of the present invention, the injection preparation includes an injection container such as a syringe as a component.

[0564] In one aspect of the invention, the solution of the pharmaceutical preparation has a viscosity of 95cP or less, 90cP or less, 85cP or less, 80cP or less, 75cP or less, 70cP or less, 65cP or less, 60cP or less, 55cP or less, 50cP or less, 45cP or less, 40cP or less, 35cP or less, 30cP or less, 25cP or less, 20cP or less, 15cP or less, 10cP or less, or 1cP to 95cP. Viscosity can be measured using, for example, an electromagnetic rotation (Electro-Magnetically Spinning; EMS) method. In this assay, a torque is applied to a probe as a conductor by remote operation, and its rotation is optically read to measure viscosity.

[0565] In one aspect of the present invention, the pharmaceutical preparation is stored at -30°C to 40°C, -30°C to 25°C, preferably at the freezing point of the solution to 25°C, more preferably at 1°C to 10°C, more preferably at 2°C to 8°C, and even more preferably at 5°C, without freezing the solution in the container. The storage is performed for 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, and 96 hours. The storage is carried out for at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 10 days, at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months.

[0566] In one aspect of the present invention, the proteins used in the solution preparation include antibodies, fusion proteins, enzymes, hormones, cytokines, and vaccines, but are not limited thereto. More specifically, they include monoclonal antibodies, granular colony stimulating factor (G-CSF), granular macrophage colony stimulating factor (GM-CSF), erythropoietin (EPO), interferon, interleukins such as IL-1 or IL-6, tissue plasminogen activator (TPA), thrombopoietin, urokinase, serum albumin, blood coagulation factor VIII, leptin, stem cell growth factor (SCF), etc.

[0567] In one aspect of the present invention, the protein used in the pharmaceutical preparation has substantially the same biological activity as the physiologically active protein of mammals, especially humans, and includes proteins of natural origin and proteins obtained by gene recombination. Proteins obtained by gene recombination include proteins with the same amino acid sequence as the natural protein, or proteins with one or more deletions, substitutions, additions of the amino acid sequence and having the biological activity.

[0568] In one aspect of the present invention, the concentration of the protein in the solution may be above 0.1 mg / mL, in the range of 0.1 to 300 mg / mL, in the range of 1 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0569] In one aspect of the present invention, the antibody used is not particularly limited, as long as it binds to the desired antigen, and can be a polyclonal antibody or a monoclonal antibody, but from the viewpoint of being able to stably produce homogeneous antibodies, monoclonal antibodies are preferred. In addition, in one aspect of the present invention, the antibody used can be a monospecific antibody, a bispecific antibody, or an antibody with multiple specificity having three or more antigen recognition sites in the molecule.

[0570] In one aspect of the present invention, the monoclonal antibodies used include not only monoclonal antibodies from animals such as humans, mice, rats, hamsters, rabbits, sheep, camels, monkeys, etc., but also artificially modified genetic recombinant antibodies such as chimeric antibodies, humanized antibodies, and bispecific antibodies. Furthermore, it also includes genetic recombinant antibodies in which the constant region of the antibody is artificially modified in order to change the physical properties of the antibody molecule for the purpose of improving blood retention and in vivo dynamics (specifically, changes in isoelectric point (p1), changes in affinity for Fc receptors, etc.).

[0571] In one aspect of the present invention, the immunoglobulin class of the antibody used is not particularly limited and may be any class such as IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, etc., but IgG is preferred, and IgG1, IgG2 and IgG4 are particularly preferred.

[0572] Furthermore, in one aspect of the present invention, the antibodies used include not only antibodies having constant regions and variable regions (full-length antibodies), but also antibody binding fragments such as Fv, Fab, F(ab)2, or low-molecular-weight antibodies such as single-chain Fv (scFv, sc(Fv)2) or bispecific antibodies such as scFv dimers in which the variable regions of antibodies are linked with linkers such as peptide linkers, but full-length antibodies are preferred.

[0573] In one aspect of the present invention, the antibody used can be prepared by a known method. Hybridomas that produce monoclonal antibodies can be prepared as follows using basically known techniques. That is, a desired antigen or a cell expressing a desired antigen is used as a sensitizing antigen, and immunized according to a conventional immunization method. The obtained immune cells are fused with known parent cells by a conventional cell fusion method, and cells (hybridomas) that produce monoclonal antibodies are screened by a conventional screening method, thereby preparing the hybridoma. The preparation of hybridomas can be carried out, for example, according to the method of Miller et al. (Kohler. G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46). In the case where the immunogenicity of the antigen is low, it can be immunized by binding to a macromolecule with immunogenicity such as albumin.

[0574] In addition, genetically recombinant antibodies produced in the following manner can be used, that is, antibody genes are cloned from hybridomas, integrated into appropriate vectors, introduced into hosts, and produced using genetic recombination techniques (for example, refer to Carl, AKBorrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990). Specifically, reverse transcriptase is used to synthesize cDNA of the variable region (V region) of the antibody from the mRNA of the hybridoma. When the DNA encoding the V region of the target antibody is obtained, it is connected to the DNA encoding the desired antibody constant region (C region) and integrated into an expression vector. Alternatively, the DNA encoding the V region of the antibody can also be integrated into an expression vector containing the DNA of the antibody C region. In a manner of expression under the control of an expression control region, such as an enhancer or a promoter, it is integrated into an expression vector. Then, the host cell can be transformed by the expression vector to express the antibody.

[0575] In one aspect of the present invention, genetically modified recombinant antibodies, such as chimeric antibodies, humanized antibodies, etc., which are artificially modified for the purpose of reducing heterologous antigenicity to humans, etc., can be used. These modified antibodies can be prepared using known methods. Chimeric antibodies are antibodies composed of the variable regions of the heavy and light chains of mammals other than humans, such as mouse antibodies, and the constant regions of the heavy and light chains of human antibodies. They can be obtained by connecting DNA encoding the variable regions of mouse antibodies with DNA encoding the constant regions of human antibodies, integrating them into expression vectors, and then introducing them into hosts to produce them, thereby obtaining them.

[0576] Humanized antibodies are also called reshaped human antibodies. They are antibodies in which the complementarity determining regions (CDRs) of mammals other than humans, such as mouse antibodies, are transplanted to the complementarity determining regions of human antibodies. The general gene recombination method is also known. Specifically, a DNA sequence designed to link the CDRs of mouse antibodies and the framework regions (FRs) of human antibodies is synthesized by PCR from multiple oligonucleotides made to have overlapping parts at the ends. The obtained DNA is connected to the DNA encoding the constant region of the human antibody, and then integrated into an expression vector, which is introduced into the host and produced, thereby obtaining (refer to European Patent Application Publication No. 239400, WO96 / 02576). As the FR of the human antibody linked by the CDR, the FR in which the complementary determining region forms a good antigen binding site is selected. As needed, the amino acids in the framework region of the antibody variable region can be replaced so that the complementary determining region of the reconstructed human antibody forms a suitable antigen binding site (Sato, K. et al., Cancer Res. (1993) 53, 851-856).

[0577] As a technology for replacing the amino acids of antibodies in order to improve the activity, physical properties, pharmacokinetics, safety, etc. of the antibodies, for example, the technology described below is known. In one aspect of the present invention, the antibodies used also include antibodies in which such amino acid replacement (including deletion or addition) has been performed.

[0578] As a technology for performing amino acid substitution on the variable region of IgG antibody, humanization (Tsurushita N, Hinton PR, Kumar S., Design of humanized antibodies: from anti-Tac to Zenapax., Methods. 2005 May; 36(1): 69-83.) is a representative one. Affinity maturation by amino acid substitution in the complementarity determining region (CDR) for enhancing binding activity (Rajpal A, Beyaz N, Haber L, Cappuccilli G, Yee H, Bhatt RR, Takeuchi T, Lerner RA, Crea R., A general method for greatly improving the affinity of antibodies by using combinatorial libraries., Proc Natl Acad Sci USA. 2005 Jun 14; 102(24): 8466-71.) and improvement of physicochemical stability by amino acid substitution in the framework (FR) (Ewert S, Honegger A, Pluckthun A., Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering., Methods. 2004 Oct; 34(2): 184-99. Review). In addition, as a technology for implementing amino acid substitution in the Fc region of an IgG antibody, a technology for enhancing antibody-dependent cellular cytotoxicity (ADCC) activity or complement-dependent cytotoxicity (CDC) activity is known ((Kim SJ, Park Y, Hong HJ., Antibody engineering for the development of therapeutic antibodies., Mol Cells. 2005 Aug 31; 20(1): 17-29. Review.).Furthermore, Fc amino acid substitution techniques have been reported to enhance not only such effector functions but also the half-life of antibodies in blood (Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N., An engineered human IgG1 antibody with longer serum half-life., J Immunol. 2006 Jan 1; 176(1): 346-56., Ghetie V, Popov S, Borvak J, Radu C, Matesoi D, Medesan C, Ober RJ, Ward ES., Increasing the serum persistence of an IgG fragment by random mutagenesis., Nat Biotechnol. 1997 Jul; 15(7): 637-40.). Furthermore, various amino acid substitution techniques for constant regions for the purpose of improving the physical properties of antibodies are also known (WO09 / / 41613).

[0579] In addition, methods for obtaining human antibodies are also known. For example, human antibodies can also be obtained in the following manner, that is, in vitro (in vitro), human lymphocytes are sensitized with the desired antigen or cells expressing the desired antigen, and the sensitized lymphocytes are fused with human myeloma cells such as U266 to obtain the desired human antibodies with binding activity to the antigen (refer to Japanese Patent Publication No. 1-59878). In addition, the desired human antibodies (WO 93 / 12227, WO 92 / 03918, WO 94 / 02602, WO 94 / 25585, WO96 / 34096, WO 96 / 33735) can be obtained by immunizing transgenic animals with a full repertoire of human antibody genes with antigens. Furthermore, it is also known to use a human antibody library (library) to obtain the technology of human antibodies by panning. For example, the variable region of human antibodies can be expressed on the phage surface as a single-chain antibody (scFv) by phage display, and the phage that binds to the antigen is selected. If the genes of the selected phage are analyzed, the DNA sequence of the variable region of the human antibody that binds to the antigen can be determined. If the DNA sequence of the scFv that binds to the antigen is revealed, an appropriate expression vector containing the sequence can be prepared and human antibodies can be obtained. These methods are well known and can refer to WO 92 / 01047, WO 92 / 20791, WO 93 / 06213, WO 93 / 11236, WO 93 / 19172, WO 95 / 01438, WO 95 / 15388. In one aspect of the present invention, the antibodies used also include such human antibodies.

[0580] Once the antibody gene is isolated and introduced into a suitable host to prepare the antibody, a combination of a suitable host and an expression vector can be used. In the case of using eukaryotic cells as hosts, animal cells, plant cells, and fungal cells can be used. As animal cells, known: (1) mammalian cells, such as CHO, COS, myeloma, BHK (babyhamster kidney), HeLa, Vero; (2) amphibian cells, such as African clawed frog oocytes; or (3) insect cells, such as sf9, sf21, Tn5, etc. As plant cells, known from the genus Nicotiana, such as cells from Nicotiana tabacum, as long as their callus is cultured. As fungal cells, known: yeast, such as the genus Saccharomyces, such as Sacchromyces serevisiae; filamentous fungi, such as the genus Aspergillus, such as Aspergillus niger, etc. In the case of using prokaryotic cells, there is a production system using bacterial cells. As bacterial cells, Escherichia coli (E. coli) and Bacillus subtilis are known. The antibody is obtained by introducing the target antibody gene into these cells by transformation and culturing the transformed cells in vitro.

[0581] Furthermore, antibodies used in pharmaceutical preparations include modified antibodies. For example, antibodies bound to various molecules such as polyethylene glycol (PEG) or cytotoxic agents can also be used (Farmaco. 1999 Aug 30; 54(8): 497-516., Cancer J. 2008 May-Jun; 14(3): 154-69). Such modified antibodies can be obtained by chemically modifying antibodies. These methods have been established in the art.

[0582] In one aspect of the invention, the antibodies of the present disclosure may be chimeric antibodies. Chimeric antibodies are described in, for example, U.S. Pat. No. 4,816,567, Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984). Chimeric antibodies may include non-human variable regions (e.g., variable regions from non-human primates such as monkeys, or mice, rats, hamsters, or rabbits, etc.) and human constant regions.

[0583] In one aspect of the invention, the antibodies of the present disclosure may be humanized antibodies. Typically, non-human antibodies are humanized to maintain the specificity and affinity of the parent non-human antibodies and to reduce immunogenicity in humans. Typically, humanized antibodies include more than one variable region, in which there is HVR, such as CDR (or a portion thereof) from non-human antibodies and FR (or a portion thereof) from human antibody sequences. Humanized antibodies may optionally include at least a portion of a human constant region. In one embodiment, the amino acid residues of the FRs in the humanized antibodies, for example, in order to maintain or improve the specificity or affinity of the antibody, may be replaced by the corresponding amino acid residues of non-human antibodies (e.g., antibodies from HVR residues).

[0584] Humanized antibodies and methods for preparing them are reviewed, for example, in the following (Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)), and further described in: Riechmann et al., Nature 332: 323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86: 10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36: 25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28: 489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the "guided selection" method for FR shuttling).

[0585] In one aspect of the invention, human frameworks that can be used for humanization may include, for example, frameworks selected using the "best fit" method (Sims et al. J. Immunol. 151:2296 (1993)), frameworks from the consensus sequence of human antibodies of a particular subgroup of heavy or light chain variable regions (Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992) and Presta et al. J. Immunol., 151:2623 (1993)), framework regions from FR libraries (Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0586] In one aspect of the invention, the antibodies disclosed herein may be human antibodies. Human antibodies may be prepared by various techniques. Human antibodies are described, for example, in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-374 (2001) or Lonberg, Curr. Opin. Immunol. 20:450-459 (2008). Human antibodies may be prepared by administering an immunogen to a transgenic animal that is engineered to produce complete human antibodies or complete antibodies with human variable regions in response to an antigen. Such an animal typically includes all or a portion of a human immunoglobulin locus, which exists in a state of replacing an endogenous immunoglobulin locus or randomly entering an extrachromosomal or intrachromosomal region of the animal. In such transgenic mice, the endogenous immunoglobulin locus is typically inactivated. For a review of methods for obtaining human antibodies from transgenic animals, reference is made to Lonberg, Nat. Biotech. 23:1117-1125 (2005). In addition, for example, refer to U.S. Patent Nos. 6,075,181 and 6,150,584 describing the XENOMOUSE (trademark) technology; U.S. Patent No. 5,770,429 describing the HUMAB (registered trademark) technology; U.S. Patent No. 7,041,870 describing the KM MOUSE (registered trademark) technology; and US2007 / 0061900 describing the VELOCIMOUSE (registered trademark) technology. The human variable region from the complete antibody produced by such an animal can be further modified by, for example, combining with a different human constant region.

[0587] In another aspect of the present invention, human antibodies can also be prepared by hybridoma-based methods. Human myeloma cells and mouse-human heteromyeloma cell lines used to produce human monoclonal antibodies are described in the following (e.g., Kozbor J. Immunol., 133: 3001 (1984); 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991)). Human antibodies generated by human B cell hybridoma technology are described in Li et al., Proc. Natl. Acad. Sci. USA, 103: 3557-3562 (2006). Other methods include, for example, U.S. Pat. No. 7,189,826 (describing the preparation of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4): 265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (trioma technology) is described in Vollmers and Brandlein, Histology and Histopathology, 20(3): 927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3): 185-91 (2005).

[0588] In another aspect of the present invention, human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human phage display libraries. Such variable domain sequences can then be combined with desired human constant regions. The method for selecting human antibodies from antibody libraries is as follows.

[0589] In one aspect of the invention, the antibodies of the present disclosure can be isolated by screening combinatorial libraries for antibodies having the desired one or more activities. For example, methods for making phage display libraries, methods for screening such libraries for antibodies having the desired binding properties, etc. are known in the art. This method is reviewed in Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and is described, for example, in McCafferty et al., Nature 348: 552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, Molecular Biology 248: 161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004).

[0590] In a specific phage display method in one aspect of the present invention, the VH and VL libraries can be cloned separately by polymerase chain reaction (PCR) and randomly recombined in a phage library, which can be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). The phage displays binding fragments of antibodies, such as scFv or Fab. Libraries from immunized supply sources can provide high-affinity antibodies to immunogens without the need to construct hybridomas. In another embodiment, as described in Griffiths et al., EMBO J, 12: 725-734 (1993), naive libraries (e.g., from humans) can also be cloned to provide a single source of antibodies against a wide range of non-self or self antigens without immunization. In another embodiment, the naive library can also be prepared by using a PCR primer containing a random sequence as described in Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992), wherein the random sequence is cloned from the V-gene segment before recombination of the stem cell, encoding the hypervariable region CDR3, and the recombination is achieved in vitro. Patent documents describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373, US2005 / 0079574, US2005 / 0119455, US2005 / 0266000, US2007 / 0117126, US2007 / 0160598, US2007 / 0237764, US2007 / 0292936, and US2009 / 0002360.

[0591] Antibodies or binding fragments thereof isolated from a human antibody library are regarded as human antibodies or binding fragments of human antibodies in the present specification.

[0592] In one aspect of the invention, the antibodies of the present disclosure are multispecific antibodies (e.g., bispecific antibodies). Multispecific antibodies are antibodies (e.g., monoclonal antibodies) that have binding specificities at at least 2 different sites. In one embodiment, one of the binding specificities is for an antigen and the other is for other antigens. In another embodiment, a bispecific antibody can bind to two different epitopes of an antigen. Bispecific antibodies can be used to localize cytotoxic agents to cells expressing an antigen. Bispecific antibodies can be prepared as full-length antibodies or binding fragments of antibodies.

[0593] There are no particular limitations on the method for preparing multispecific antibodies, and examples include recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (e.g., Milstein and Cuello, Nature 305: 537 (1983), WO93 / 08829, and Traunecker et al., EMBO J. 10: 3655 (1991)), and knob-in-hole technology (e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies can also be prepared by the following methods: modifying electrostatic steering effects to produce Fc heterodimeric molecules (e.g., WO2009 / 089004A1); cross-linking two or more antibodies or their binding fragments (e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce antibodies with two specificities (e.g., Kostelny et al., J. Immunol., 148(5): 1547-1553 (1992)); using "diabody" technology to produce bispecific binding fragments (e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993)); using scFv dimers (e.g., Gruber et al., J. Immunol., 152: 5368-5371 (1993)); (1994)); and preparation of trispecific antibodies (e.g., Tutt et al. J. Immunol. 147:60 (1991)). Furthermore, antibodies including "octopus antibodies" may be manipulated to have three or more functional antigen-binding sites (e.g., US2006 / 0025576).

[0594] In one aspect of the invention, the antibodies or binding fragments thereof disclosed herein may be "bi-Fab" or "DAF", which comprises one antigen binding site that binds to an antigen and another different antigen (eg, US 2008 / 0069820).

[0595] In one aspect of the invention, a modified version (variant) of the amino acid sequence of an antibody disclosed herein can be prepared by introducing appropriate modifications or synthetic peptides into the nucleic acid encoding the antibody molecule. Such modifications can be combined with one or more of any deletion, insertion, or substitution of any amino acid (residue) into the amino acid sequence as appropriate. Any combination of deletion, insertion, or substitution can be used as long as the final construct has the desired characteristics (e.g., antigen binding).

[0596] In one aspect of the present invention, when providing antibody remodels (variants) with one or more amino acid substitutions, the target sites for introducing the substitution mutations may include HVR and FR.

[0597] Examples of antibodies used in pharmaceutical preparations include anti-tissue factor antibodies, anti-IL-6 receptor antibodies, anti-IL-6 antibodies, anti-glypican-3 antibodies, anti-CD3 antibodies, anti-CD20 antibodies, anti-GPIIb / IIIa antibodies, anti-TNF antibodies, anti-CD25 antibodies, anti-EGFR antibodies, anti-Her2 / neu antibodies, anti-RSV antibodies, anti-CD33 antibodies, anti-CD52 antibodies, anti-IgE antibodies, anti-CD11a antibodies, anti-VEGF antibodies, anti-VLA4 antibodies, anti-HM1.24 antigen antibodies, anti-parathyroid hormone-related peptide antibodies (anti-PTHrP antibodies), anti-ganglioside GM3 antibodies, anti-TPO receptor agonist antibodies, coagulation factor VIII replacement antibodies, anti-IL31 receptor antibodies, anti-HLA antibodies, anti-AXL antibodies, anti-CXCR4 antibodies, anti-NR10 antibodies, bispecific antibodies of factor IX and factor X, etc., but are not limited thereto.

[0598] Preferred reconstructed humanized antibodies for use as drugs in pharmaceutical preparations include humanized anti-interleukin 6 (IL-6) receptor antibodies (tocilizumab, hPM-1 or MRA, see WO92 / 19759), humanized anti-HM1.24 antigen monoclonal antibodies (see WO98 / 14580), humanized anti-parathyroid hormone-related peptide antibodies (anti-PTHrP antibodies) (see WO98 / 13388), humanized anti-tissue factor antibodies (see WO99 / 51743), anti-glypican-3 humanized IgG1κ antibodies (codrituzumab, GC33, see WO2006 / 006693), anti-NR10 humanized antibodies (see WO2009 / 072604), bispecific antibodies of factor IX and factor X (ACE910, see WO2012 / 067176), and the like.

[0599] In one aspect of the present invention, the active ingredient contained in the solution filled into the syringe is an antibody selected from emicizumab, tocilizumab and satralizumab. Emicizumab, tocilizumab and satralizumab are antibodies contained as active ingredients in HEMLIBRA (registered trademark), ACTEMRA (registered trademark) and ENSPRYNG (registered trademark), respectively, and their respective amino acid sequences are well known. In this specification, antibodies specified by terms such as emicizumab, tocilizumab and satralizumab include antibodies whose amino acid sequences are substantially the same as these antibodies and have homogeneous pharmacodynamics.

[0600] In one aspect of the present invention, the pharmaceutical preparation can be mixed with appropriate pharmaceutically acceptable carriers, media, etc. as needed to form a solution preparation. The solvent of the solution preparation is water or a pharmaceutically acceptable organic solvent. As such an organic solvent, propylene glycol (1,2-propylene glycol), polyethylene glycol 300, polyethylene glycol 400, ethanol, glycerol, acetic acid, etc. can be cited. As suitable pharmaceutically acceptable carriers and media, for example, sterile water or physiological saline, stabilizers, antioxidants (ascorbic acid, etc.), buffers (phosphoric acid, citric acid, histidine, other organic acids, etc.), preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.), adhesives, etc. can be cited. In addition, it can also contain other low molecular weight polypeptides, serum albumin, gelatin or immunoglobulin and other proteins, glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine and lysine and other amino acids, polysaccharides and monosaccharides and other sugars or carbohydrates, mannitol or sorbitol and other sugar alcohols. In the case of injection solutions, examples include isotonic solutions containing physiological saline, glucose or other auxiliary drugs, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and can also be used in combination with appropriate dissolution aids, such as alcohols (ethanol, etc.), polyols (propylene glycol, PEG, etc.), non-ionic surfactants (polysorbate 80, polysorbate 20, poloxamer 188, HCO-50), etc.

[0601] In one aspect of the present invention, the buffer used in the solution preparation is prepared using a substance for maintaining the pH of the solution. In one aspect of the present invention, in a solution preparation containing a high concentration of an antibody, the pH of the solution is preferably 4.5 to 7.5, more preferably 5.0 to 7.0, and further preferably 5.5 to 6.5. In one aspect of the present invention, the buffer that can be used is a buffer that can adjust the pH in this range and is pharmaceutically acceptable. Such buffers are well known to those skilled in the art in the field of solution preparations, for example, inorganic salts such as phosphates (sodium or potassium) and sodium bicarbonate; organic acid salts such as citrates (sodium or potassium), sodium acetate, and sodium succinate; or acids such as phosphoric acid, carbonic acid, citric acid, succinic acid, malic acid, and gluconic acid can be used. Furthermore, Good's buffers such as Tris and MES, MOPS, and HEPES can also be used; histidine (e.g., histidine hydrochloride), glycine, and the like.

[0602] The concentration of the buffer is usually 1 to 500 mmol / L, preferably 5 to 100 mmol / L, and more preferably 10 to 20 mmol / L. When a histidine buffer is used, the buffer preferably contains 5 to 25 mmol / L histidine, and more preferably 10 to 20 mmol / L histidine.

[0603] In one aspect of the present invention, the high-concentration antibody solution formulation is preferably stabilized by adding a stabilizer suitable for the antibody as an active ingredient. In one aspect of the present invention, a "stable" high-concentration antibody solution formulation is stored at a refrigerated temperature (2-8°C) for at least 12 months, preferably 2 years, and more preferably 3 years; or at room temperature (22-28°C) for at least 3 months, preferably 6 months, and more preferably 1 year. No significant changes are observed. For example, the total amount of dimers and decomposition products after being stored at 5°C for 2 years is less than 5.0%, preferably less than 2%, and more preferably less than 1.5%, or the total amount of dimers and decomposition products after being stored at 25°C for 6 months is less than 5.0%, preferably less than 2%, and more preferably less than 1.5%.

[0604] In one aspect of the present invention, typical examples of surfactants include: nonionic surfactants, such as sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate, and sorbitan monopalmitate; glycerol fatty acid esters such as glycerol monocaprylate, glycerol monomyristate, and glycerol monostearate; polyglycerol fatty acid esters such as decaglycerol monostearate, decaglycerol distearate, and decaglycerol monolinoleate; polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitan monooleate. Polyoxyethylene sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, and polyoxyethylene sorbitan tristearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan tetrastearate and polyoxyethylene sorbitan tetraoleate; polyoxyethylene glycerol fatty acid esters such as polyoxyethylene glycerol monostearate; polyethylene glycol fatty acid esters such as polyethylene glycol distearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene Polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene propyl ether and polyoxyethylene polyoxypropylene hexadecyl ether; polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether; polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil) and other polyoxyethylene hardened castor oils; polyoxyethylene beeswax derivatives such as polyoxyethylene sorbitol beeswax; polyoxyethylene lanolin derivatives such as polyoxyethylene lanolin; polyoxyethylene fatty acid amides such as polyoxyethylene stearic acid amide and other substances having HLB 6 to 18; anionic surfactants such as deca Alkyl sulfates having an alkyl group with 10 to 18 carbon atoms, such as sodium hexadecyl sulfate, sodium lauryl sulfate, and sodium oleyl sulfate; polyoxyethylene alkyl ether sulfates having an average addition mole number of ethylene oxide of 2 to 4 and an alkyl group with 10 to 18 carbon atoms, such as sodium polyoxyethylene lauryl sulfate; alkyl sulfosuccinate salts having an alkyl group with 8 to 18 carbon atoms, such as sodium lauryl sulfosuccinate; natural surfactants, such as lecithin and glycerophospholipids; sphingolipids such as sphingomyelin; sucrose fatty acid esters of fatty acids with 12 to 18 carbon atoms, etc. In one aspect of the present invention, one or a combination of two or more of these surfactants may be added to the preparation.

[0605] Preferred surfactants are polyoxyethylene sorbitan fatty acid esters and polyoxyethylene polyoxypropylene alkyl ethers, particularly preferred are polysorbate 20, 21, 40, 60, 65, 80, 81, 85 and Pluronic (registered trademark) type surfactants, and most preferred are polysorbate 20, 80 and Pluronic F-68 (Poloxamer 188).

[0606] In one aspect of the present invention, the amount of the surfactant added to the antibody preparation is generally 0.0001 to 10% (mg / mL), preferably 0.001 to 5%, and more preferably 0.005 to 3%.

[0607] Furthermore, the preparation of the present invention may contain, as necessary, a cryoprotectant, a suspending agent, a solubilizing agent, an isotonic agent, a preservative, an anti-adsorption agent, a diluent, an excipient, a pH adjuster, an analgesic, a sulfur-containing reducing agent, an antioxidant, and the like.

[0608] Examples of the cryoprotectant include sugars such as trehalose, sucrose, and sorbitol.

[0609] Examples of the solution auxiliary agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, polyethylene glycol, and castor oil fatty acid ethyl ester.

[0610] Examples of the isotonic agent include sodium chloride, potassium chloride, and calcium chloride.

[0611] Examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0612] Examples of the adsorption inhibitor include human serum albumin, lecithin, dextran, ethylene oxide-propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, and polyethylene glycol.

[0613] Examples of the sulfur-containing reducing agent include N-acetylcysteine, N-acetylhomocysteine, lipoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, glutathione, and substances having a mercapto group such as thioalkanoic acid having 1 to 7 carbon atoms.

[0614] Examples of the antioxidant include erythrosonic acid, butylated hydroxytoluene, butylated hydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, tripentyl gallate, propyl gallate or chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0615] In one aspect of the invention, the pharmaceutical formulation is used to treat tumors and neoplastic diseases including autoimmune diseases, immune diseases, infections, inflammatory diseases, neurological diseases and cancer.In a specific embodiment, the use of the medicament is for the treatment of: congestive heart failure (CHF), ischemia-induced severe arrhythmias, hypercholesterolemia, vasculitis, rosacea, acne, eczema, myocarditis and other conditions of the myocardium, Kawasaki disease, systemic lupus erythematosus, diabetes, spondylosis, synovial fibroblasts and bone marrow stroma; osteopenia; Paget's disease, giant cell tumor of bone; breast cancer; disuse osteopenia; malnutrition, periodontal disease, Gaucher's disease, Langerhans cell histiocytosis, spinal cord injury, acute suppurative arthritis, osteomalacia, Cushing's syndrome, monoostotic fibrodysplasia, polyostotic fibrodysplasia, periodontal membrane remodeling and fractures melanoma, prostate cancer, pancreatic cancer, osteolytic bone cancer, breast cancer, lung cancer, gastric cancer, kidney cancer, and colorectal cancer; bone metastases, bone pain management, and humoral hypercalcemia of malignancy, ankylosing spondylitis and other spondyloarthropathies; transplant rejection, viral infections, hematologic neoplasms and neoplasm-like conditions, such as Hodgkin lymphoma; lymphocytes including non-Hodgkin lymphomas (Burkitt lymphoma, small lymphocytic lymphoma / chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal layer lymphoma, hairy cell leukemia, and lymphoplasmacytic leukemia), B-cell acute lymphocytic leukemia / lymphoma, and T-cell acute lymphocytic leukemia / lymphoma Precursor cell tumors, thymomas, mature T-cell and mature NK-cell tumors including peripheral T-cell leukemia, adult T-cell leukemia / T-cell lymphoma and large granular lymphocytic leukemia, Langerhans cell histiocytosis, AML with maturation, AML without differentiation, acute myeloid leukemia including acute promyelocytic leukemia, acute myelomonocytic leukemia and acute monocytic leukemia, myelodysplastic syndrome and myeloid neoplasms such as chronic myeloproliferative diseases including chronic myeloid leukemia, central nervous system tumors such as brain tumors (glioma, neuroblastoma, astrocytoma, myeloid blastoma, ependymoma and retinoblastoma), solid tumors ( Nasopharyngeal carcinoma, basal cell carcinoma, pancreatic cancer, bile duct cancer, Kaposi's sarcoma, testicular cancer, uterine cancer, vaginal cancer or cervical cancer, ovarian cancer, primary liver cancer or endometrial cancer, as well as vascular system tumors (angiosarcoma and hemangiopericytoma), osteoporosis, hepatitis, HIV, AIDS, spondyloarthritis, rheumatoid arthritis, inflammatory bowel disease (IBD), sepsis and septic shock, Crohn's disease, psoriasis, scleroderma, graft-versus-host disease (GVHD), allogeneic islet transplant rejection, multiple myeloma (MM), myelodysplastic syndrome (MDS) and hematological malignancies such as acute myeloid leukemia (AML), tumor-related inflammation, peripheral nerve damage or demyelinating diseases.In a specific embodiment, the use of the medicament is for the treatment of psoriasis vulgaris, pancreatitis, ulcerative colitis, non-Hodgkin's lymphoma, breast cancer, colorectal cancer, mesothelioma, soft tissue sarcoma, juvenile idiopathic arthritis, macular degeneration, respiratory syncytial virus, Crohn's disease, rheumatoid arthritis, psoriatic arthritis, Castleman's disease, ankylosing spondylitis, osteoporosis, therapy-induced osteopenia, bone metastasis, multiple brain tumors, Alzheimer's disease, glaucoma, Sjogren's disease, Still's disease, multiple sclerosis, hyperimmunoglobulinemia, anemia, mesangial proliferative nephritis and asthma.

[0616] In one aspect of the present invention, the antigen to which the antibody has specific binding can be a ligand such as a transmembrane molecule (e.g., a receptor) or a growth factor. Exemplary antigens include molecules such as renin; growth hormones including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoprotein; alpha-1-antitrypsin; insulin A chain; insulin B chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; coagulation factors such as factor VIIIC, factor IX, tissue factor (TF) and von Willebrand factor; anticoagulant factors such as protein C; atrial natriuretic factor; pulmonary surfactant; plasminogen activators such as urokinase or human urine or tissue plasminogen activator (t-PA); bombesin; thrombin; hematopoietic growth factor; tumor necrosis factor-α and -β; enkephalin; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophage inflammatory protein (MIP-1-α); serum albumins such as human serum albumin; Mullerian inhibitor; relaxin A chain; relaxin B chain; prorelaxin; mouse gonadotropin-releasing hormone-related peptide; microbial proteins such as beta-lactamase; DNA enzymes; IgE; cytotoxic T-lymphocyte-associated antigen (CTLA) such as CTLA-4; inhibins; activins; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; proteins A or D; rheumatoid factor; neurotrophic factors such as bone-derived neurotrophic factor (BDNF), nerve growth factor-3, -4, -5 or -6 (NT-3, NT-4, NT-5 or NT-6) or nerve growth factors such as NGF-b; platelet-derived proliferation factor (PDGF); aF Fibroblast growth factors such as GF and bFGF; epithelial growth factor (EGF); transforming growth factors (TGF) such as TGF-α and TGF-β including TGF-b1, TGF-b2, TGF-b3, TGF-b4 or TGF-b5; tumor necrosis factors (TNF) such as TNF-α or TNF-β; insulin-like growth factor-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding protein; CD proteins such as CD3, CD4, CD8, CD19, CD20, CD22 and CD40; erythropoietin; osteoinductive factors; antitoxins; bone morphogenetic proteins (BMPs); interferons such as interferon-α, -β and -γ; colony stimulating factors (CSFs) such as M-CSF, GM-CSF, G-CSF;For example, interleukins (IL) such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9 and IL-10; superoxide dismutase; T cell receptor; surface membrane protein; decay accelerating factor; viral antigens such as a part of the AIDS envelope; transporter; homing receptor; addressin; regulatory protein; integrin such as CD11a, CD11b, CD11c, CD18, ICAM, VLA-4 and VCAM; tumor-associated antigens such as HER2, HER3 or HER4 receptors; and any fragment of the above-mentioned polypeptides. ;

[0617] In one aspect of the present invention, exemplary molecular targets of the antibodies included include: CD proteins, such as CD3, CD4, CD8, CD19, CD20, CD22, CD34 and CD40; ErbB receptor family members such as EGF receptor, HER2, HER3 or HER4 receptor; B cell surface antigens, such as CD20 or BR3; tumor necrosis receptor superfamily members including DR5; prostate stem cell antigen (PSCA); including LFA-1, Mac1, p150.95, VLA-4, ICAM -1, VCAM, α4 / β7 integrin and any of its α or β subunits, αv / β3 integrin (e.g., anti-CD11a, anti-CD18 or anti-CD11b antibodies) and other cell adhesion molecules; growth factors, such as VEGF and its receptors; tissue factor (TF); tumor necrosis factor (TNF), such as TNF-α or TNF-β, α interferon (α-IFN); interleukins such as IL-8; IgE; blood group antigens; flk2 / flk3 receptors; obesity (OB) receptor; mp1 receptor; CTLA-4; protein C, etc.

[0618] (4) Particles

[0619] In one aspect of the present invention, "removing visually detectable particles" means that in a solution of a pharmaceutical preparation that produces visually detectable particles under specified conditions, the drug is injected through a filter provided in the barrel when the solution is injected from a syringe, and visually detectable particles are removed from the injected solution. In one aspect of the present invention, in the injected solution, the number of visually detectable particles becomes 0. The size and number of particles can be measured by light shielding particle counting method, microscopic particle counting method, flow cytometric particle image analysis method, visual inspection, and separation of particles followed by microscopic infrared spectroscopy (IR) measurement or microscopic Raman spectroscopy measurement, preferably by a combination of visual inspection and microscopic infrared spectroscopy or microscopic Raman spectroscopy measurement.

[0620] (5) Visually detectable particles

[0621] In this specification, particles that can be visually detected refer to particles that can be visually detected under high illumination, with a particle size of more than 40 μm. Among them, particles that can be visually detected under the standard illumination (about 2000-3000lx) specified in the pharmacopoeia are called "visible particles" or "insoluble visible particles". Visible particles usually have a particle size greater than 100 μm (non-patent literature 1). The size is smaller than the visible particles, and it cannot be visually detected under the standard illumination (about 2000-3000lx) specified in the pharmacopoeia, but the particles that can be visually detected by increasing the illumination or extending the observation time are "particles that can be visually detected only under high illumination", with a particle size of 40 μm~100 μm. Visible particles can be confirmed in the following manner: under illumination, under standard illumination (about 2000-3000lx), the container is slowly rotated or flipped for more than 5 seconds in front of a black background or a white background, and visually inspected with the naked eye. Particles that can only be visually detected under high illumination can be confirmed by slowly rotating or turning the container for more than 5 seconds under high illumination (6000lx or more) in front of a black background and visually inspecting with the naked eye. Visible particles can also be confirmed during inspection under high illumination.

[0622] In this specification, "particles derived from proteins" or "particles derived from solution components" refer to visually detectable particles produced by proteins, including particles consisting only of proteins and particles consisting of a complex of proteins and polydimethylsiloxane (PDMS). The formation of particles by protein molecules can be confirmed by micro-Raman spectroscopy. The solution contains only active pharmaceutical ingredients (API) as proteins, and the visually detectable particles are produced by API. The number of visually detectable particles can be determined by light-shielding particle counting method, microscope particle counting method, flow cytometric particle image analysis method, visual inspection, microscopic infrared spectroscopy (IR) measurement or micro-Raman spectroscopy measurement after separation of particles, preferably by a combination of visual inspection and microscopic infrared spectroscopy or micro-Raman spectroscopy measurement.

[0623] In the present specification, "foreign particles" or "particles originating from other than solution components" refer to particles other than the above particles that can be detected visually.

[0624] "Agglomerates" in this specification are relatively high molecular weight protein species produced by the aggregation of a large number of denatured proteins, and can be used interchangeably with the terms "high molecular species" and "HMWS". Protein aggregates can generally differ in size (aggregates ranging from small (dimers) to large (microscope-confirmable particles or even visible particles), with diameters in the nanometer to micrometer range), morphology (roughly spherical to fibrous), protein structure (natural vs. non-natural / denatured), type of intermolecular bonds (covalent vs. non-covalent), reversibility and solubility. Soluble aggregates cover a size range of about 1 to 100 nm, and protein particles cover a range that can be confirmed by a microscope (about 0.1 to 100 μm) and a visible range (>100 μm). All of the above types of protein aggregates are generally included in this term. Therefore, the term "(protein) aggregate" refers to any type of non-natural species in which two or more protein monomers are physically or chemically combined.

[0625] In one aspect of the present invention, a "prefilled syringe" refers to a syringe filled with a liquid composition in a syringe as a container. In one aspect, the prefilled syringe is filled with a pharmaceutical composition for administration to a patient in the syringe. Here, the syringe may also be covered with a syringe closure, such as a stopper, but is not limited thereto. In one aspect, the composition is placed in a syringe in a manufacturing filling facility. In one aspect, the syringe is sterilized before the composition is placed in the syringe. In one aspect, the prefilled syringe has a shelf life of 1 day, or at least 7 days, or at least 14 days, or at least 1 month, or at least 6 months, or at least 1 year, or at least 2 years before the composition is administered to the patient. In one aspect, the prefilled syringe generally maintains a non-contact state between the solution in the syringe and the filter even when the expected level of stress is loaded during manufacture or circulation.

[0626] Example

[0627] Example 1 Selection of filter material with high particle removal capability

[0628] The antibody solution (satelizumab (mAb1): 120 mg / mL, buffer: 20 mmol / L histidine, stabilizer: 150 mmol / L arginine and 162 mmol / L aspartic acid, surfactant: 0.50 mg / mL poloxamer 188, pH 6.0) was added to a common COP syringe with a 27G needle (1 mL specification) and a syringe containing different materials (polyethersulfone (PES) (Supor (registered trademark); Nihon Pall Ltd.), polyvinylidene fluoride (PVDF) (Durapore (registered trademark); Merck Co., Ltd.), polyethylene terephthalate (PET), nylon, polysulfone (Asymmetric Super Micron Polysulfone; Nihon Pall Ltd.), hydrophobic acrylic copolymer (VERSAPOR (registered trademark); Nihon A total of 6 types of COP syringes (1 mL specification) with 27G needles and filters with a pore size of 5 μm (Pall Ltd.) were filled with 1.0 mL of solution and plugged with stoppers. The antibody solution was stored at 25°C and 40°C to intentionally increase the amount of particles in the preparation, and then provided for testing. The antibody solution is in contact with the filter. For the filled and plugged samples, the antibody solution in the syringe was discharged into a clean glass bottle after cleaning and sterilization using an autograph (model: AG-1, manufactured by Shimadzu Corporation) at a speed of 210 mm / min or 100 mm / min. Phosphate-buffered saline was added to the discharged solution or the original solution at an appropriate rate, and then mixed by inversion 20 times and allowed to stand for 2 hours. Slowly invert and mix 3 times just before the measurement. Tests 1 and 2 used a microflow imaging device (model: DPA4100, manufactured by Bright WELL), and test 3 used a microflow imaging device (model: MFI5200, manufactured by protein simple) to measure the number of particles in the solution.

[0629] [Evaluation results]

[0630] Table 1 shows the number of particles of 10 μm or larger and 25 μm or larger in the solution discharged from a general COP syringe with a 27G needle and a 27G COP syringe with a built-in filter.

[0631] The results show that when the antibody solution is discharged from a syringe with a built-in filter made of PES, PVDF, polysulfone, or hydrophobic acrylic copolymer, the amount of particles in the solution can be greatly reduced, while on the other hand, when discharged from a syringe with a built-in filter made of PET or nylon, the amount of particles in the solution is not sufficiently reduced. The reason for these differences is believed to be that the filters made of PES, PVDF, polysulfone, and hydrophobic acrylic copolymer are all membrane filters, while the filters made of PET and nylon are mesh filters, which are one of the depth filters.

[0632] [Table 1]

[0633] Table 1 Number of particles in the solution after discharge from a common syringe and a syringe with a built-in filter

[0634]

[0635] Example 2 Selection of the Optimal Filter Pore Size

[0636] The antibody solution (satelizumab (mAb1): 120 mg / mL, buffer: 20 mmol / L histidine, stabilizer: 150 mmol / L arginine and 162 mmol / L aspartic acid, surfactant: 0.50 mg / mL poloxamer 188, pH 6.0) was filtered through a stainless steel filter unit equipped with a PES filter with a pore size of 1.2 μm or a pore size of 5 μm punched into a 47 mm diameter circle, and recovered in a clean plastic container. Phosphate-buffered saline was added to the recovered discharge solution or stock solution at an appropriate rate, and then inverted and mixed 20 times and allowed to stand for 2 hours. Slowly inverted and mixed 3 times before the measurement, and the number of particles in the solution was measured using a microfluidics device (model: MFI5200, manufactured by Protein Simple). In addition, the antibody solution was stored at 25°C and 40°C in the same way as in Example 1 to intentionally increase the amount of particles in the preparation, and then provided for the test.

[0637] [Evaluation results]

[0638] Table 2 shows the number of particles of 25 μm or more and 70 μm or more in the stock solution and the sample solution filtered through a filter having a pore size of 1.2 μm or 5 μm.

[0639] The results showed that there was no significant difference in the ability to reduce the amount of particles in the solution when filtering through a filter with a pore size of 1.2μm and a pore size of 5μm, and a pore size of about 5μm was sufficient. In addition, the water flow rate at a pressure of 70kPa was 315mL / min / cm when the pore size was 1.2μm. 2 , 778mL / min / cm when the pore size is 5μm 2Therefore, the ejection resistance associated with the introduction of the filter is about 2.5 times greater when the pore size is 1.2 μm than when the pore size is 5 μm. Considering the balance between the particle reduction capability to be achieved and the increase in ejection resistance, it is determined that the pore size of 5 μm is the best.

[0640] In addition, 1.0 mL of sucrose solution (viscosity 7 cP) was filled in a 27G needle COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter and plugged with a stopper. The sucrose solution was kept in a non-contact state with the filter. For the filled and plugged samples, the sucrose solution in the syringe was discharged into a suitable container at a speed of 100 mm / min or 210 mm / min using an automatic plotter (model: AG-1, manufactured by Shimadzu Corporation). The average sliding resistance values ​​of 10 mm to 25 mm are shown in Table 3. The average sliding resistance value was calculated based on the data obtained by the automatic plotter.

[0641] As a result, it was found that the average sliding resistance value of the syringe with a built-in filter was within 1.3 times that of a normal syringe, and was suppressed to a sufficiently low value even with the presence of the filter.

[0642] [Table 2]

[0643] Table 2 Number of particles in the solution after discharge from the syringe with 1.2 μm and 5 μm built-in filters

[0644]

[0645] [Table 3]

[0646] Table 3 Average sliding resistance values ​​of ordinary syringes and syringes with built-in filters from 10 mm to 25 mm

[0647]

[0648] Example 3 Evaluation of filter durability

[0649] 1.0 mL of three sucrose solutions (viscosities of 10 cP, 15 cP, and 20 cP) were filled into a 27G COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter, and plugged with a stopper. In addition, the drug solution was discharged from Cimzia (registered trademark): 200 mg AutoClicks for subcutaneous injection, and 1.0 mL was filled into a 27G COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter, and plugged with a stopper. The viscosity of the Cimzia solution was measured with an EMS viscometer (model: EMS-1000, manufactured by Kyoto Electronics Industry Co., Ltd.), and the result was 96.4 cP at 25°C. The sucrose solution and the Cimzia solution were kept in a non-contact state with the filter. For the filled and plugged samples, the sucrose solution in the syringe was discharged into a suitable container at a speed of 1000 mm / min using an autograph (Model: AG-1, manufactured by Shimadzu Corporation). In addition, the Cimzia solution in the syringe was manually discharged (N=10). The discharge time was measured with a stopwatch and the speed was calculated. The filter unit was removed from the discharged syringe to check whether the filter was damaged.

[0650] [Evaluation results]

[0651] Table 3 shows the maximum load when a sucrose solution with a viscosity of 10-20 cP was discharged at a speed of 1000 mm / min and whether the filter was damaged after the discharge. Table 4 shows the discharge speed when a Cimzia solution with a viscosity of 96.4 cP was manually discharged and whether the filter was damaged after the discharge. Figure 1 Examples of a normal filter and a damaged filter are shown in . The evaluation results show that no damage to the filter was observed in any sample, and the sample has sufficient durability and can be used for a wide range of drugs.

[0652] [Table 4]

[0653] Table 4 Maximum load after sucrose solution was discharged at a speed of 1000 mm / min and the presence or absence of filter damage

[0654]

[0655] [Table 5]

[0656] Table 5 Estimated discharge rate of Cimzia solution after manual discharge and presence of filter damage

[0657]

[0658] Example 4 Evaluation of the ability to remove proteinaceous foreign matter

[0659] The following three drug preparations were evaluated:

[0660] [Preparation 1] ACTEMRA (registered trademark) (active ingredient: tocilizumab): subcutaneous injection 162 mg;

[0661] [Preparation 2] HEMLIBRA (registered trademark) (active ingredient: emicizumab): subcutaneous injection 150 mg;

[0662] [Preparation 3] ENSPRYNG (registered trademark) (active ingredient: satelizumab): 120 mg subcutaneously injected.

[0663] After the preparation was discharged into a plastic container, 1.0 mL was filled into a 27G needle COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter, and plugged with a stopper. In addition, for preparation 1, a sample was used in which the buffer was replaced with the same buffer composition as preparations 2 and 3 (buffer: 20 mmol / L histidine, stabilizer: 150 mmol / L arginine and 162 mmol / L aspartic acid, surfactant: 0.50 mg / mL poloxamer 188, pH 6.0). By storing the sample at 40°C, proteinaceous foreign matter was intentionally generated inside the syringe. Samples containing proteinaceous foreign matter were prepared for each preparation (N=5). Before the solution was discharged, the syringe was slowly rotated or turned over in front of a black background at a brightness position of about 10,000 lx directly below a white light source, and a visual inspection was performed for about 30 seconds by naked eyes to confirm whether there were foreign matter in the solution filled in the syringe and its number if there were any. In addition, the syringe was slowly rotated or turned over in front of a black and white background under an illumination of about 3000 lx, and a visual inspection was performed with the naked eye for about 30 seconds to confirm the presence of foreign matter in the solution filled in the syringe and the number of foreign matter if present. The number of protein foreign matter confirmed inside the syringe was 1 in a small sample under an illumination of about 10000 lx, and more than 10 in a large sample. In addition, the number was 0 to 4 at an illumination of about 3000 lx. The filled and plugged samples were manually discharged into a clean glass bottle after cleaning and disinfection. After discharge, the presence of foreign matter inside the bottle and the number of foreign matter if present were confirmed under illumination of about 10000 lx and 3000 lx.

[0664] [Evaluation results]

[0665] The presence rate and number of proteinaceous foreign matter after discharge from a 27G COP syringe with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter are shown in Tables 4 and 5. As a result, it was confirmed that all 10 types of proteinaceous foreign matter could be appropriately removed when discharged from a syringe with a built-in hydrophobic acrylic copolymer filter having a pore size of 5 μm.

[0666] [Table 6]

[0667] Table 6 Presence rate of proteinaceous foreign matter before and after discharge from the syringe with built-in filter

[0668]

[0669] [Table 7]

[0670] Table 7 Number of proteinaceous foreign matter before and after discharge from the syringe with built-in filter

[0671]

[0672] ※1 For the sake of convenience, the number of foreign matter found in each sample is set to 10 for 10 pieces.

[0673] The same test was also conducted on 5 prefilled syringe preparations or bottle preparations that have been marketed other than the above 3 preparations. Among them, 3 doses were subcutaneous injections and 2 doses were intravenous injections. After the sample was discharged from the container, it was stored in a plastic tube at 40°C, thereby intentionally generating proteinaceous foreign matter. 1.0 mL of the solution was filled in a COP syringe (1 mL specification) with a 27G needle and a built-in hydrophobic acrylic copolymer (pore size 5μm) filter, and plugged with a stopper. As the test results of these 5 preparations, it was confirmed that 13 to 31 proteinaceous foreign matters could be removed when the observation illumination was 10000lx, and 4 to 7 proteinaceous foreign matters could be removed when the observation illumination was 3000lx.

[0674] Example 5 Evaluation of foreign matter removal capability

[0675] 1.0 mL of sucrose solution with a viscosity of 7 cP was filled into a 27G COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter. Using tweezers, 5 of each of 5 types of foreign matter (size: about 700 μm to 6000 μm, material: glass, SUS, rubber stopper, plastic, fiber) were added to different syringes and plugged with stoppers. N=3 samples containing each foreign matter were prepared, and before the solution was discharged from the syringe, the presence of foreign matter inside the syringe was confirmed at an illumination of about 3000 lx. After assembling the plunger rod and removing the Rigid Needle Shield (RNS), the solution in the syringe was manually discharged into a clean glass bottle after washing and sterilization. The solution discharged into the bottle was checked for the presence of foreign matter at an illumination of about 3000 lx.

[0676] [Evaluation results]

[0677] The presence or absence of foreign matter in the solution discharged from a COP syringe with a 27G needle and a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter is shown in Table 6. The results of this test confirmed that all five types of foreign matter could be appropriately removed by discharging the solution containing foreign matter from a syringe with a built-in hydrophobic acrylic copolymer filter having a pore size of 5 μm.

[0678] [Table 8]

[0679] Table 8 Presence rate of foreign matter before and after discharge from a syringe with a built-in filter (%)

[0680]

[0681] Example 6 Drug Solution and Stability

[0682] The preparation 2 was filled with 1.0 mL into a common COP syringe (1 mL specification) with a 27G needle and a COP syringe (1 mL specification) with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter, and plugged with a stopper. For the filled and plugged samples, after being stored at 5°C for 12 months, or stored at 25°C for 6 months, size exclusion chromatography (SE-HPLC) determination, UV determination (model: UV-2700i, manufactured by Shimadzu Corporation), and PX188 concentration determination were performed under the following conditions. In the size exclusion chromatography determination, the main peak detected was defined as the main peak (Main Peak), the total of the peaks detected before the main peak (Main Peak) was defined as the high molecular weight (High Molecular Weight, HMW), and the total of the peaks detected after the main peak (Main Peak) was defined as the low molecular weight (Low Molecular Weight, LMW). The results are shown in Table 9. After storage at 5°C for 12 months or at 25°C for 6 months, the physical properties of any sample were almost unchanged in a normal COP syringe or a COP syringe with a built-in filter. In summary, it was confirmed that the COP syringe with a built-in filter has high compatibility with the drug solution.

[0683] [Table 9]

[0684] Table 9 Physical properties of ordinary syringes and syringes with built-in filters after long-term storage

[0685]

[0686] *ND Not Detected

[0687] ･Size Exclusion Chromatography

[0688] -Size Exclusion Chromatography Apparatus: "2695 or e2695" manufactured by Waters

[0689] -Detector: UV absorbance spectrophotometer

[0690] -Measurement wavelength: 280nm

[0691] - Column: TSKgel G3000SWXL (manufactured by Tosoh)

[0692] - Column temperature: 25℃

[0693] -Mobile phase: phosphate buffer (pH 7.0)

[0694] -Flow rate: 0.5mL / min

[0695] -Injection volume: 60μL

[0696] ･PX188 concentration measurement

[0697] -PX188 Concentration measuring device: "2690, 2695, e2795 or e2695" manufactured by Waters

[0698] -Detector: Differential Refractometer (2414 Refractive Index Detector)

[0699] - Column: TSKgel SuperSW2000 (manufactured by Tosoh)

[0700] - Column temperature: 25℃

[0701] -Mobile phase: 40% acetonitrile solution containing 30mmol / L sodium chloride

[0702] -Flow rate: 0.3mL / min

[0703] -Injection volume: 20μL

[0704] Explanation of symbols

[0705] 1 ... prefilled syringe, 2 ... syringe, 3 ... piston, 4 ... injection needle, 5 ... protective cap, 6 ... cylinder, 7 ... partition, 8 ... housing, 9 ... plug member, 30 ... rod member, 31 ... washer, 32 ... operating member, 33 ... front end surface, 60 ... front end portion, 61 ... base end portion, 62 ... cylindrical member, 63 ... flange portion, 64 ... injection hole, 80 ... filter, 81 ... engagement member when closed, 82 ... inner peripheral surface, 83 ... mounting portion, 84 ... main body portion, 85 ... extension portion, 86 ... filter member, 90 ... engagement member when closed, 91 ... restriction device, 92 ... cover portion, 93 ... step engagement member, 94 ... foot portion, 95 ... protruding portion, 96 ... annular portion, 97 ... cover recessed portion, 98 ... Contact surface, 103 ... Plug, 104 ... Needle component, 105 ... Cavity, 107 ... Closure structure, 108 ... Outer closing component, 109 ... Closure plug body, 180 ... Groove, 181 ... Flow path, 600 ... Base end side end surface, 800 ... Outer peripheral surface, 801 ... Base end outer peripheral surface portion, 802 ... Front end outer peripheral surface portion, 810 ... Step surface, 821 ... Base end inner peripheral surface portion, 822 ... Front end inner peripheral surface portion, 830 ... Front end surface, 901 ... Engaged component when base end side is closed, 902 ... Engaged component when front end side is closed, 920 ... Outer peripheral portion, 921 ... Inner peripheral portion, 922 ... Cover foot component, S ... Space, S1 ... Base end side space, S2 ... Front end side space, S21 ... Front end side space, S22 ...second distal end side space, S3 ...third distal end side space, S4 ...fourth distal end side space, S101 ...wetted portion, S102 ...dry portion, C8 ...liquid flow path, C9 ...piston flow path, C91 ...axial flow path, C92 ...connecting flow path, ML ...liquid agent, MS ...solid agent, MM ...mixed agent, 80 ...filter, 10 ...retaining member, 34 ...close contact portion, 35 ...protrusion portion, 65 ...inner peripheral surface, 71 ...distal end side subspace, 72 ...base end side subspace, 110 ...base end side portion, 111 ...flow path, 112 ...Mounting part, 113 ... foot part, 600 ... base end side end surface, 601 ... base end side edge, 200 ... contact surface (base end side end surface), 201 ... base end side contact surface, 201a ... first base end side contact surface, 201b ... second base end side contact surface, 202 ... front end side contact surface, 203 ... connection contact surface, 203a ... first connection contact surface, 203b ... second connection contact surface, 203c ... second connection contact surface, 204 ... front end surface, 220 ... mounting outer peripheral portion, 221 ... mounting inner peripheral portion, 222 ... outer peripheral front end surface, 223 ... inner peripheral front end surface, 224 ... shoulder portion, 225 ... protruding portion, 226 ... mounting inner peripheral surface, 230 ... base end surface. .

Claims

1. A preparation for injection in which a solution is filled in a syringe, wherein: The syringe has: a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole, The filter is configured so that the solution flows through the filter from the base end side to the front end side of the filter. The filter is a filter membrane, and its material includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

2. A preparation for injection in which a solution is filled in a syringe, wherein: The syringe has: a barrel having a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an outlet hole for injecting a solution contained inside to the outside, and a filter, the filter being arranged inside the cylinder and closer to the base end side than the outlet hole, The filter is configured so that the solution flows through the filter from the base end side to the front end side of the filter. The filter is a filter membrane, and its material includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer. During the discharge of the solution, particles that can be visually detected can be removed from the discharged solution.

3. The injection preparation according to claim 1 or 2, wherein The material of the filter membrane is acrylic copolymer.

4. The injection preparation according to claim 3, wherein Acrylic acid copolymers are hydrophobic.

5. The injection preparation according to any one of claims 1 to 4, wherein The filter has a pore size of 5 μm or less, preferably 5 μm.

6. The injection preparation according to any one of claims 1 to 5, wherein A front end subspace is provided at the front end side of the filter, and a base end subspace is provided at the base end side of the filter. When viewed from the axial direction of the cylinder, the area of ​​the injection hole is smaller than the area of ​​the base end subspace and smaller than the area of ​​the front end subspace.

7. The injection preparation according to any one of claims 1 to 6, wherein The syringe includes a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space. The partition device comprises: a cylindrical shell, which is arranged in a liquid-tight contact manner with the inner side of the cylinder; and an inner plug member, which can open and close the interior of the shell so that the base end side space and the front end side space are connected or not connected through the interior of the shell, The housing has an engaging member when closed, The inner plug member has a closing-time engaged member that is engaged from the base end side with the closing-time engaging member. The partition device is configured in the following manner: when a pressing force is applied to the base end side by a piston inserted from the base end side of the inside of the cylinder, one of the closed engaging member and the closed engaged member passes over the other, the engagement between the closed engaging member and the closed engaged member is released, the inner plug member is opened relative to the inside of the shell, and the base end side space is communicated with the front end side space, The filter is held at a front end side portion of the housing.

8. The injection preparation according to claim 7, wherein One of the closing engaging member and the closing engaged member is arranged at the distal end side and the proximal end side relative to the other of the closing engaging member and the closing engaged member.

9. The injection preparation according to claim 7 or 8, wherein The material of the inner plug member is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

10. The injection preparation according to any one of claims 1 to 6, wherein The syringe includes a partitioning device for partitioning the space inside the barrel into a base end side space and a front end side space. The partition device includes a cylindrical housing arranged in liquid-tight contact with the inner side surface of the cylindrical body. The filter is held at the front end side portion of the housing.

11. The injection preparation according to any one of claims 7 to 10, wherein The volume of the space at the front end side of the cylinder is 150mm. 3 Configure in the following way.

12. The injection preparation according to any one of claims 1 to 11, wherein The compound contained in the solution as an effective ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

13. The injection preparation according to any one of claims 1 to 12, wherein The solution contains emicizumab as an active ingredient.

14. A method for removing visually detectable particles contained in an injectable preparation, wherein: The injection preparation is a solution filled in a syringe. The syringe includes a barrel and a filter, wherein the barrel is formed in a cylindrical shape having a front end portion and a base end portion, wherein the front end portion is provided with an injection hole for injecting a solution contained inside to the outside, and the filter is arranged inside the barrel and closer to the base end side than the injection hole, and the filter is arranged so that the solution passes through the filter and flows from the base end side of the filter to the front end side. The method comprises the step of discharging the solution filled in the syringe through a filter, wherein the filter is a filter membrane whose material comprises at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

15. The method according to claim 14, wherein: The compound contained in the solution as an effective ingredient is a low molecular weight compound, a medium molecular weight compound or a protein.

16. The method according to claim 14 or 15, wherein: The solution contains emicizumab as an active ingredient.

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