Syringe with built-in filter containing pharmaceutical preparation

Abstract

To provide a preparation capable of removing particles from a solution preparation filled in a syringe immediately before administration, and to provide a method for removing visually detectable particles contained in an injectable preparation.SOLUTION: Provided is an injectable preparation in which a solution is filled in a syringe. The syringe comprises: a barrel 6 formed in a cylindrical shape having a tip end 60 and a base end and having the tip end provided with a spouting hole 64 for spouting the solution contained therein to the outside; and a filter 8 arranged on the base end side rather than the spouting hole in the inside of the barrel. The filter is provided so that the solution flows from the base end side to the tip end side of the filter through the filter, and the filter is a membrane. A material thereof includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.SELECTED DRAWING: Figure 3

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 technology]

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

[0003] When designing an antibody-containing formulation for subcutaneous injection, it is essential to increase the concentration of the antibody in the administration solution because, while the amount of antibody administered per dose is large (approximately 80 to 200 mg), subcutaneous injections generally have limitations on the amount of injection solution.

[0004] In recent years, in preparations used in medical settings as prefilled syringe preparations for self-injection, a syringe is used that includes a cylindrical syringe body filled with a drug, an injection needle attached to the tip of the syringe body, a syringe cap that covers the detachably attached injection needle, and a plunger that is inserted into the syringe body and can slide in the axial direction of the syringe body.

[0005] When using a prefilled syringe formulation, the syringe cap is removed, the needle is inserted into the administration site, and the drug solution is dispensed and administered by moving the plunger forward with the plunger rod. In general, to ensure the sliding properties of the plunger, a lubricant such as silicone oil is applied to the inner wall and plunger of the prefilled syringe.

[0006] In antibody-containing preparations, particle formation in aqueous solutions is a problem. The particles that form are aggregates larger than multimers such as dimers and trimers, but are generally difficult to see with the naked eye. Sub-visible particles (SVPs), which are fine particles with a diameter of less than 1.5 μm to 50 μm, and visible particles (VPs, larger than 100 μm) that can be detected by the naked eye at standard illuminance (about 2,000-3,000 lx) are known. The visual detection rate of visible particles in pharmaceutical preparations varies greatly between practitioners, but it has been reported that at the standard illuminance (about 2,000-3,000 lx) specified in the Japanese Pharmacopoeia, the detection sensitivity of particles with a diameter of 100 μm is about 40%, the detection sensitivity of particles with a diameter of 150 μm is about 70%, and the detection sensitivity of particles with a diameter of 200 μm is almost 100% (Non-Patent Document 1). In addition, by increasing the illuminance for observing the pharmaceutical preparation or lengthening the observation time, it is actually possible to visually detect particles with even smaller diameters, down to about 40 μm. In this specification, such particles with diameters of 40 μm to 100 μm are particularly referred to as particles that can be visually detected only at high illuminance. Moreover, particles with diameters of 40 μm or more are particles that can be visually detected at high illuminance, and are referred to as visually detectable particles.

[0007] Generally, antibodies have the property of agglutinating at interfaces such as an air-liquid interface and a solid-liquid interface. The presence of these interfaces may contribute to the formation of the above-mentioned visually detectable particles. It has been reported that a significant increase in fine particles due to the presence of interfaces occurs when mechanical stress is applied to a syringe filled with an antibody solution (Non-Patent Document 2). In the antibody solution filled in the syringe, the presence of air bubbles creates an air-liquid interface, which contacts the plunger and the syringe barrel to form a solid-liquid interface. In addition, when the plunger and barrel of the prefilled syringe are coated with silicone, the antibody solution comes into contact with the silicone on the solid phase surface, and a new solid-liquid interface occurs. It has also been reported that proteins that are adsorbed and aggregated at the solid-liquid interface peel off into the liquid due to the movement of air in the solution of the prefilled syringe formulation, and appear as visible particles (Non-Patent Document 3).

[0008] Such proteinaceous particles formed in an aqueous solution are desirably not administered into the body, since there is an undeniable risk of immunogenicity. Furthermore, endogenous and exogenous foreign particles can be a problem not only in antibody-containing preparations, but also in prefilled syringe preparations that contain low- or medium-molecular-weight compounds as active ingredients.

[0009] As a method for removing particles in a formulation filled in a vial immediately before administration, a filter needle equipped with a filter having a pore size of 5 μm on a transfer needle or an in-line filter in an infusion set can be used. Filter needles are commercially available under the product names BD Blunt Filter Needle (Becton Dickinson Japan) and Sterifix (registered trademark) (B Braun). In addition, in a syringe for mixing and administering a plurality of contents, a syringe having a sealing mechanism and a filter that divides the space in the chamber into a wet part and a dry part (Patent Documents 1 to 3) and a syringe equipped with a filter for filtering foreign matter in the syringe when the drug solution in an ampoule is sucked through the injection needle and injected using the injection needle (Patent Document 4) are known. On the other hand, a method for removing particles in a prefilled syringe formulation immediately before administration has not been established so far. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] JP 2007-508898 A [Patent Document 2] JP 2019-051338 A [Patent Document 3] Special Publication No. 2005-537106 [Patent Document 4] Special Publication No. 2015-536213 [Non-patent literature]

[0011] [Non-Patent Document 1] James A. Melchore, AAPS PharmSciTech; 2011; 12(1): 215-221. [Non-Patent Document 2] Torisu et al., J. Pharm. Sci. 106 (2017) 2966-2978. [Non-Patent Document 3] Gerhardt et al., J. Pharm. Sci. 103 (2014) 1601-1612. Summary of the Invention [Problem to be solved by the invention]

[0012] While methods are known for removing particles from formulations filled in vials immediately prior to administration, there is no established method for removing particles from solution formulations filled in syringes immediately prior to administration, and this method is technically difficult. [Means for solving the problem]

[0013] The present inventors therefore conducted extensive research into a novel syringe with a built-in filter and completed the present invention. [1-1] An injectable preparation in which a solution is filled in a syringe, The syringe, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside; A filter is disposed inside the barrel on the base end side of the pouring hole, A filter is provided so that a solution flows through the filter from a proximal side to a distal side of the filter, An injectable preparation, wherein the filter is a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0014] [1-2] The injectable preparation according to [1-1], wherein the material of the membrane is an acrylic copolymer. [1-3] The injectable formulation according to [1-2], wherein the acrylic copolymer is hydrophobic.

[0015] [1-4] The injectable 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. [1-5] The injectable preparation according to any of [1-1] to [1-4], wherein a distal collateral space is provided at the distal end of the filter and a proximal collateral space is provided at the proximal end of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0016] [1-6] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [1-1] to [1-5], wherein the filter is held in a tip portion of the housing.

[0017] [1-7] The injectable preparation described in [1-6], wherein one of the closing engagement portion and the closing engagement portion is disposed on the tip side and base side relative to the other of the closing engagement portion and the closing engagement portion.

[0018] [1-8] The injectable preparation according to [1-6] or [1-7], wherein the material of the inner plug is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0019] [1-9] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [1-1] to [1-5], wherein the filter is held in a tip portion of the housing.

[0020] [1-10] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The injectable preparation according to any one of [1-6] to [1-9], wherein the injectable preparation is arranged as follows: [1-11] The injectable preparation according to any one of [1-6] to [1-10], wherein the material of the housing is linear low density polyethylene (LLDPE) or low density polyethylene (LDPE), preferably low density polyethylene (LDPE).

[0021] [1-12] The injectable preparation according to any one of [1-1] to [1-11], wherein the compound that is an active ingredient contained in the solution is a low molecular weight compound, a medium molecular weight compound, or a protein. [1-13] The injectable formulation according to [1-12], wherein the compound comprises an antibody or a binding fragment thereof, or a cyclic peptide.

[0022] [1-14] The injectable formulation described in [1-12], wherein the low molecular weight compound has a molecular weight of less than 500. [1-15] The injectable formulation according to [1-12], wherein the medium molecular weight compound has a molecular weight of 500 to 15,000.

[0023] [1-16] The injectable formulation described in [1-12], wherein the compound is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0024] [1-17] The injectable preparation according to any one of [1-1] to [1-16], wherein the solution is kept in a state of not contacting the filter before use. [1-18] The injectable preparation according to any one of [1-1] to [1-16], wherein the solution is kept in contact with a filter before use.

[0025] [1-19] The injectable preparation according to [1-17], wherein during or after production of the injectable preparation in which the solution is filled into a syringe, the solution is kept in a state of not contacting a filter before use.

[0026] [1-20] The injectable 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 speed of 300 mm / min, the filter is not broken and the adhesive surface between the filter and the housing is not peeled off.

[0027] [1-21] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0028] [1-22] The injectable formulation according to any one of [1-1] to [1-21], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers.

[0029] [1-23] The injectable preparation according to any one of [1-1] to [1-22], which is provided with an injection needle connected to a syringe. [1-24] The injectable preparation according to any one of [1-1] to [1-23], wherein the solution is an aqueous solution. [1-25] The injectable formulation according to any one of [1-1] to [1-24], wherein the solution contains emicizumab as an active ingredient.

[0030] [2-1] An injectable preparation in which a solution is filled in a syringe, The syringe, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside; A filter is disposed inside the barrel on the base end side of the pouring hole, A filter is provided so that a solution flows through the filter from a proximal side to a distal side of the filter, The filter is a membrane, and the material thereof includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer; An injectable formulation, which upon expulsion of said solution, is capable of removing visually detectable particles from the expelled solution.

[0031] [2-2] The injectable preparation according to [2-1], wherein the material of the membrane is an acrylic copolymer. [2-3] The injectable formulation described in [2-2], wherein the acrylic copolymer is hydrophobic.

[0032] [2-4] The injectable 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. [2-5] The injectable preparation according to any of [2-1] to [2-4], wherein a distal collateral space is provided at the distal end of the filter and a proximal collateral space is provided at the proximal end of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0033] [2-6] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [2-1] to [2-5], wherein the filter is held in a tip portion of the housing.

[0034] [2-7] The injectable preparation described in [2-6], wherein one of the closing engagement portion and the closing engaged portion is disposed on the tip side and base side relative to the other of the closing engagement portion and the closing engaged portion.

[0035] [2-8] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [2-1] to [2-5], wherein the filter is held in a tip portion of the housing.

[0036] [2-9] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The injectable preparation according to any one of [2-6] to [2-8], wherein the injectable preparation is arranged as follows: [2-10] The injectable preparation according to any one of [2-1] to [2-9], wherein the particles have a particle size of more than 40 μm.

[0037] [2-11] The injectable 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 derived from a component other than the solution. [2-12] An injectable formulation according to [2-11], wherein the particles are derived from components of a solution.

[0038] [2-13] An injectable formulation according to [2-11], wherein the particles are derived from components other than those of the solution. [2-14] The injectable preparation according to any one of [2-1] to [2-13], wherein the compound that is an active ingredient contained in the solution is a low molecular weight compound, a medium molecular weight compound, or a protein.

[0039] [2-15] The injectable formulation described in [2-14], wherein the compound comprises an antibody or a binding fragment thereof, or a cyclic peptide. [2-16] An injectable formulation according to [2-14], wherein the low molecular weight compound has a molecular weight of less than 500.

[0040] [2-17] The injectable formulation according to [2-14], wherein the medium molecular weight compound has a molecular weight of 500 to 15,000. [2-18] The injectable formulation described in [2-14], wherein the compound is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0041] [2-19] The injectable preparation according to any one of [2-1] to [2-18], wherein the solution is kept in a state of not contacting the filter before use. [2-20] The injectable preparation according to any one of [2-1] to [2-18], wherein the solution is kept in contact with a filter before use.

[0042] [2-21] The injectable preparation according to [2-19], wherein the solution is kept in a non-contact state with the filter during or after production of the injectable preparation in which the solution is filled into a syringe. [2-22] The injectable 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 speed of 300 mm / min, the filter is not broken and the adhesive surface between the filter and the housing is not peeled off.

[0043] [2-23] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0044] [2-24] The injectable formulation according to any one of [2-1] to [2-23], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [2-25] The injectable preparation according to any one of [2-1] to [2-24], wherein the solution is an aqueous solution. [2-26] The injectable formulation according to any one of [2-1] to [2-25], wherein the solution contains emicizumab as an active ingredient.

[0045] [3-1] A method for removing visually detectable particles contained in an injectable formulation, comprising: The injectable preparation is a solution and is filled in a syringe; The syringe is provided with a barrel formed in a cylindrical shape having a tip end and a base end, an outlet hole for injecting an injectable preparation contained inside to the outside provided at the tip end, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that a solution flows from the base end side to the tip end side of the filter via the filter, The method includes discharging a solution filled in a syringe through a filter, the filter being a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer.

[0046] [3-2] The method according to [3-1], wherein the material of the membrane is an acrylic copolymer. [3-3] The method according to [3-2], wherein the acrylic copolymer is hydrophobic. [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.

[0047] [3-5] The method according to any of [3-1] to [3-4], wherein a distal collateral space is provided at the distal end of the filter and a proximal collateral space is provided at the proximal end of the filter, and when viewed from the axial direction of the barrel, the area of ​​the pouring hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0048] [3-6] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The method according to any one of [3-1] to [3-5], wherein the filter is held in a tip portion of the housing.

[0049] [3-7] The method described in [3-6], wherein one of the closing-time engaging portion and the closing-time engaged portion is positioned on the tip side and base end side relative to the other of the closing-time engaging portion and the closing-time engaged portion.

[0050] [3-8] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The method according to any one of [3-1] to [3-5], wherein the filter is held in a tip portion of the housing.

[0051] [3-9] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The method according to any one of [3-6] to [3-8], wherein the following arrangement is performed: [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.

[0052] [3-11] The method according to any one of [3-1] to [3-10], wherein the particles include particles derived from a component of the solution or particles derived from a component other than the solution. [3-12] The method according to [3-11], wherein the particles are derived from components of a solution.

[0053] [3-13] The method according to [3-11], wherein the particles are derived from components other than those of the solution. [3-14] The method according to any one of [3-1] to [3-13], wherein the compound that is an active ingredient contained in the solution is a low molecular weight compound, a medium molecular weight compound, or a protein.

[0054] [3-15] The method according to [3-14], wherein the compound comprises an antibody or a binding fragment thereof, or a cyclic peptide. [3-16] The method according to [3-14], wherein the low molecular weight compound has a molecular weight of less than 500.

[0055] [3-17] The method according to [3-14], wherein the medium molecular weight compound has a molecular weight of 500 to 15,000. [3-18] The method according to [3-14], wherein the compound is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0056] [3-19] The method according to any one of [3-1] to [3-18], wherein the solution is kept out of contact with the filter before use. [3-20] The method according to any one of [3-1] to [3-18], wherein the solution is placed in contact with a filter before use.

[0057] [3-21] The method according to [3-19], wherein the solution is kept in a non-contact state with the filter during or after production of the injectable preparation in which the solution is filled in a syringe. [3-22] The method according to any one of [3-1] to [3-21], in which the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge speed of 300 mm / min.

[0058] [3-23] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0059] [3-24] The method according to any of [3-1] to [3-23], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [3-25] The method according to any one of [3-1] to [3-24], wherein the solution is an aqueous solution. [3-26] The method according to any of [3-1] to [3-25], wherein the solution contains emicizumab as an active ingredient.

[0060] [4-1] A syringe filled with a solution, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that the solution flows from the base end side of the filter to the tip end side via the filter, A syringe having a membrane filter made of a material containing one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer, in which the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off 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.

[0061] [4-2] A syringe filled with a solution, the syringe is provided with a barrel formed in a cylindrical shape having a tip end and a base end, an outlet hole for injecting a solution contained inside to the outside provided at the tip end, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that the solution flows from the base end side to the tip end side of the filter via the filter; A syringe in which the filter is a membrane, the material of which is one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer, and in which, when a solution having a viscosity of 95 cP or less is discharged through the 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.

[0062] [4-3] The syringe according to [4-1] or [4-2], wherein the material of the membrane is an acrylic copolymer. [4-4] The syringe according to [4-3], wherein the acrylic copolymer is hydrophobic.

[0063] [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. [4-6] The syringe according to any of [4-1] to [4-5], wherein a distal collateral space is provided on the distal side of the filter and a proximal collateral space is provided on the proximal side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0064] [4-7] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The syringe according to any one of [4-1] to [4-6], wherein the filter is held in a tip portion of the housing.

[0065] [4-8] A syringe as described in [4-7], wherein one of the closing engagement portion and the closing engaged portion is positioned on the tip side and base end side relative to the other of the closing engagement portion and the closing engaged portion.

[0066] [4-9] The syringe according to [4-7] or [4-8], wherein the material of the inner plug is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0067] [4-10] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The syringe according to any one of [4-1] to [4-6], wherein the filter is held in a tip portion of the housing.

[0068] [4-11] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The syringe according to any one of [4-7] to [4-10], arranged as follows: [4-12] A syringe according to any one of [4-7] to [4-11], wherein the material of the housing is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0069] [4-13] A syringe according to any one of [4-1] to [4-12], wherein the compound that is an active ingredient contained in the solution is a low molecular weight compound, a medium molecular weight compound, or a protein. [4-14] The syringe described in [4-13], wherein the compound comprises an antibody or a binding fragment thereof, or a cyclic peptide.

[0070] [4-15] A syringe according to [4-13], wherein the low molecular weight compound has a molecular weight of less than 500. [4-16] The syringe according to [4-13], wherein the medium molecular weight compound has a molecular weight of 500 to 15,000.

[0071] [4-17] The syringe described in [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).

[0072] [4-18] A syringe according to any one of [4-1] to [4-17], wherein the solution is kept out of contact with the filter before use. [4-19] A syringe according to any one of [4-1] to [4-17], wherein the solution is placed in contact with a filter before use.

[0073] [4-20] The syringe according to [4-18], wherein the solution is kept out of contact with the filter during or after production of the injectable preparation in which the solution is filled in the syringe. [4-21] A syringe described in any of [4-1] to [4-20], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [4-22] The syringe according to any one of [4-1] to [4-21], wherein the solution is an aqueous solution. [4-23] A syringe described in any of [4-1] to [4-22], wherein the solution contains emicizumab as an active ingredient.

[0074] [5-1] An injectable preparation for use as a medicine, the preparation being filled in a syringe and capable of being stored for 10 days or more, the syringe is formed in a cylindrical shape having a tip end and a base end, the barrel having an outlet hole at the tip end for injecting a solution contained therein to the outside, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being disposed so that the solution flows from the base end side of the filter to the tip end side via the filter; An injectable preparation, wherein the filter is a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0075] [5-2] The injectable formulation according to [5-1], which exhibits less change in physical properties even after storage at 5°C, 25°C, or 40°C, as compared with a formulation filled in a prefilled syringe not incorporating a filter.

[0076] [5-3] The injectable preparation according to [5-1] or [5-2], wherein the material of the membrane is an acrylic copolymer. [5-4] An injectable formulation according to [5-3], wherein the acrylic copolymer is hydrophobic.

[0077] [5-5] The injectable 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. [5-6] The injectable preparation according to any of [5-1] to [5-5], wherein a distal collateral space is provided on the distal side of the filter and a proximal collateral space is provided on the proximal side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0078] [5-7] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [5-1] to [5-6], wherein the filter is held in a tip portion of the housing.

[0079] [5-8] The injectable preparation described in [5-7], wherein one of the closing engagement portion and the closing engaged portion is arranged on the tip side and base side relative to the other of the closing engagement portion and the closing engaged portion.

[0080] [5-9] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [5-1] to [5-6], wherein the filter is held in a tip portion of the housing.

[0081] [5-10] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The injectable preparation according to any one of [5-7] to [5-9], wherein the injectable preparation is arranged as follows: [5-11] The injectable preparation according to any one of [5-1] to [5-10], wherein the compound that is an active ingredient contained in the solution is a low molecular weight compound, a medium molecular weight compound, or a protein.

[0082] [5-12] The injectable formulation described in [5-11], wherein the compound comprises an antibody or a binding fragment thereof, or a cyclic peptide. [5-13] An injectable formulation according to [5-11], wherein the low molecular weight compound has a molecular weight of less than 500.

[0083] [5-14] The injectable formulation described in [5-11], wherein the medium molecular weight compound has a molecular weight of 500 to 15,000. [5-15] The injectable formulation described in [5-11], wherein the compound is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0084] [5-16] The injectable preparation according to any one of [5-1] to [5-15], wherein the injectable preparation is kept in a state of not being in contact with a filter before use. [5-17] An injectable preparation according to any one of [5-1] to [5-15], wherein the injectable preparation is kept in contact with a filter before use.

[0085] [5-18] An injectable preparation according to [5-16], wherein even if stress is applied during or after the production of the injectable preparation in which the solution is filled into a syringe, the solution is kept in a non-contact state with the filter.

[0086] [5-19] The injectable 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, the filter is not broken and the adhesive surface between the filter and the housing is not peeled off.

[0087] [5-20] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0088] [5-21] An injectable formulation according to any one of [5-1] to [5-20], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [5-22] The injectable preparation according to any one of [5-1] to [5-21], wherein the solution is an aqueous solution. [5-23] An injectable formulation according to any one of [5-1] to [5-22], wherein the solution contains emicizumab as an active ingredient.

[0089] [6-1] An injectable preparation in which a solution containing a protein as an active ingredient is filled in a syringe, The syringe, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside; A filter is disposed inside the barrel on the base end side of the pouring hole, A filter is provided so that a solution flows through the filter from a proximal side to a distal side of the filter, An injectable preparation, wherein the filter is a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0090] [6-2] The injectable preparation described in [6-1], wherein the material of the membrane is an acrylic copolymer. [6-3] The injectable formulation described in [6-2], wherein the acrylic copolymer is hydrophobic.

[0091] [6-4] The injectable 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. [6-5] The injectable preparation according to any of [6-1] to [6-4], wherein a distal collateral space is provided at the distal side of the filter and a proximal collateral space is provided at the proximal side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0092] [6-6] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [6-1] to [6-5], wherein the filter is held in a tip portion of the housing.

[0093] [6-7] The injectable preparation described in [6-6], wherein one of the closing engagement portion and the closing engagement portion is arranged on the tip side and base end side relative to the other of the closing engagement portion and the closing engagement portion.

[0094] [6-8] The injectable preparation according to [6-6] or [6-7], wherein the material of the inner plug is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0095] [6-9] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [6-1] to [6-5], wherein the filter is held in a tip portion of the housing.

[0096] [6-10] The partition means has a volume of the tip side space of the barrel of 150 mm 3The injectable preparation according to any one of [6-6] to [6-9], wherein the injectable preparation is arranged as follows: [6-11] The injectable preparation according to any one of [6-6] to [6-10], wherein the material of the housing is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0097] [6-12] The injectable preparation according to any one of [6-1] to [6-11], wherein the protein is a monoclonal antibody. [6-13] The injectable preparation according to any one of [6-1] to [6-12], wherein the solution is kept in a state of not contacting the filter before use.

[0098] [6-14] An injectable preparation according to any one of [6-1] to [6-12], wherein the solution is kept in contact with a filter before use. [6-15] An injectable preparation according to [6-13], wherein during or after production of the injectable preparation in which a solution containing a protein as an active ingredient is filled into a syringe, the solution is kept in a non-contact state with a filter before use.

[0099] [6-16] The injectable 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. [6-17] The injectable preparation according to any one of [6-1] to [6-16], wherein the concentration of the protein in the solution is in the range of 0.1 to 300 mg / mL.

[0100] [6-18] The injectable 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 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0101] [6-19] The injectable 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, the filter is not broken and the adhesive surface between the filter and the housing is not peeled off.

[0102] [6-20] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0103] [6-21] An injectable formulation according to any one of [6-1] to [6-20], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers.

[0104] [6-22] An injectable preparation according to any one of [6-1] to [6-21], comprising an injection needle connected to a syringe. [6-23] The injectable preparation according to any one of [6-1] to [6-22], wherein the solution is an aqueous solution. [6-24] The injectable preparation according to any one of [6-1] to [6-23], wherein the protein is emicizumab.

[0105] [7-1] An injectable preparation in which a solution containing a protein as an active ingredient is filled in a syringe, The syringe, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside; A filter is disposed inside the barrel on the base end side of the pouring hole, A filter is provided so that a solution flows through the filter from a proximal side to a distal side of the filter, The filter is a membrane, and the material thereof includes at least one selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer; An injectable formulation, which upon expulsion of said solution, is capable of removing visually detectable particles from the expelled solution.

[0106] [7-2] The injectable preparation described in [7-1], wherein the material of the membrane is an acrylic copolymer. [7-3] The injectable formulation described in [7-2], wherein the acrylic copolymer is hydrophobic.

[0107] [7-4] The injectable 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. [7-5] The injectable preparation according to any of [7-1] to [7-4], wherein a distal collateral space is provided at the distal end of the filter and a proximal collateral space is provided at the proximal end of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0108] [7-6] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [7-1] to [7-5], wherein the filter is held in a tip portion of the housing.

[0109] [7-7] The injectable preparation described in [7-6], wherein one of the closing engagement portion and the closing engaged portion is arranged on the tip side and base side relative to the other of the closing engagement portion and the closing engaged portion.

[0110] [7-8] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [7-1] to [7-5], wherein the filter is held in a tip portion of the housing.

[0111] [7-9] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The injectable preparation according to any one of [7-6] to [7-8], wherein the injectable preparation is arranged as follows: [7-10] The injectable preparation according to any one of [7-1] to [7-9], wherein the particles have a particle size of greater than 40 μm.

[0112] [7-11] The injectable 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 derived from a component other than the solution. [7-12] An injectable formulation according to [7-11], wherein the particles are derived from components of a solution.

[0113] [7-13] An injectable formulation according to [7-11], wherein the particles are derived from components other than those of the solution. [7-14] An injectable preparation according to any one of [7-1] to [7-13], wherein the protein is a monoclonal antibody.

[0114] [7-15] The injectable preparation according to any one of [7-1] to [7-14], wherein the solution is kept in a state of not contacting the filter before use. [7-16] An injectable preparation according to any one of [7-1] to [7-14], wherein the solution is kept in contact with a filter before use.

[0115] [7-17] An injectable formulation according to [7-15], wherein during or after production of the injectable formulation in which a solution containing a protein as an active ingredient is filled into a syringe, the solution is kept in a state of not contacting a filter.

[0116] [7-18] The injectable 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. [7-19] The injectable 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.

[0117] [7-20] The injectable 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 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0118] [7-21] An injectable preparation according to any one of [7-1] to [7-20], in which the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off 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.

[0119] [7-22] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0120] [7-23] An injectable formulation according to any one of [7-1] to [7-22], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [7-24] The injectable preparation according to any one of [7-1] to [7-23], wherein the solution is an aqueous solution. [7-25] The injectable formulation according to any one of [7-1] to [7-24], wherein the protein is emicizumab.

[0121] [8-1] A method for removing visually detectable particles contained in an injectable formulation, comprising: The injectable preparation is a solution containing a protein as an active ingredient and is filled in a syringe; The syringe is provided with a barrel formed in a cylindrical shape having a tip end and a base end, an outlet hole for injecting an injectable preparation contained inside to the outside provided at the tip end, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that a solution flows from the base end side to the tip end side of the filter via the filter, The method includes discharging a solution filled in a syringe through a filter, the filter being a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer.

[0122] [8-2] The method according to [8-1], wherein the membrane is made of an acrylic copolymer. [8-3] The method according to [8-2], wherein the acrylic copolymer is hydrophobic. [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.

[0123] [8-5] The method according to any of [8-1] to [8-4], wherein a distal collateral space is provided at the distal end of the filter and a proximal collateral space is provided at the proximal end of the filter, and when viewed from the axial direction of the barrel, the area of ​​the pouring hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0124] [8-6] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The method according to any one of [8-1] to [8-5], wherein the filter is held in a tip portion of the housing.

[0125] [8-7] The method described in [8-6], wherein one of the closing-time engaging portion and the closing-time engaged portion is arranged on the tip side and base end side relative to the other of the closing-time engaging portion and the closing-time engaged portion.

[0126] [8-8] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The method according to any one of [8-1] to [8-5], wherein the filter is held in a tip portion of the housing.

[0127] [8-9] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The method according to any one of [8-6] to [8-8], wherein the following arrangement is made: [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.

[0128] [8-11] The method according to any one of [8-1] to [8-10], wherein the particles include particles derived from a component of the solution or particles derived from a component other than the solution. [8-12] The method according to [8-11], wherein the particles are derived from components of a solution.

[0129] [8-13] The method according to [8-11], wherein the particles are derived from other than components of the solution. [8-14] The method according to any one of [8-1] to [8-13], wherein the protein is a monoclonal antibody.

[0130] [8-15] The method according to any one of [8-1] to [8-14], wherein the solution is kept out of contact with the filter before use. [8-16] The method according to any one of [8-1] to [8-14], wherein the solution is placed in contact with a filter before use.

[0131] [8-17] The method according to [8-15], wherein during or after production of an injectable preparation in which a solution containing a protein as an active ingredient is filled into a syringe, the solution is kept in a state of not being in contact with a filter.

[0132] [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. [8-19] The method according to any 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.

[0133] [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 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0134] [8-21] The method according to any one of [8-1] to [8-20], in which the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off even after a solution having a viscosity of 95 cP or less is discharged through the filter at a discharge speed of 300 mm / min.

[0135] [8-22] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe not incorporating a filter.

[0136] [8-23] The method according to any of [8-1] to [8-22], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [8-24] The method according to any one of [8-1] to [8-23], wherein the solution is an aqueous solution. [8-25] The method according to any one of [8-1] to [8-24], wherein the protein is emicizumab.

[0137] [9-1] A syringe filled with a solution containing a protein as an active ingredient, a barrel formed in a cylindrical shape having a tip end and a base end, the tip end being provided with an outlet hole for outletting a solution contained therein to the outside, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that the solution flows from the base end side of the filter to the tip end side via the filter, A syringe having a membrane filter made of a material containing one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer, in which the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off 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.

[0138] [9-2] A syringe filled with a solution containing a protein as an active ingredient, the syringe is provided with a barrel formed in a cylindrical shape having a tip end and a base end, an outlet hole for injecting a solution contained inside to the outside provided at the tip end, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being provided so that the solution flows from the base end side to the tip end side of the filter via the filter; A syringe in which the filter is a membrane, the material of which is one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and an acrylic copolymer, and in which, when a solution having a viscosity of 95 cP or less is discharged through the 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.

[0139] [9-3] A syringe according to [9-1] or [9-2], wherein the material of the membrane is an acrylic copolymer. [9-4] A syringe according to [9-3], wherein the acrylic copolymer is hydrophobic.

[0140] [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. [9-6] The syringe according to any of [9-1] to [9-5], wherein a distal collateral space is provided on the distal side of the filter and a proximal collateral space is provided on the proximal side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0141] [9-7] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The syringe according to any one of [9-1] to [9-6], wherein the filter is held in a tip portion of the housing.

[0142] [9-8] A syringe as described in [9-7], wherein one of the closing engagement portion and the closing engagement portion is positioned on the tip side and base end side relative to the other of the closing engagement portion and the closing engagement portion.

[0143] [9-9] The material of the inner plug portion is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE), according to [9-7] or [9-8]. Syringe .

[0144] [9-10] The syringe includes a partition means for dividing a space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The syringe according to any one of [9-1] to [9-6], wherein the filter is held in a tip portion of the housing.

[0145] [9-11] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The syringe according to any one of [9-7] to [9-10], arranged as follows: [9-12] A syringe according to any one of [9-7] to [9-11], wherein the material of the housing is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE), preferably low-density polyethylene (LDPE).

[0146] [9-13] A syringe according to any one of [9-1] to [9-12], wherein the protein is a monoclonal antibody. [9-14] A syringe according to any one of [9-1] to [9-13], wherein the solution is kept out of contact with the filter before use.

[0147] [9-15] A syringe according to any one of [9-1] to [9-13], wherein the solution is placed in contact with a filter before use. [9-16] The syringe according to [9-14], wherein during or after production of an injectable preparation in which a solution containing a protein as an active ingredient is filled into the syringe, the solution is kept in a non-contact state with the filter.

[0148] [9-17] A 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. [9-18] A 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.

[0149] [9-19] A 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 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0150] [9-20] A syringe described in any of [9-1] to [9-19], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers. [9-21] The syringe according to any one of [9-1] to [9-20], wherein the solution is an aqueous solution. [9-22] The syringe described in any one of [9-1] to [9-21], wherein the protein is emicizumab.

[0151] [10-1] An injectable preparation for use as a medicine, the preparation being filled in a syringe and capable of being stored for 10 days or more, the syringe is formed in a cylindrical shape having a tip end and a base end, the barrel having an outlet hole at the tip end for injecting a solution contained therein to the outside, and a filter disposed inside the barrel on the base end side of the outlet hole, the filter being disposed so that the solution flows from the base end side of the filter to the tip end side via the filter; An injectable preparation, wherein the filter is a membrane, the material of which includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0152] [10-2] The injectable formulation according to [10-1], which exhibits less change in physical properties even after storage at 5°C, 25°C, or 40°C, as compared with a formulation filled in a prefilled syringe not incorporating a filter.

[0153] [10-3] The injectable preparation according to [10-1] or [10-2], wherein the material of the membrane is an acrylic copolymer. [10-4] The injectable formulation described in [10-3], wherein the acrylic copolymer is hydrophobic.

[0154] [10-5] The injectable 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. [10-6] The injectable preparation according to any of [10-1] to [10-5], wherein a distal collateral space is provided at the distal side of the filter and a proximal collateral space is provided at the proximal side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the injection hole is smaller than the area of ​​the proximal collateral space and smaller than the area of ​​the distal collateral space.

[0155] [10-7] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partitioning means comprises a cylindrical housing arranged in liquid-tight contact with the inner surface of the barrel, and an inner plug portion arranged in a manner that can be opened and closed with respect to the inside of the housing so that the base end space and the tip end space are in communication or not in communication with each other through the inside of the housing, The housing has a closing engagement portion, The inner plug portion has a closing-time engaged portion that engages with the closing-time engaging portion from a base end side, the partition means is configured such that, when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closing-time engaging portion and the closing-time engaged portion overcomes the other, the engagement between the closing-time engaging portion and the closing-time engaged portion is released, the inner plug portion is opened to the inside of the housing, and the base end space and the tip end space communicate with each other, The injectable preparation according to any one of [10-1] to [10-6], wherein the filter is held in a tip portion of the housing.

[0156] [10-8] The injectable preparation described in [10-7], wherein one of the closing engagement portion and the closing engaged portion is arranged on the tip side and base side relative to the other of the closing engagement portion and the closing engaged portion.

[0157] [10-9] The syringe includes a partition means for partitioning the space inside the barrel into a base end space and a tip end space, the partition means comprises a cylindrical housing disposed in liquid-tight contact with the inner surface of the barrel; The injectable preparation according to any one of [10-1] to [10-6], wherein the filter is held in a tip portion of the housing.

[0158] [10-10] The partition means has a volume of the tip side space of the barrel of 150 mm 3 The injectable preparation according to any one of [10-7] to [10-9], wherein the injectable preparation is arranged as follows: [10-11] The injectable preparation according to any one of [10-1] to [10-10], wherein the protein is a monoclonal antibody.

[0159] [10-12] The injectable preparation according to any one of [10-1] to [10-11], wherein the injectable preparation is kept in a state of not being in contact with a filter before use. [10-13] An injectable preparation according to any one of [10-1] to [10-11], wherein the injectable preparation is kept in contact with a filter before use.

[0160] [10-14] An injectable preparation according to [10-12], in which a solution containing a protein as an active ingredient is filled into a syringe, and even if stress is applied during or after the production of the injectable preparation, the solution is kept in a non-contact state with the filter.

[0161] [10-15] The injectable preparation according to any one of [10-1] to [10-14], wherein the concentration of the protein in the solution is 0.1 mg / mL or more. [10-16] The injectable 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.

[0162] [10-17] The injectable 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 to 200 mg / mL, 50 to 200 mg / mL, or 80 to 200 mg / mL.

[0163] [10-18] The 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, the filter is not damaged and the adhesive surface between the filter and the housing is not peeled off.

[0164] [10-19] The 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 speed of 100 mm / min, the average sliding resistance value at 10 mm is within 1.3 times, 1.4 times, or 1.5 times, compared to a syringe without a built-in filter.

[0165] [10-20] The injectable formulation according to any one of [10-1] to [10-19], wherein the solution contains one or more pharma- ceutically acceptable excipients selected from sugars, sugar alcohols, buffers, preservatives, carriers, antioxidants, chelating agents, natural polymers, synthetic polymers, cryoprotectants, bulking agents, and stabilizers.

[0166] [10-21] The injectable preparation according to any one of [10-1] to [10-20], wherein the solution is an aqueous solution. [10-22] The injectable formulation according to any one of [10-1] to [10-21], wherein the solution contains emicizumab as an active ingredient. Effect of the Invention

[0167] According to the present invention, even if visually detectable particles are present in the solution of the injectable preparation filled in the syringe, the entire amount of the solution filled in the syringe is filtered through a filter when it is discharged, making it possible to supply a high-quality preparation that does not contain particles. [Brief description of the drawings]

[0168] [Figure 1] FIG. 1 is a cross-sectional view for illustrating a closed state of an inner plug portion of a prefilled syringe according to this embodiment. [Diagram 2] FIG. 2 is a cross-sectional view for illustrating an open state of the inner plug portion of the prefilled syringe. [Diagram 3] FIG. 3 is an enlarged cross-sectional view of a region indicated by III in FIG. [Figure 4] FIG. 4 is an enlarged cross-sectional view of a region indicated by IV in FIG. [Diagram 5]FIG. 5 is a perspective view of an inner plug portion of the syringe. [Figure 6] FIG. 6 is a perspective view of the inner plug portion. [Figure 7] FIG. 7 is a side view for illustrating a closed state of an inner plug portion of a prefilled syringe according to a modified example. [Figure 8] FIG. 8 is a cross-sectional view for illustrating an open state of the inner plug portion of the prefilled syringe. [Figure 9] FIG. 9 is an enlarged cross-sectional view of a region indicated by IX in FIG. [Figure 10] FIG. 10 is an enlarged cross-sectional view of the area indicated by X in FIG. [Figure 11] FIG. 11 is a perspective view of the inner plug of the syringe. [Figure 12] FIG. 12 is a perspective view of the inner plug portion. [Figure 13] FIG. 13 is a schematic cross-sectional view of a prefilled syringe according to a modified example when in use, where (a) shows the inner stopper part in a closed state, (b) shows the state immediately after the inner stopper part is opened, (c) shows the inner stopper part in an open state, and (d) shows the state after administration of a drug. [Figure 14] FIG. 14 is a schematic cross-sectional view of a prefilled syringe according to a modified example when in use, where (a) shows the inner stopper part in a closed state, (b) shows the state immediately after the inner stopper part is opened, (c) shows the inner stopper part in an open state, and (d) shows the state after administration of a drug. [Figure 15] FIG. 15 is a cross-sectional view of a pre-filled syringe equipped with a holding member. [Figure 16] FIG. 16 is an enlarged cross-sectional view of a region indicated by III in FIG. [Figure 17] FIG. 17 is a schematic diagram for explaining attachment of the filter to the holding member. [Figure 18] FIG. 18 is a side view of a pre-filled syringe according to a modified example. [Figure 19] FIG. 19 is an enlarged cross-sectional view of a region indicated by VI in FIG. [Figure 20]FIG. 20 is a side view of a syringe according to a modified example. [Figure 21] FIG. 21 is an enlarged cross-sectional view of the area indicated by VIII in FIG. [Figure 22] FIG. 22 shows photographs of (a) a normal, unbroken filter and (b) an abnormally broken filter after the solution was discharged. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0169] (1) Prefilled syringe Hereinafter, a pre-filled syringe equipped with a syringe according to an embodiment of the present invention will be described with reference to FIGS.

[0170] As shown in Figures 1 and 2, the prefilled syringe 1 includes a syringe 2 for administering a drug. The prefilled syringe 1 also includes a piston 3 inserted into the syringe 2. The prefilled syringe 1 also includes an injection needle 4 connected to the syringe 2. The prefilled syringe 1 also includes a cap 5 that caps the injection needle 4. The drug is a liquid drug, for example, a protein preparation.

[0171] The syringe 2 is formed in a cylindrical shape having a tip end portion 60 and a base end portion 61, and includes a barrel 6 and a partitioning means 7 that partitions a space S inside the barrel 6 into a base end side space S1 and a tip end side space S2. The syringe 2 is also substantially cylindrical.

[0172] Hereinafter, in the prefilled syringe 1 and the syringe 2, the side where the tip portion 60 is arranged (lower side in Figs. 1 to 4) will be simply referred to as the "tip side", and the side where the base end portion 61 is arranged (upper side in Figs. 1 to 4) will be simply referred to as the "base side". In addition, the cylindrical axis direction of the syringe 2 will also be simply referred to as the "cylindrical axis direction".

[0173] The barrel 6 is a member that contains a medicine inside. In addition, the barrel 6 has an outlet hole in the tip portion 60 for outletting the medicine contained inside to the outside. In this embodiment, the barrel 6 includes a cylindrical portion 62 that connects the tip portion 60 and the base portion 61 in addition to the tip portion 60 and the base portion 61. The barrel 6 also has a flange portion 63 that extends outward (in the radially outward direction of the cylindrical portion 62) from the entire outer periphery of the other end of the cylindrical portion 62 in the cylindrical axis direction.

[0174] The barrel 6 is formed of, for example, a transparent material that can withstand the internal pressure applied when administering 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 such as COP (cycloolefin polymer), which is a homopolymer of a cyclic olefin, or COC (cycloolefin copolymer), which is a copolymer of a cyclic olefin and ethylene or the like. The material of the barrel 6 may be PP (polypropylene) or glass.

[0175] In addition, to the inner surface of the barrel 6 (for example, the inner surface of the cylindrical portion 62), silicone oil may be applied in order to reduce the sliding resistance of the piston 3 against the inner peripheral surface of the barrel 6. The tip portion 60 of the barrel 6 is provided at one end (specifically, the end portion on the tip side) in the cylindrical axial direction of the tubular portion 62. As shown in Figures 3 and 4, the tip portion 60 is provided with an ejection hole 64 for ejecting the medicine contained inside to the outside. In the barrel 6 of this embodiment, the ejection hole 64 is a needle hole through which the injection needle 4 is inserted.

[0176] When the needle inserted into the ejection hole 64 is, for example, 27 gauge, the inner diameter of the ejection hole 64 is 0.27 mm, and the area of ​​the ejection hole 64 when viewed from the axial direction of the cylinder is 0.057 mm. 2 In addition, when the needle inserted into the ejection hole 64 is 29 gauge, the inner diameter of the ejection hole 64 is 0.21 mm, and the area of ​​the ejection hole 64 when viewed from the axial direction of the cylinder is 0.035 mm. 2 It is.

[0177] The base end surface 600 of the tip portion 60 is formed so as to close the edge portion located on the tip side of the tubular portion 62 other than the pouring hole 64. The base end surface 600 extends, for example, at an incline so that the radially inward side is positioned closer to the tip side.

[0178] The area of ​​the cylindrical portion 62 when viewed from the cylindrical axis direction is, for example, approximately constant, specifically, 12.56 mm 2 More than 314mm 2 The inner diameter of the cylindrical portion 62 is, for example, approximately constant, and specifically, is not less than 4 mm and not more than 20 mm.

[0179] A partitioning means 7 is housed inside such a barrel 6, and the partitioning means 7 divides the space S inside the barrel 6 into a base end space S1 on the base end side in the axial direction and a tip end space S2 on the tip end side in the axial direction. In the barrel 6 of this embodiment, as shown in Figs. 2 to 5, the base end space S1, which is the space on the base end side of the partitioning means 7, contains a liquid medicine, and the tip end space S2, which is the space on the tip end side of the partitioning means 7, is empty and contains no medicine. Specifically, the tip end space S2 includes a first tip end space S21, which is the space on the tip end side of the filter 80 and does not contain any medicine, and a second tip end space S22, which is the space on the base end side of the filter 80 and does not contain any medicine.

[0180] A solid agent may be contained in either the first distal end space S21 or the second distal end space S22. A liquid agent may be contained in each of the base end space S1 and the distal end space S2.

[0181] The partitioning means 7 comprises a cylindrical housing 8 and an inner plug portion 9 that can be opened and closed relative to the inside of the housing 8. In this embodiment, the partitioning means 7 comprises one housing 8 and one inner plug portion 9. The partitioning means 7 is disposed at the tip portion 60 of the barrel 6 (see Figs. 3 and 4). Furthermore, the partitioning means 7 comprises a filter 80 attached to the housing 8 inside the barrel 6. The partitioning means 7 comprises one filter 80, but may comprise a plurality of overlapping filters 80.

[0182] The partitioning means 7 does not necessarily have to include the filter 80. In this case, the partitioning means 7 is composed of, for example, a cylindrical housing 8 and an inner plug portion 9 that can be opened and closed relative to the inside of the housing 8.

[0183] The housing 8 is a member disposed so as to be in liquid-tight contact with the inner surface of the barrel 6 (for example, the inner surface of the cylindrical portion 62). The housing 8 is accommodated in the barrel 6 while being pressed against the barrel 6. Specifically, at least a portion of the outer circumferential surface 800 of the housing 8 is in close contact with the inner surface of the barrel 6.

[0184] In this embodiment, the outer peripheral surface 800 of the housing 8 includes a base end outer peripheral surface portion 801 arranged on the base end side and a tip outer peripheral surface portion 802 arranged on the tip end side, and the tip outer peripheral surface portion 802 is formed to have a smaller diameter than the base end outer peripheral surface portion 801. The base end outer peripheral surface portion 801 is in liquid-tight contact with the inner peripheral surface of the barrel 6. The tip outer peripheral surface portion 802 faces the inner peripheral surface of the barrel 6 with a gap therebetween.

[0185] Moreover, the housing 8 is formed of a flexible material. The housing 8 of this embodiment is more flexible than the barrel 6. Specifically, the material of the housing 8 is, for example, a resin, rubber, elastomer, or the like that is softer than the material of the barrel 6. The flexibility of the barrel 6 and the housing 8 can be confirmed, for example, by measuring the durometer hardness. By forming the housing 8 from such a material, the flexibility of the housing 8 relative to the barrel 6 can be ensured, and cracks in the barrel 6 can be prevented.

[0186] The housing 8 has a cylindrical shape. In this embodiment, the housing 8 is disposed on the proximal side of the filter 80. In other words, the housing 8 is composed of only a proximal side portion disposed on the proximal side of the filter 80.

[0187] In addition, although the housing 8 in this embodiment is composed of only the base end portion, it may be configured to include a tip end portion that is positioned distal to the filter 80, either integrally with the base end portion or separately.

[0188] The housing 8 has a closing engagement portion 81. Specifically, the housing 8 has one closing engagement portion 81. The closing engagement portion 81 is a portion that engages with the inner plug portion 9 when the inner plug portion 9 is in a closed state (see FIG. 3).

[0189] The closing engagement portion 81 protrudes radially inward from the inner circumferential surface 82 of the housing 8, and is formed in a plurality of portions connected together over the entire circumferential direction, or spaced apart over the entire circumferential direction. In this embodiment, the closing engagement portion 81 is a rib that protrudes from the inner circumferential surface 82 of the housing 8 toward the cylindrical axis (diametrically inward). Specifically, the closing engagement portion 81 is a rib that is continuous in the circumferential direction. The closing engagement portion 81 is provided at the center of the inner circumferential surface 82 in the cylindrical axis direction. The base end side end face of the closing engagement portion 81 is a flat surface extending in the radial direction.

[0190] In addition, in this embodiment, the inner surface 82 of the housing 8 has a base end inner surface portion 821 arranged on the base end side and a tip end inner surface portion 822 arranged on the tip end side, and the base end inner surface portion 821 is formed with a larger diameter than the tip end inner surface portion 822.

[0191] The above-mentioned housing 8 has a small diameter inner circumferential surface (specifically, tip inner circumferential surface portion 822) on the tip side, a large diameter inner circumferential surface (specifically, base inner circumferential surface portion 821) on the base end side, and a closing engagement portion 81 between the small diameter inner circumferential surface and the large diameter inner circumferential surface.

[0192] Furthermore, the housing 8 has a stepped surface 810 that extends radially inward from the inner circumferential surface 82 and faces the base end side. In this housing 8, the base end side end face of the closing engagement portion 81 is the stepped surface 810, but a surface in a position other than the closing engagement portion 81 may be the stepped surface 810. Furthermore, the stepped surface 810 may be located on either the tip side or the base end side of the closing engagement portion 81.

[0193] In this embodiment, the housing 8 includes an attachment portion 83 to which the filter 80 is attached, a main body portion 84 in which the closing engagement portion 81 is located, and an extension portion 85 extending from the main body portion 84. In this housing 8, the attachment portion 83, the main body portion 84, and the extension portion 85 are arranged in this order from the tip side to the base end side. In this housing 8, the attachment portion 83, the main body portion 84, and the extension portion 85 are all 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 perpendicular to the cylindrical axis direction) is non-uniform. Specifically, the thickness of the attachment portion 83 is thicker than the thickness of the extension portion 85.

[0194] The outer circumferential surface of the attachment portion 83 is slightly spaced from the inner circumferential surface of the barrel 6 (specifically, the inner circumferential surface of the tubular portion 62 of the barrel 6). Furthermore, the attachment portion 83 has a tapered shape with an outer diameter that decreases toward the tip. The inner circumferential surface of the attachment portion 83 has a tapered shape with an inner diameter that increases toward the tip.

[0195] The main body part 84 is a part that connects the attachment part 83 and the extension part 85. The outer peripheral surface of the main body part 84 is slightly spaced from the inner peripheral surface of the barrel 6 (specifically, the inner peripheral surface of the tubular part 62 of the barrel 6). Furthermore, the main body part 84 has a tapered shape with an outer diameter that decreases toward the tip side. The inner peripheral surface of the main body part 84 is formed by the protruding end surface of the closing engagement part 81. Furthermore, the inner peripheral surface of the main body part 84 is located at the radially innermost part of the inner peripheral surface of the housing 8.

[0196] The outer peripheral surface of extension portion 85 is in surface contact with the inner peripheral surface of barrel 6 (specifically, the inner peripheral surface of tubular portion 62 of barrel 6). In this way, the outer peripheral surface of extension portion 85 is in close contact with the inner peripheral surface of barrel 6, thereby preventing the drug from leaking out to the tip side through a gap between the outer peripheral surface of housing 8 and the inner peripheral surface of barrel 6. The inner peripheral surface of extension portion 85 is located radially outward of the inner peripheral surface of attachment portion 83. That is, the inner diameter of extension portion 85 is larger than the inner diameter of attachment portion 83.

[0197] In the above-described housing 8, a liquid flow path C8 that serves as a flow path for the medicinal liquid from the base end space S1 to the tip end space S2 is formed on the radially inner side of the closing engagement portion 81 (see FIG. 4). That is, the liquid flow path C8 is formed on the inner side of the inner circumferential surface of the main body part 84.

[0198] The inner plug portion 9 is a member disposed so as to be able to open and close relative to the inside of the housing 8 so that the base end side space S1 and the tip end side space S2 are in communication or not in communication with each other via the inside of the housing 8. In this embodiment, the inner plug portion 9 is a plug provided inside the housing 8, but it may be a lid that covers the housing 8 from the tip side.

[0199] Furthermore, the inner plug portion 9 has a closing-time engaged portion 90 that engages with the closing-time engaging portion 81 from the base end side when the inner plug portion 9 is in the closed state (see FIG. 3). The closing-time engaged portion 90 is disposed on the tip end side and the base end side with respect to the closing-time engaging portion 81. Specifically, the closing-time engaged portion 90 includes a base end-side closing-time engaged portion 901 located on the base end side, and a tip end-side closing-time engaged portion 902 located on the tip end side. That is, the inner plug portion 9 has a plurality of (for example, two) closing-time engaged portions 90.

[0200] The inner plug portion 9 has a restricting means 91 that restricts movement of the inner plug portion 9 toward the tip side when the engagement between the closing-time engaging portion 81 and the closing-time engaged portion 90 is released and the base end space S1 and the tip end space S2 are in communication. By having the restricting means 91, the inner plug portion 9 prevents the inner plug portion 9 from blocking flow paths such as the spout hole 64 when the base end space S1 and the tip end space S2 are in communication.

[0201] In this embodiment, the restricting means 91 restricts the movement of the inner plug portion 9 toward the distal end side at a position where the inner plug portion 9 is spaced away from the base end side relative to the filter 80. This makes it possible to prevent the inner plug portion 9 from blocking the holes of the filter 80.

[0202] The inner plug portion 9 also has a lid portion 92 having a closing-time engaged portion 90 on its outer circumferential surface and configured to be capable of opening and closing a liquid flow path C8 of the housing 8. The inner plug portion 9 also has a step engagement portion 93 disposed on the base end side of the lid portion 92 and protruding radially outward from the lid portion 92, and a plug flow path C9 disposed radially inside the step engagement portion 93 and formed between the lid portion 92 and the step engagement portion 93 in the axial direction of the cylinder (see FIG. 4). As a result, when the inner plug portion 9 is restricted in the open state, the medicinal liquid contained in the base end space S1 flows from the base end side to the tip end side (in the direction of the arrow in FIG. 4) through the plug flow path C9 radially inside the step engagement portion 93, and the liquid flow path C8 radially inside the closing time engagement portion 81, and then flows smoothly between the lid portion 92 and the closing time engagement portion 81 into the tip end space S2. Furthermore, since the outer periphery 920 of the lid part 92 and the tip inner periphery 822 of the housing 8 are configured so as not to come into contact over the entire circumference, the medicinal liquid can flow evenly over the entire circumference.

[0203] In this embodiment, the inside plug portion 9 has, as the regulating means 91, a stepped surface 810 and a step engaging portion 93 that protrudes radially outward and is engageable with the stepped surface 810 from the base end side. Since the regulating means 91 includes the stepped surface 810 and the step engaging portion 93, the step engaging portion 93 engages with the stepped surface 810 from the base end side, so that the movement of the inside plug portion 9 can be reliably regulated.

[0204] The stepped engagement portion 93 is provided, for example, continuously or intermittently around the entire circumference in the circumferential direction, and is provided continuously in this embodiment. In this configuration, when the closing-time engagement portion 81 and the closing-time engaged portion 90 are disengaged and the inner plug portion 9 moves toward the tip side, and the base-end side space S1 and the tip-end side space S2 are completely connected, the stepped engagement portion 93 provided continuously or intermittently around the entire circumference engages with the stepped surface 810 from the base end side, and the movement of the inner plug portion 9 toward the tip side is restricted. Since both the stepped engagement portion 93 and the stepped surface 810 are formed so as to extend around the entire circumference radially outside the lid portion 92, the movement of the inner plug portion 9 is restricted in a stable posture.

[0205] The inside plug part 9 includes, in addition to the lid part 92, a leg part 94 extending from the lid part 92. In this embodiment, the inside plug part 9 includes a plurality of leg parts 94 (specifically, four leg parts 94) as shown in Figs. 5 and 6. The inside plug part 9 also includes a plurality of protruding parts 95 (specifically, four protruding parts 95) that respectively protrude from each leg part 94 toward the housing 8 side (diametrically outward). Furthermore, the inside plug part 9 includes an annular part 96 that connects the plurality of protruding parts 95.

[0206] The inner plug portion 9 has a protruding portion 95 as the stepped engagement portion 93 , and more specifically, the inner plug portion 9 has an annular portion 96 in addition to the protruding portion 95 as the stepped engagement portion 93 . The lid portion 92 is a portion that fits into the inside of the housing 8 (see Figs. 3 and 4). The lid portion 92 has a closed-time engaged portion 90 on its outer circumferential surface and is a portion that can be opened and closed with respect to the inside of the housing 8. The lid portion 92 is a portion that separates the base end space S1 from the tip end space S2. For example, the lid portion 92 is substantially disk-shaped. The closed-time engaged portion 90 is provided on an outer circumferential portion 920 of the lid portion 92. An inner circumferential portion 921 of the lid portion 92 (a portion located radially inward from the outer circumferential portion 920 of the lid portion 92) has a lid leg portion 922 that extends from the disk-shaped portion to the base end side. In this embodiment, the base end side end face of the lid leg portion 922 is located on the tip side of the base end side end face of the leg portion 94. The base end side end face of the lid leg portion 922 is located on the tip side of the base end side end face of the protruding portion 95. Furthermore, the base end surface of the cover leg portion 922 is located closer to the tip side than the base end surface of the annular portion 96 .

[0207] The lid leg portion 922 protrudes from the radial center of the lid portion 92 toward the base end side. The outer diameter of the lid leg portion 922 is smaller than the outer diameter of the lid portion 92. The lid leg portion 922 is provided in the radial center of an area surrounded by a plurality of leg portions 94 (a plurality of protruding portions) arranged in the circumferential direction. The lid leg portion 922 is also disposed in the radial center of an area surrounded by the annular portion 96.

[0208] The closing-time engaged portion 90 is, for example, a convex portion protruding toward the housing 8. Specifically, the closing-time engaged portion 90 is a rib protruding toward the housing 8. In this embodiment, the closing-time engaged portion 90 is a rib provided continuously in the circumferential direction, but it may be a plurality of ribs provided at intervals around the entire circumferential direction.

[0209] The base end side engaged portion 901 when closed is provided at the end portion on the base end side of the lid part 92. The tip end side engaged portion 902 when closed is provided at the end portion on the tip end side of the lid part 92. The base end side closing engaged portion 901 and the tip end side closing engaged portion 902 are provided apart in the tubular axial direction. A lid recess 97 is formed between the base end side closing engaged portion 901 and the tip end side closing engaged portion 902. The closing engaging portion 81 of the housing 8 is fitted into this lid recess 97 from the radially outer direction. In this fitted state, the base end side closing engaged portion 901 engages with the closing engaging portion 81 from the base end side, and movement of the inner plug portion 9 toward the tip side relative to the housing 8 is restricted. Also, in the fitted state, the tip end side closing engaged portion 902 engages with the closing engaging portion 81 from the tip side, and movement of the inner plug portion 9 toward the base end side relative to the housing 8 is restricted.

[0210] The leg portion 94 is a portion that extends toward the base end from the end portion on the base end side of the outer circumferential portion 920 of the lid portion 92. The multiple leg portions 94 (specifically, four leg portions 94) are disposed at equal intervals in the circumferential direction.

[0211] A plug flow passage C9 is formed on the radially inner side of the leg portion 94. The plug flow passage C9 includes an axial flow passage C91 formed on the radially inner side of the leg portion 94 in the cylindrical axis direction, and a communication flow passage C92 that communicates the axial flow passage C91 with a space on the radially outer side of the leg portion 94 (see FIG. 4). The axial flow passage C91 is disposed on the radially inner side of the protruding portion 95, and is formed between the protruding portion 95 and the cover portion 92 along the cylindrical axis direction. The communication flow passage C92 is formed between the multiple leg portions 94, opens to the radially outer side, and communicates with the axial flow passage C91 on the radially outer side of the axial flow passage C91.

[0212] The protruding portion 95 is a portion that extends from the base end side end of the leg portion 94 toward the housing 8. The multiple protruding portions 95 (specifically, four protruding portions 95) are arranged at equal intervals in the circumferential direction.

[0213] The annular portion 96 is a portion that connects the ends (diametrically outer ends) of the protruding portions 95 on the housing 8 side. The annular portion 96 has, for example, a circular ring shape. The annular portion 96 may have an annular shape other than a circular ring shape, for example, a rectangular tube shape.

[0214] In the above-described inner plug portion 9, when the inner plug portion 9 is in an open state, the stepped engagement portion 93 of the inner plug portion 9 (specifically, the protruding portion 95, in this embodiment the protruding portion 95 and the annular portion 96) engages with the stepped surface 810 of the housing 8 (the base end face of the closing engagement portion 81), thereby restricting further movement of the inner plug portion 9 toward the tip side (falling off of the inner plug portion 9 from the closing engagement portion 81).

[0215] Furthermore, the piston 3 inserted into the barrel 6 from the base end side can abut against the inner plug portion 9. That is, the inner plug portion 9 has an abutment surface 98 against which the inserted piston 3 can abut. The abutment surface 98 is an end surface on the base end side of the inside plug portion 9. Specifically, the abutment surface 98 is constituted by the end surface on the base end side of the lid portion 92. More specifically, the abutment surface 98 is constituted by the base end side end surface of the lid leg portion 922 and the base end side end surface of the leg portion 94.

[0216] The inner plug portion 9 is formed of a flexible material. The inner plug portion 9 of this embodiment is more flexible than the barrel 6. Specifically, the material of the inner plug portion 9 is, for example, a resin, rubber, elastomer, or the like that is softer than the material of the barrel 6. The flexibility of the inner plug portion 9 can be confirmed, for example, by measuring the durometer hardness. The material of the inner plug portion 9 is, for example, the same as the material of the housing 8, but may be different.

[0217] The filter 80 is a filter for filtering the medicine. The filter 80 is disposed in the distal end portion of the housing 8 (in this embodiment, the distal end surface 830 of the mounting portion 83 of the housing 8), and is disposed inside the barrel 6 on the proximal side of the ejection hole 64.

[0218] In this embodiment, the filter 80 is attached to the tip side portion of the housing 8, specifically, adhered to the tip surface 830. This adhesion is ultrasonic welding, but an adhesion method including another welding method such as thermal welding may also be used. The filter 80 may be adhered to the tip surface 830.

[0219] In the above-described syringe 2, when a pressing force is applied from the base end side by the piston 3 inserted from the base end side into the barrel 6, one of the closing-time engaging portion 81 and the closing-time engaged portion 90 overcomes the other, and the engagement between the closing-time engaging portion 81 and the closing-time engaged portion 90 is released. This causes the inner plug portion 9 to be opened to the inside of the housing 8, and the base end space S1 and the tip end space S2 communicate with each other. That is, the partition means 7 is configured such that this pressing force causes the inner plug portion 9 to change state from a closed state (see FIG. 3) to an open state (see FIG. 4). Specifically, when a pressing force is applied from the base end by the piston 3, at least one of the closing engagement portion 81 and the closing engagement portion 90 elastically deforms, the closing engagement portion 90 overcomes the closing engagement portion 81, and the middle plug portion 9 moves toward the tip side, thereby releasing the engagement between the closing engagement portion 81 and the closing engagement portion 90, and opening the middle plug portion 9 to the inside of the housing 8, thereby connecting the base end space S1 and the tip end space S2.

[0220] Furthermore, in the syringe 2, the filter 80 is sandwiched between the barrel 6 and the attachment part 83 of the housing 8. Specifically, the filter 80 is sandwiched in the cylindrical axial direction between the base end surface 600 of the tip portion 60 of the barrel 6 and the tip surface 830 of the attachment part 83. This makes it difficult for the filter 80 to come off the attachment of the filter 80 to the attachment part 83 even if pressure is applied to the filter 80 when the medicinal liquid is administered.

[0221] Furthermore, in the syringe 2, the base end space S1, the tip end space S2, and the ejection hole 64 are arranged in this order from the base end side to the tip end side. In the syringe 2 of this embodiment, the central axis of the base end space S1 and the central axis of the tip end space S2 both coincide with the central axis of the ejection hole 64. This ensures a good flow of the drug from the base end space S1 to the ejection hole 64 when the drug is administered.

[0222] The syringe 2 of this embodiment may be sterilized by radiation such as gamma rays. This sterilization may be performed by a gas such as ethylene oxide gas, or may be performed in an autoclave.

[0223] The piston 3 is a member that is operated when dispensing the medicine in the barrel 6. The piston 3 in this embodiment has an axial rod portion 30, a gasket 31 that is attached to one end of the rod portion 30 in the longitudinal direction and that is in close contact with the entire inner circumferential surface of the cylindrical portion 62 of the barrel 6, and an operating portion 32 that is attached to the other end of the rod portion 30 in the longitudinal direction.

[0224] In the piston 3 of this embodiment, the tip surface 33 is formed by the tip surface of the gasket 31. Specifically, the tip surface 33 abuts against the end surface on the base end side of the inner plug portion 9 when administration of the medicine is completed. The piston 3 is operated by a doctor, a nurse, or the like, but may be operated by a patient. In this case, the prefilled syringe 1 may be attached to an autoinjector.

[0225] The injection needle 4 is a member for administering the medicine in the barrel 6 to a patient. The tip of the injection needle 4 is covered with a cap 5. According to the above-described syringe 2, from an engaged state between the closing engaging portion 81 and the closing engaged portion 90, one overcomes the other due to the pressing force of the piston 3 (in this embodiment, from an engaged state between the closing engaging portion 81 and the base end closing engaged portion 901, the base end closing engaged portion 901 overcomes the closing engaging portion 81 due to the pressing force), and this engagement is suddenly released. Therefore, the partitioning means 7 that separates the inside of the barrel 6 is reliably opened, and the base end space S1 and the tip end space S2 communicate with each other, allowing the medicinal liquid to be smoothly dispensed.

[0226] In the syringe 2 of this embodiment, one of the closing engagement portion 81 and the closing engaged portion 90, which are arranged at the tip and base ends, is located between the other (in this embodiment, the closing engagement portion 81 is located between the base end closing engaged portion 901 and the tip end closing engaged portion 902), so that movement of the inner plug portion 9 in the closed state toward the tip end and base end in the axial direction relative to the housing 8 can be restricted, and unintended movement during transportation, etc. can be restricted.

[0227] Furthermore, in the syringe 2 of this embodiment, a filter 80 is disposed at the tip portion of the housing 8, and the partition means 7 separates the interior of the barrel 6 until the drug is ejected. Therefore, if the drug is contained in the base end space S1, the filter 80 can be prevented from coming into contact with the drug until it is ejected.

[0228] Furthermore, in the syringe 2 of this embodiment, the partition means 7 is disposed at the tip of the barrel 6, thereby preventing the filter 80 from coming into contact with the drug contained in the base end space S1 until the drug is ejected, and enabling the filter 80 to filter the drug after the partition means 7 that divides the interior of the barrel 6 is opened.

[0229] The configuration of the partition means 7 may be different from that described above. For example, the inside plug portion 9 may have a different configuration from that described above as long as it includes the closed-time engaged portion 90. Specifically, as shown in Fig. 7 to Fig. 12, the inner plug portion 9 does not have to include the annular portion 96. That is, the inner plug portion 9 includes a closed state engaged portion 90, a lid portion 92 that covers the base end side space S1, and a Legs It is considered that the housing 8 includes a portion 94 (specifically, four leg portions 94) and a plurality of protruding portions 95 (specifically, four protruding portions 95) each protruding from each leg portion 94 toward the housing 8 (diametrically outward).

[0230] Furthermore, the inner plug portion 9 may include a connection portion that connects the lid portion 92 (specifically, the lid leg portion 922 of the lid portion 92) and the leg portion 94. In this case, the connection portion can regulate radial deflection of the leg portion 94 that occurs in a state in which the step engagement portion 93 (protruding portion 95) is engaged with the stepped surface 810 when the inner plug portion 9 is pressed against the piston 3.

[0231] Furthermore, the inner plug portion 9 may have a plug extension portion extending circumferentially from the end portion (diametrically outer end portion) of the protruding portion 95 on the housing 8 side, instead of the annular portion 96. For example, a plurality of plug extension portions may be provided, each extending from each protruding portion 95. The plurality of plug extension portions may be arranged with gaps between them in the circumferential direction.

[0232] Moreover, the inner plug portion 9 does not have to include the leg portion 94 or the protruding portion 95, and may be composed of the closed-time engaged portion 90 and the lid portion 92, for example. In the above embodiment, when a pressing force is applied from the base end by the piston 3, at least one of the closing engagement portion 81 and the closing engagement portion 90 elastically deforms, so that the closing engagement portion 90 overcomes the closing engagement portion 81, the inner plug portion 9 moves toward the tip side, and the engagement between the closing engagement portion 81 and the closing engagement portion 90 is released; however, when this pressing force is applied, at least one of the closing engagement portion 81 and the closing engagement portion 90 may elastically deform, so that the closing engagement portion 81 overcomes the closing engagement portion 90, and the housing 8 moves toward the tip side, and the engagement between the closing engagement portion 81 and the closing engagement portion 90 is released.

[0233] Even with this configuration, when the closing engaging portion 81 and the closing engaged portion 90 are in an engaged state, the engagement is suddenly released when one overcomes the other due to the pressing force of the piston 3. Therefore, the partitioning means 7 that separates the inside of the barrel 6 is reliably opened, and the base end space S1 and the tip end space S2 communicate with each other, allowing the medicinal liquid to be smoothly dispensed.

[0234] In the above embodiment, the partition means 7 has one closing engagement part 81 and a plurality (specifically, two) closing engaged parts 90, but may have a plurality of closing engagement parts 81 and one closing engaged part 90. Specifically, the closing engagement parts 81 may be arranged on the distal end side and the proximal end side with respect to the closing engaged part 90. In such a case, a recess may be formed between the closing engagement parts 81 arranged on the distal end side and the proximal end side in the housing 8. The closing engaged part 90 of the inner plug part 9 fits into this recess from the radially inward direction. In this fitted state, the closing engagement part 81 arranged on the proximal end side engages with the closing engaged part 90 from the proximal end side, and the movement of the inner plug part 9 toward the proximal end side relative to the housing 8 is restricted. Also, in the fitted state, the closing engagement part 81 arranged on the distal end side engages with the closing engaged part 90 from the distal end side, and the movement of the inner plug part 9 toward the distal end side relative to the housing 8 is restricted. The partition means 7 may have one closing engaging portion 81 and one closing engaged portion 90.

[0235] In the above embodiment, the partitioning means 7 is disposed at the tip 60 of the barrel 6, but may be disposed at a midway position in the axial direction of the barrel 6. For example, the partitioning means 7 may be disposed at a midway position in the axial direction of the barrel 6, and may partition the base end space S1 and the tip end space S2, with the liquid agent ML contained in the base end space S1 and the solid agent MS contained in the tip end space S2 (specifically, the first tip end space S21) (see FIG. 13(a)). From this state, a pressing force is applied from the base end side by the piston 3, and as shown in FIG. 13(b), the inside plug portion 9 is opened to the inside of the housing 8, and the base end space S1 and the tip end space S2 are communicated with each other. Then, the liquid agent ML flows from the base end space S1 into the tip end space S2, and as shown in FIG. 13(c), a mixed agent MM in which the solid agent MS and the liquid agent ML are mixed is obtained. Furthermore, as shown in FIG. 13(d), a mixed agent MM can be administered by applying a pressing force from the base end side by the piston 3.

[0236] Thus, in this embodiment, the partition means 7 is positioned midway in the axial direction of the barrel 6 and divides the space within the barrel 6 into a base end space S1 and a tip end space S2. When the pressure applied by the piston 3 from the base end space S1 side reaches a predetermined pressure, the partition means 7 is released and moves in the released state to the tip portion 60 of the barrel 6 as the piston 3 is pushed toward the tip side of the barrel 6.

[0237] In addition, since the partitioning means 7 separating the base end space S1 and the tip end space S2 is equipped with a filter 80, when the partitioning means 7 is opened and the liquid ML flows from the base end space S1 to the tip end space S2, unnecessary solid matter is captured by the filter 80.

[0238] Also, the partitioning means 7 may not include the filter 80. For example, as shown in Fig. 14(a), the partitioning means 7 may include only a housing 8 and an inner plug portion 9, and may be disposed midway through the barrel 6, and a filter member 86 including a filter 80 may be disposed closer to the tip side than the partitioning means 7, with a distance between them.

[0239] Even in this case, it is considered that the space S inside the barrel 6 is partitioned by the partitioning means 7 into a base end space S1, which is a space on the base end side of the housing 8 and the inner plug portion 9, and a tip end space S2, which is a space on the tip end side of the housing 8 and the inner plug portion 9. In this embodiment, the tip end space S2 includes a third tip end space S3, which is a space between the housing 8 and the inner plug portion 9 and the filter member 86, and a fourth tip end space S4, which is a space on the tip side of the filter member 86. In this configuration, it is considered that the liquid agent ML is contained in the base end space S1, the liquid agent ML or the solid agent MS is contained in the third tip end space S3, and the solid agent MS is contained in the fourth tip end space S4 or this space is empty. In this embodiment, the liquid agent ML is contained in the base end space S1, the solid agent MS is contained in the third tip end space S3, and the fourth tip end space S4 is empty.

[0240] In this partition means 7, the housing 8 does not include the filter 80, but the filter member includes the filter 80. The housing 8 and the filter member 86 are both substantially cylindrical. In this embodiment, the inner circumferential surface of the filter member 86 is formed to have a smaller diameter than the inner circumferential surface of the housing 8, but the inner circumferential surface of the filter member 86 may be formed to have substantially the same diameter as the inner circumferential surface of the housing 8.

[0241] In this configuration, when the partitioning means 7 separates the base end space S1 from the third tip end space S3, the liquid agent ML contained in the base end space S1 and the solid agent MS contained in the third tip end space S3 are separated. From this state, when a pushing force is applied from the base end side by the piston 3, the inside plug portion 9 is opened to the inside of the housing 8 as shown in Fig. 14(b) and the base end space S1 and the third tip end space S3 communicate with each other, the liquid agent ML flows from the base end space S1 into the third tip end space S3, and a mixed agent MM in which the solid agent MS and the liquid agent ML are mixed is obtained as shown in Fig. 14(c). Furthermore, by applying a pushing force from the base end side by the piston 3, the mixed agent MM can be administered as shown in Fig. 14(d).

[0242] In this manner, the partitioning means 7 is configured such that the housing 8 and the inside plug portion 9 disposed at a midway position in the axial direction of the barrel 6 divide the space S in the barrel 6 into the base end space S1 and the tip end space S2, and opens when the pressure from the base end space S1 by the piston 3 reaches a predetermined pressure, and moves in an open state to the tip portion 60 of the barrel 6 as the piston 3 is pushed toward the tip side of the barrel 6. In addition, this configuration includes a filter member 86 disposed on the tip side of the housing 8 and having a flow hole communicating from the base end side to the tip side, and a filter 80 attached to the filter member 86 for filtering the liquid flowing through the flow hole. Therefore, when the inside plug portion 9 is opened relative to the housing 8 and the liquid agent ML flows from the base end space S1 into the tip end space S2 and is mixed with the solid agent MS and poured out from the tip portion 60 of the barrel 6, unnecessary solid matter is captured by the filter 80. Furthermore, since the filter member 86 is disposed at the tip portion 60 of the barrel 6 so as not to move towards the tip side, the pressing resistance of the piston 3 when the housing 8 moves towards the tip side can be made uniform.

[0243] Furthermore, for example, it is conceivable that the partition means 7 has two sets of a housing 8 and an inner plug portion 9, one set being disposed on the base end side and the other set being disposed on the tip end side at a distance. In this case, a configuration is conceivable in which a liquid drug ML is contained in the space on the base end side of the housing 8 and inner plug portion 9 located on the base end side, a liquid drug ML or a solid drug MS is contained in the space between the housing 8 and inner plug portion 9 located on the base end side and the housing 8 and inner plug portion 9 located on the tip end side, and a solid drug MS is contained in the space on the tip end side of the housing 8 and inner plug portion 9 located on the tip end side or this space is empty.

[0244] In addition, when the closing engaging portions 81 are provided at intervals around the entire circumference, the closing engaging portions 81 may be arranged on opposite sides of the cylindrical axis. The closing engaging portions 81 may also be arranged at equal intervals around the circumference. Similarly, when the closing engaged portions 90 are provided at intervals around the entire circumference, the closing engaged portions 90 may be arranged on opposite sides of the cylindrical axis, or may be arranged at equal intervals around the circumference. In this configuration, the closing engaging portions 81 and the closing engaged portions 90 are stably engaged with each other, so that the inner plug portion 9 is less likely to come off the housing 8 during transportation of the syringe 2, etc.

[0245] In one aspect of the present invention, a retaining member 10 may be disposed in the barrel instead of the partition means. In this specification, the retaining member 10 is a partition means that does not have an inner plug and is composed only of a housing. The retaining member 10 is a member to which the filter 80 is attached. The retaining member 10 is housed in the barrel 6 in a state of being pressed against the barrel 6. Specifically, at least a portion of the outer circumferential surface of the retaining member 10 is in close contact with the inner circumferential surface of the barrel 6.

[0246] Moreover, the holding member 10 is formed of a flexible material. The holding member 10 of this embodiment is more flexible than the barrel 6. Specifically, the material of the holding member 10 is, for example, a resin, rubber, elastomer, or the like that is softer than the material of the barrel 6. The flexibility of the barrel 6 and the holding member 10 can be confirmed, for example, by measuring the durometer hardness. By forming the holding member 10 from such a material, the flexibility of the holding member 10 relative to the barrel 6 can be ensured, and cracks in the barrel 6 can be prevented.

[0247] The holding member 10 includes a base end portion 110 that is disposed on the base end side of the filter 80. The holding member 10 of this embodiment is composed only of the base end portion 110. The base end portion 110 of the holding member 10 is provided with a flow path 111 through which the drug flows from the base end side to the tip end side.

[0248] The base end portion 110 of the holding member 10 has a contact surface 200 as a base end face 200 against which the piston 3 inserted from the base end side into the barrel 6 can come into contact. The base end portion 110 has a cylindrical shape whose tip side is blocked by a disk having a through hole in the center.

[0249] The contact surface 200 of the base end portion 110 has a shape corresponding to the tip surface 33 of the piston 3. In addition, the contact surface 200 is configured so that the tip surface 33 of the piston 3 comes into surface contact with the barrel 6 over the entire circumferential direction.

[0250] The abutment surface 200 of this embodiment includes, for example, a base end abutment surface 201 located on the base end side, a tip end abutment surface 202 located on the tip end side, and a connecting abutment surface 203 connecting the base end abutment surface 201 and the tip end abutment surface 202, as shown in Figure 16.

[0251] The base end contact surface 201 is, for example, a surface that is substantially perpendicular to the axial direction. The tip end contact surface 202 is, for example, a surface that is substantially perpendicular to the axial direction. The connection abutment surface 203 is a surface extending along the axial direction. For example, the central portion of the connection abutment surface 203 in the axial direction is recessed radially outward.

[0252] The base end portion 110 of the present embodiment includes an attachment portion 112 to which the filter 80 is attached, and leg portions 113 extending from the attachment portion 112. In this base end portion 110, the attachment portion 112 is provided on the tip side, and the leg portions 113 are disposed on the base end side.

[0253] The flow passage 111 is provided in an attachment portion 112 of the base end portion 80. In this embodiment, the area of ​​the flow passage 111 when viewed from the axial direction (the cross-sectional area of ​​the flow passage 111 in a direction perpendicular to the axis) is constant. In addition, the area of ​​the flow passage 111 when viewed from the axial direction is 0.64 mm 2 More than 1.33mm 2The inner diameter of the flow path 111 in this embodiment is constant. 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, and specifically, is cylindrical, but may be a square tube.

[0254] The mounting part 112 has a shape in which the outer periphery protrudes toward the tip side. In this embodiment, the outer periphery surface of the mounting part 112 is slightly spaced from the inner periphery surface of the barrel 6 (specifically, the inner periphery surface of the tubular part 62 of the barrel 6). Furthermore, the mounting part 112 has a tapered shape in which the outer diameter becomes smaller toward the tip side. The mounting part 112 also has an outer periphery mounting part 220 that constitutes the outer periphery, and an inner periphery mounting part 221 that is located radially inward of the outer periphery mounting part 220 and defines the flow path 111.

[0255] Furthermore, in the mounting portion 112, an outer peripheral tip surface 222, which is the tip surface of the outer peripheral mounting portion 220, is located on the tip side of an inner peripheral tip surface 223, which is the tip surface of the inner peripheral mounting portion 221. In other words, the tip surface of the mounting portion 112 is recessed in the central portion in the circumferential direction. The outer peripheral mounting portion 220 has a shoulder portion 224 as the outer peripheral portion on the tip side.

[0256] The leg parts 113 have a shape in which the outer periphery protrudes toward the base end. A base end surface 230 of the leg parts 113 constitutes the abutment surface 200 of the base end portion 110. The outer periphery of the leg parts 113 is in surface contact with the inner periphery of the barrel 6 (specifically, the inner periphery of the tubular part 62 of the barrel 6). In this way, the outer periphery of the leg parts 113 is in close contact with the inner periphery of the barrel 6, so that the drug reliably passes through the flow path 111 of the holding member 10 and is filtered by the filter 80.

[0257] The filter 80 of this embodiment is attached to the distal end surface 804 of the base end portion 110 of the holding member 10. Specifically, the filter 80 is adhered to the distal end surface 204. More specifically, the filter 80 is adhered to the outer peripheral distal end surface 222 of the outer mounting portion 220. This adhesion is ultrasonic welding, but an adhesion method including another welding method such as heat welding may also be used. The filter 80 may also be adhered to the distal end surface 204.

[0258] 17, before the filter 80 is bonded, the base end portion 110 (e.g., the outer peripheral mounting portion 220) is provided with a protrusion 225 that protrudes toward the tip side. When the filter 80 is bonded, the protrusion 225 melts and spreads, so that after the filter 80 is bonded, the tip surface 204 of the base end portion 110 becomes a substantially flat surface.

[0259] The tip side subspace 71 is defined by the inner circumferential surface 65 of the barrel 6 (specifically, the base end surface 600 of the tip portion 60) and the filter 80 (specifically, the tip side surface of the filter 80). The tip side subspace 71 is continuous with the pouring hole 64. In this specification, the tip side subspace 71 corresponds to the first tip side space S21.

[0260] Furthermore, the distal side sub-space 71 has a shape in which the area (cross-sectional area in a direction perpendicular to the axis) when viewed from the cylindrical direction becomes smaller from the base end side toward the distal side, that is, the area (cross-sectional area in a direction perpendicular to the axis) when viewed from the cylindrical direction becomes smaller toward the distal side. ) The tip sub-space 71 of this embodiment is substantially cylindrical. The tip sub-space 71 has a shape in which the inner diameter becomes smaller from the base end side to the tip side, that is, a tapered shape in which the inner diameter becomes smaller toward the tip side. The tip sub-space 71 has a shape in which the distance between the filter 80 and the base end surface 600 of the tip portion 60 of the barrel 6 becomes smaller toward the outer periphery side. As a result, when administering a drug, the drug solution is pushed out into the tip sub-space 71 in a state in which it is easy to move from the outer periphery side to the cylinder axis side in the circumferential direction, so that the pouring resistance can be suppressed. The tip sub-space 71 may be a square tube.

[0261] The base end portion of the tip side secondary space 71, i.e., the portion of the tip side secondary space 71 with the largest area (e.g., inner diameter), is aligned with the shoulder portion 224 in the axial direction of the barrel 6, and the inner diameter thereof is approximately the same as the outer diameter of the shoulder portion of the retaining member 10.

[0262] The base-side subspace 72 is defined by the filter 80 (specifically, the base-side side surface of the filter 80) and a tip surface 204 of the base-side portion 110 (specifically, an inner peripheral tip surface 223 of the inner mounting portion 221 and an inner mounting surface 226 which is the inner peripheral surface of the outer mounting portion 220). The base-side subspace 72 is formed by the inner peripheral tip surface 223 of the inner mounting portion 221 being recessed toward the base end side relative to the outer peripheral tip surface 222 of the outer mounting portion 220, that is, the tip surface of the mounting portion 112 being recessed toward the base end side. In this specification, the base-side subspace 72 corresponds to the second tip-side space S22. The space formed by combining the tip-side subspace 71 and the base-side subspace 72 corresponds to the tip-side space S2.

[0263] The base-side subspace 72 is continuous with the flow path 111. The base-side subspace 72 has a shape in which the area increases from the base side to the tip side when viewed from the axial direction, that is, a tapered shape in which the area increases toward the tip side when viewed from the axial direction. The base-side subspace 72 in this embodiment is substantially cylindrical. The base-side subspace 72 has a shape in which the inner diameter increases from the base side to the tip side, that is, a tapered shape in which the inner diameter increases toward the tip side. The inclination angle of the mounting inner circumferential surface 226 of the mounting outer circumferential portion 220 that defines the base-side subspace 72 with respect to the axial direction is smaller than the inclination angle of the base-side end surface 600 of the tip portion 60 that defines the tip side subspace 71 with respect to the axial direction. The base-side subspace 72 may be a rectangular tube.

[0264] In the above-described syringe 2, the filter 80 is sandwiched between the barrel 6 and the base end portion 110 of the holding member 10. Specifically, the filter 80 is sandwiched in the axial direction between the base end surface 600 of the tip portion 60 of the barrel 6 (specifically, the base end edge 601 of the base end surface 600) and the shoulder portion 224 of the base end portion 110. This makes it difficult for the filter 80 to come off from the base end portion 110 even if pressure is applied to the filter 80 when the medicinal liquid is administered.

[0265] From the base end side to the tip end side, the flow path 111, the base end sub-space 72, the tip end sub-space 71, and the ejection hole 64 are arranged in this order.111 The central axis of the flow channel 111, the central axis of the proximal side sub-space 72, and the central axis of the distal side sub-space 71 all coincide with the central axis of the ejection hole 64. This ensures a good flow of the drug from the flow channel 111 to the ejection hole 64 when the drug is administered.

[0266] Dimension L in the axial direction of the flow path 111 111 is larger than the dimension L72 in the axial direction of the base-side sub-space 72. In addition, the dimension L71 in the axial direction of the distal sub-space 71 (specifically, the dimension at the central axis of the distal sub-space 71) is larger than the dimension L72 in the axial direction of the base-side sub-space 72.

[0267] When viewed from the axial direction, the area of ​​the outlet hole 64 is smaller than the area of ​​the base end ancillary space 72, smaller than the area of ​​the tip end ancillary space 71, and smaller than the area of ​​the flow path 111. This means that the area of ​​the outlet hole 64 is smaller than the area of ​​any portion in the axial direction of the base end ancillary space 72, smaller than the area of ​​any portion in the axial direction of the tip end ancillary space 71, and smaller than the area of ​​any portion in the axial direction of the flow path 111. Specifically, the area of ​​the outlet hole 64 is smaller than the area of ​​the base end ancillary space 72, smaller than the maximum area of ​​the tip end ancillary space 71 (the area at the base end edge of the tip end ancillary space 71), and smaller than the area of ​​the flow path 111.

[0268] Furthermore, when viewed in the axial direction, the area of ​​the flow path 111 is smaller than the area of ​​the proximal secluded space 72. This means that the area of ​​the flow path 111 is smaller than the area of ​​any portion of the proximal secluded space 72 in the axial direction.

[0269] Specifically, the inner diameter R64 of the outlet hole 64 is smaller than the inner diameter R72 of the base end sub-space 72 and is smaller than the maximum inner diameter R71 of the tip end sub-space 71 (the inner diameter at the base end edge of the tip end sub-space 71). 111 In addition, the inner diameter R 111 is smaller than the inner diameter R72 of the proximal secundum 72.

[0270] Regarding such a dimensional relationship, the barrel 6 in which the inner diameter R64 of the injection hole 64 is 0.27 mm and 0.21 mm and the inner diameter R 111 In the experiment, the holding member 10 having the inner diameter R72 of the base end secondary space 72 of 0.3 mm, 0.6 mm, and 0.9 mm and the inner diameter R72 of the base end secondary space 72 of 0.6 mm, 2.1 mm, and 3.6 mm was combined with the holding member 10 to examine the effect on the pouring resistance (specifically, the sliding load).

[0271] The results of this experiment are as follows. When the inner diameter R72 of the proximal secluded space 72 is 0.6 mm, an increase in the sliding load was confirmed. When the inner diameter R72 of the proximal secluded space 72 is 2.1 mm or 3.6 mm, no significant change in the sliding load was observed. 111 When the value was changed within the above range, no significant change was observed in the sliding load.

[0272] For example, the inner diameter R of the flow path 111 111 is preferably more than 1 and not more than 5 times the inner diameter R64 of the pouring hole 64, and is desirably 1.1 to 4.3 times the inner diameter R64 of the pouring hole 64. 111 The inner diameter R72 of the proximal secundary space 72 (the filtration area of ​​the filter 80) is preferably 5 to 20 times the inner diameter R64 of the outlet hole 64, and desirably 7 to 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 proximal secundary space 72 can be selected from 2.1 mm and 3.6 mm. When the inner diameters R72 and R71 of the proximal secundary space 72 and the distal secundary space 71 are within this range, the filtration area when administering a drug can be secured while suppressing the outlet resistance.

[0273] The syringe 2 of this embodiment is sterilized by radiation such as gamma rays. This sterilization may be performed by a gas such as ethylene oxide gas, or may be performed in an autoclave.

[0274] The piston 3 is a member that is operated when dispensing the medicine in the barrel 6. The piston 3 in this embodiment has an axial rod portion 30, a gasket 31 that is attached to one end of the rod portion 30 in the longitudinal direction and that is in close contact with the entire inner circumferential surface of the cylindrical portion 62 of the barrel 6, and an operating portion 32 that is attached to the other end of the rod portion 30 in the longitudinal direction.

[0275] In the piston 3 of this embodiment, the tip surface 33 is formed by the tip surface of the gasket 31. Specifically, when administering a drug, the tip surface 33 abuts at least against the base-end abutment surface 201 of the base-end portion 110 of the holding member 10, and more specifically, abuts against the connection abutment surface 203 in addition to the base-end abutment surface 201.

[0276] The piston 3 has a contact portion 34 that contacts the inner peripheral surface of the barrel 6, and a protruding portion 35 that protrudes from the tip surface of the contact portion 34. The tip surface of the contact portion 34 contacts the base end contact surface 201, and the tip surface of the protruding portion 35 contacts the tip end contact surface 802. The outer peripheral surface of the protruding portion 35 contacts the connection contact surface 203.

[0277] The injection needle 4 is a member for administering the medicine in the barrel 6 to a patient. The tip of the injection needle 4 is covered with a cap 5. According to the above-described syringe 2, even if particles are present in the drug contained in the barrel 6, the particles can be captured by the filter 80 when the drug is administered. Furthermore, the drug flows through the flow path 111, the base end ancillary space 72, and the distal end ancillary space 71, which have a larger area (e.g., inner diameter) than the ejection hole 64, and is ejected from the ejection hole 64. This makes it possible to suppress resistance when the drug flows through the flow path 111, the base end ancillary space 72, and the distal end ancillary space 71, and as a result, it is possible to suppress the ejection resistance of the drug.

[0278] In the syringe 2 of this embodiment, the area (e.g., inner diameter) of the flow path 111 is small and the area (e.g., inner diameter) of the base end secondary space 72 is large, so that the amount of drug remaining in the flow path 111 can be reduced while ensuring the area with which the drug comes into contact in the filter 80 (the filtration area by the filter 80), and the amount of residual liquid can be reduced while suppressing the discharge resistance.

[0279] Furthermore, in the syringe 2 of this embodiment, when administering a drug, the tip surface 33 of the piston 3 moves until it comes into surface contact with the abutment surface 200 of the holding member 10 around the entire circumference, thereby reducing residual liquid between the piston 3 and the holding member 10 and reducing the amount of residual drug in the barrel 6.

[0280] The syringe of the present invention is not limited to the above-described embodiment, and various modifications can be made without departing from the scope of the present invention. For example, the configuration of one embodiment can be added to the configuration of another embodiment, and part of the configuration of one embodiment can be replaced with the configuration of another embodiment. Furthermore, part of the configuration of one embodiment can be deleted.

[0281] The configuration of the retaining member 10 may be different from that described above. For example, the contact surface 200 of the base end portion 80 may have a different shape as long as it matches the contact surface 33 of the piston 3.

[0282] Specifically, the connection abutment surface 203 in the above embodiment extends along the axial direction, but may include a portion extending in a direction inclined relative to the axial direction. More specifically, as shown in Figures 18 and 19, the connection abutment surface 203 may include a first connection abutment surface 203a that is a surface approximately perpendicular to the axial direction, and second connection abutment surfaces 203b, 203c that are a pair of surfaces extending along the axial direction from both end edges of the first connection abutment surface 203a.

[0283] Specifically, the base-end contact surface 201 in the above embodiment is a surface that is substantially perpendicular to the axial direction, but may include a portion that is inclined at an angle other than perpendicular to the axial direction. More specifically, as shown in Fig. 20 and Fig. 21, the base-end contact surface 201 may include a first base-end contact surface 201a that is a surface that is substantially perpendicular to the axial direction, and a second base-end contact surface 201b that is a surface that extends further inward in the radial direction from an edge in the radial direction of the first base-end contact surface 201a and is inclined so that the portion on the radially inner side is located closer to the tip side.

[0284] Even with this configuration, the tip surface 33 of the piston 3 moves until it makes surface contact with the abutment surface 200 of the retaining member 10 around the entire circumference, thereby reducing residual liquid between the piston 3 and the retaining member 10 and reducing the amount of residual drug in the barrel 6.

[0285] The retaining member 10 in the above embodiment was composed of a base end portion 110, but it may also be composed to include a tip end portion that is positioned distal to the filter 80, either integral with the base end portion 110 or separately.

[0286] In addition, in the holding member 10 of the above embodiment, the inner diameter of the flow passage 111 is smaller than the inner diameter of the proximal side secluded space 72, but it may be approximately the same as the inner diameter of the proximal side secluded space 72. In the holding member 10 of the above embodiment, the abutment surface 200 of the base end portion 110 is configured so that the tip surface 33 of the piston 3 comes into surface contact with the barrel 6 over the entire circumferential direction, but the abutment surface 200 may be configured so that the tip surface 33 of the piston 3 comes into surface contact with a portion of the tip surface 33 in the circumferential direction. For example, it is conceivable to provide the base end abutment surface 201 of the abutment surface 200 of the base end portion 110 with recesses or protrusions intermittently in the circumferential direction.

[0287] In the syringe 2 of the above embodiment, the tip side sub-space 71 has a tapered shape in which the inner diameter becomes smaller toward the tip side, but may have another shape such as a shape in which the inner diameter is uniform. In this case, the base side end surface 600 may extend in a direction perpendicular to the axial direction, for example.

[0288] Although the proximal side secondary space 72 has a tapered shape with the inside diameter decreasing toward the tip side, it may have another shape, such as a shape with a uniform inside diameter. In addition, the dimension of the flow path 111 in the axial direction may be equal to or smaller than the dimension of the base end secondary space 72 in the axial direction.

[0289] Furthermore, the dimension in the axial direction of the tip side sub-space 71 may be equal to or smaller than the dimension in the axial direction of the base side sub-space 72. In this case, for example, it is possible to reduce the inclination angle of the base side end face 600 of the tip portion 60 of the barrel 6 with respect to the cylinder axis, and then dispose the base side portion 110 of the holding member 10 at a position where it abuts against the base side end face 600, or to increase the dimension in the axial direction of the base side portion 110 of the holding member 10.

[0290] The partitioning means 7 or the holding member 10 is configured so that the volume of the space at the tip end of the barrel 6 is 150 mm 3 Below, 110mm 3 Below, 40mm 3 Below 20mm depending on the case 3 Less than or equal to 18 mm, preferably 3 The volume of the tip side space (S2) of the barrel 6 is 15 vol % or less, 7 vol % or less, 5 vol % or less, 2 vol % or less, and preferably 1.8 vol % or less of the entire volume of the barrel 6.

[0291] In this specification, the sliding resistance of a syringe is the resistance when a piston slides in a barrel, and is expressed as a sliding load. In this specification, the term "pouring resistance" is also used in the same sense as "sliding resistance." (2) Filter The filter 80 may be, for example, a membrane, a mesh, a sintered body, or a foam. The material of the filter 80 is resin, ceramic, metal, paper, or the like. In this embodiment, the filter 80 is, for example, a membrane filter. The filter 80 may be a pre-filter.

[0292] In one aspect, the filtration area of ​​the filter 80 is the area of ​​the distal edge of the proximal collateral space (72, S22) and the area of ​​the proximal edge of the distal collateral space (71, S21). The area of ​​the distal edge of the proximal collateral space (72, S22) is, for example, equal to the area of ​​the proximal edge of the distal collateral space (71, S21).

[0293] In one aspect, the filter has a membrane thickness of 100 μm to 400 μm, 125 μm to 350 μm, or 150 μm to 310 μm. 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.

[0294] In one aspect, the filter has a breaking elongation of 10% or more, 20% or more, 30% or more, 40% or more when dry or wet, and preferably 45% or more. Breaking Elongation More preferably, the filter has a moisture content of 50% or more when dry and 60% or more when wet. Breaking Elongation has.

[0295] In one aspect, the material of the filter includes one or more selected from polyethersulfone (PES), polyvinylidene fluoride (PVDF), polysulfone (PS) and acrylic copolymer.

[0296] Polyethersulfone (PES) has the following formula:

[0297] [ka]

[0298] In one aspect, preferred polyethersulfones are Supor (registered trademark) (Nihon Pall Corporation), Millipore Express (Merck Ltd.), and Sartopore (registered trademark) (Sartorius), with Supor being particularly preferred.

[0299] Polyvinylidene fluoride (PVDF) has the following formula:

[0300] [ka]

[0301] In one aspect, the repeat unit Polyvinylidene Fluoride As the polymerizable polymer, Durapore® (Merck Co., Ltd.) and Fluorodyne® II (Nihon Pall Corporation) are preferred, and Durapore is particularly preferred.

[0302] Polysulfone (PS) has the following formula:

[0303] [ka]

[0304] In one aspect, the polysulfone is preferably Asymmetric Super Micron Polysulfone (Nihon Pall Corporation).

[0305] In one aspect, the acrylic copolymer may be formed on a non-woven nylon support. The acrylic copolymer may also be coated with a hydrophilic or hydrophobic coating. In one aspect, the acrylic copolymer filter is preferably a hydrophobic acrylic copolymer filter, particularly VERSAPOR® (Nihon Pall Corporation). Hydrophilic filters can experience a phenomenon called airlock, where air gets trapped inside the membrane after being wetted with a solution. Prefilled syringes have a certain amount of voids inside, and depending on the orientation of use, the air contained in the voids can pass through after the solution has passed, causing an airlock. If an airlock occurs, the filtration performance will be significantly reduced, but it is known that such an event does not generally occur with hydrophobic filters. Therefore, the above risk can be avoided by using a hydrophobic filter.

[0306] In one aspect, the filter has a pore size of 5 μm or less, preferably 5 μm. In this specification, the pore size of a filter is a property of a filter that is rated according to the diameter of particles that can be clearly expected to be captured with high efficiency. As the rated filtration accuracy, "nominal filtration accuracy" and "absolute filtration accuracy" are used. The nominal filtration accuracy is a range of particle sizes that a filter manufacturer can guarantee a certain rate of impurity removal. The absolute filtration accuracy is a value that represents the size of the smallest particle that the filter can completely remove. An example of a method for measuring the nominal filtration accuracy is ACFTD (AC Fine Test Dust), and in this method, the particle size that satisfies the set particle removal rate is defined as the filtration accuracy. An example of a method for measuring the absolute filtration accuracy is a method in which ACFTD or glass beads are passed through a filter once and the maximum diameter of the ACFTD or beads that flow out to the downstream side is measured. In this specification, the pore size is expressed as absolute filtration accuracy.

[0307] In this specification, the integrity of a filter is a standard for the quality of a filter, and indicates whether the filter has the expected filtration performance in a critical process that requires sterility assurance. Examples of filter integrity tests include forward flow test and bubble point test. The forward flow test is a quantitative test in which a constant test pressure is applied to the primary side of a filter when the secondary side of the membrane is at atmospheric pressure for a completely wetted membrane, and the diffusion flow rate through the liquid membrane is measured due to the pressure difference between the primary side and the secondary side of the filter. The bubble point test is a quantitative test in which a constant test pressure is applied to the primary side of a filter when the secondary side of the membrane is at atmospheric pressure for a completely wetted membrane, and the diffusion flow rate through the liquid membrane is measured due to the pressure difference between the primary side and the secondary side of the filter.

[0308] In the present specification, "the solution is kept in a state of not contacting the filter before use" refers to the solution being filled into the barrel so as not to come into contact with the filter in the barrel, and being maintained in a state of not contacting the filter even when a normally expected level of stress is applied until use. In this case, "before use of the injectable formulation" includes during and after the manufacture of the injectable formulation. The normally expected level of stress refers to mechanical stress including, but not limited to, drop stress, vibration stress, and rotational stress applied during or after the manufacture of the formulation, such as transportation. In one aspect, the injectable formulation is subjected to drop stress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 25 or more times, 30 or more times, or 40 or more times as the normally expected level of stress. The stress applied to the prefilled syringe when dropped varies depending on 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 dividing the inside of the barrel with a partitioning means, containing the pharmaceutical preparation in the base end space, and disposing the filter on the tip side of the partitioning means. "The solution is placed in contact with the filter before use" refers to the solution being placed in contact with the filter for a certain period or the entire period during the production of the injectable preparation or during storage, transportation, etc. after production.

[0309] In this specification, "the solution flows from the base end side to the tip end side of the filter through the filter" means that the solution filled in the barrel of the syringe on the base end side of the filter moves from the filter to the tip end side in the barrel by pressure including a piston or weight. The solution that moves from the filter to the tip end side in the barrel is poured out through the pouring hole.

[0310] (3) Pharmaceutical preparations In one aspect of the present invention, the pharmaceutical preparation is a solution containing a low molecular weight compound, a natural product, a polynucleotide, a medium molecular weight compound including a peptide, or a protein as an active ingredient. In this specification, a low molecular weight compound refers to a compound having a molecular weight of less than 500, and a medium molecular weight compound refers to a compound having a molecular weight of 500 to 1500. In one aspect of the present invention, the medium molecular weight compound includes a natural product having a molecular weight of 500 to 2000, a polynucleotide having a molecular weight of 3000 to 15000, and a peptide having a molecular weight of 600 to 6000. The peptide includes a cyclic peptide. In addition, the polynucleotide includes a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA). The pharmaceutical preparation may be an injectable preparation.

[0311] In one aspect of the present invention, the injectable formulation is a pharmaceutical formulation that contains a protein as an active ingredient in a solution and is filled in an injection container for administration by injection. In one aspect of the present invention, the injectable formulation includes an injection container such as a syringe as a component.

[0312] In one aspect of the present invention, the solution of the pharmaceutical formulation has a viscosity of 95 cP or less, 90 cP or less, 85 cP or less, 80 cP or less, 75 cP or less, 70 cP or less, 65 cP or less, 60 cP or less, 55 cP or less, 50 cP or less, 45 cP or less, 40 cP or less, 35 cP or less, 30 cP or less, 25 cP or less, 20 cP or less, 15 cP or less, 10 cP or less, or 1 cP to 95 cP. The viscosity can be measured, for example, using the Electro-Magnetically Spinning (EMS) method. In this measurement method, a torque is applied to a conductive probe by remote control, and the rotation is optically read to measure the viscosity.

[0313] In one aspect of the present invention, the pharmaceutical preparation is stored without freezing the solution in the container at -30°C to 40°C, -30°C to 25°C, preferably the freezing point of the solution to 25°C, more preferably 1°C to 10°C, more preferably 2°C to 8°C, and even more preferably 5°C. The storage is carried out 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, or 96 hours. The storage may be 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, or at least 12 months.

[0314] In one aspect of the present invention, the protein used in the solution formulation includes, but is not limited to, an antibody, a fusion protein, an enzyme, a hormone, a cytokine, and a vaccine. More specifically, the protein includes a monoclonal antibody, a granulocyte colony-stimulating factor (G-CSF), a granulocyte macrophage colony-stimulating factor (GM-CSF), an erythropoietin (EPO), an interferon, an interleukin such as IL-1 or IL-6, a tissue plasminogen activator (TPA), a thrombopoietin, an urokinase, a serum albumin, a blood coagulation factor VIII, a leptin, a stem cell factor (SCF), and the like.

[0315] In one aspect of the present invention, the protein used in the pharmaceutical preparation has substantially the same biological activity as a physiologically active protein of a mammal, particularly a human, and includes naturally occurring proteins and those obtained by recombinant gene techniques. Proteins obtained by recombinant gene techniques include those having the same amino acid sequence as a naturally occurring protein, or those having one or more amino acid sequences deleted, substituted or added and having the biological activity.

[0316] In one aspect of the present invention, the concentration of the protein in the solution may be 0.1 mg / mL or more, 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.

[0317] In one aspect of the present invention, the antibody used is not particularly limited as long as it binds to the desired antigen, and may be a polyclonal or monoclonal antibody, with monoclonal antibodies being preferred in terms of the ability to stably produce homogeneous antibodies. In addition, in one aspect of the present invention, the antibody used may be a monospecific or bispecific antibody, or an antibody having multiple specificities having three or more antigen recognition sites in the molecule.

[0318] In one aspect of the present invention, the monoclonal antibody used includes not only monoclonal antibodies derived from animals such as humans, mice, rats, hamsters, rabbits, sheep, camels, and monkeys, but also artificially modified recombinant antibodies such as chimeric antibodies, humanized antibodies, and bispecific antibodies.Furthermore, recombinant antibodies in which the constant region of an antibody has been artificially modified to modify the physical properties of the antibody molecule for the purpose of improving blood retention or pharmacokinetics (specifically, modification of the isoelectric point (p1), modification of the affinity of Fc receptors, etc.) are also included.

[0319] In addition, 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 IgG, such as IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, etc., although IgG is preferred, and IgG1, IgG2, and IgG4 are particularly preferred.

[0320] Furthermore, in one aspect of the present invention, the antibodies used include not only antibodies having a constant region and a variable region (full-length antibodies), but also binding fragments of antibodies such as Fv, Fab, and F(ab)2, and minibodies such as bispecific antibodies such as single-chain Fv (scFv, sc(Fv)2) and scFv dimers having one or two sites in which the variable regions of antibodies are linked via a linker such as a peptide linker, although full-length antibodies are preferred.

[0321] In one aspect of the present invention, the antibody used can be prepared by a known method. Hybridomas producing monoclonal antibodies can be prepared basically using known techniques as follows. That is, a desired antigen or cells expressing the desired antigen are used as a sensitizing antigen, which is immunized according to a conventional immunization method, the resulting immune cells are fused with a known parent cell by a conventional cell fusion method, and monoclonal antibody-producing cells (hybridomas) are screened by a conventional screening method. Hybridomas can be prepared, for example, according to the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46) or the like. When the antigen has low immunogenicity, it may be bound to a macromolecule having immunogenicity such as albumin and then immunized.

[0322] Alternatively, a recombinant antibody can be produced by cloning an antibody gene from a hybridoma, incorporating it into a suitable vector, and introducing it into a host using recombinant gene technology (see, for example, Carl, AK Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990). Specifically, cDNA of the variable region (V region) of an antibody is synthesized from the mRNA of a hybridoma using reverse transcriptase. Once DNA encoding the V region of the desired antibody is obtained, it is linked to DNA encoding the desired antibody constant region (C region), and this is incorporated into an expression vector. Alternatively, DNA encoding the V region of an antibody may be incorporated into an expression vector containing DNA of the antibody C region. It is incorporated into the expression vector so that it is expressed under the control of an expression control region, such as an enhancer or promoter. Next, the host cell is transformed with this expression vector to express the antibody.

[0323] In one aspect of the present invention, a genetically engineered antibody that has been artificially modified for the purpose of reducing heterologous antigenicity against humans, for example, a chimeric antibody or a humanized antibody, can be used. These modified antibodies can be produced using known methods. A chimeric antibody is an antibody that consists of the variable regions of the heavy and light chains of an antibody from a mammal other than human, for example, a mouse, and the constant regions of the heavy and light chains of a human antibody, and can be obtained by linking DNA encoding the variable region of a mouse antibody to DNA encoding the constant region of a human antibody, incorporating this into an expression vector, and introducing the vector into a host for production.

[0324] A humanized antibody is also called a reshaped human antibody, and is a human antibody that is produced by converting the complementarity determining region (CDR) of an antibody from a non-human mammal, such as a mouse, into a corresponding CDR of a human antibody. Complementary sex determination regionThe human antibody is a mouse antibody that has been transplanted into a human antibody, and the general gene recombination techniques are also known. Specifically, a DNA sequence designed to link the CDR of a mouse antibody with the framework region (FR) of a human antibody is synthesized by PCR from several oligonucleotides that have been prepared so as to have overlapping portions at the ends. The resulting DNA is linked to DNA encoding the human antibody constant region, which is then incorporated into an expression vector, which is then introduced into a host for production (European Patent Application Publication No. 239400, WO 96 / 02576). The FRs of the human antibody linked via the CDRs are selected such that the complementarity determining regions form a good antigen-binding site. If necessary, amino acids in the framework regions of the antibody variable region may be substituted so that the complementarity determining regions of the reshaped human antibody form a suitable antigen-binding site (Sato, K. et al., Cancer Res. (1993) 53, 851-856).

[0325] Techniques for substituting amino acids in an antibody to improve the activity, physical properties, pharmacokinetics, safety, etc. of the antibody are known, for example, the techniques described below. In one aspect of the present invention, the antibodies used also include antibodies with such amino acid substitutions (including deletions and additions).

[0326] Technologies for making amino acid substitutions in the variable regions of IgG antibodies include humanization (Tsurushita N, Hinton PR, Kumar S. , Design of humanized antibodies: from anti-Tac to Zenapax., Methods. 2005 May;36(1):69-83.), affinity maturation by amino acid substitution in the complementarity determining region (CDR) to enhance 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 US A. 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 (Kim SJ, Park Y, Hong HJ., Antibody engineering for the development of therapeutic antibodies., Mol Cells. 2005 Aug 31;20(1):17-29. Review.) In addition, a technique for enhancing antibody-dependent cellular cytotoxicity (ADCC) activity and complement-dependent cytotoxicity (CDC) activity by performing amino acid substitution in the Fc region of an IgG antibody 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, a technique for amino acid substitution in Fc that not only enhances such effector functions but also improves the half-life of an antibody in blood has been reported (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 in the constant region for the purpose of improving the physical properties of antibodies are also known (WO 09 / 41613).

[0327] Methods for obtaining human antibodies are also known. For example, human lymphocytes can be sensitized in vitro with a desired antigen or cells expressing the desired antigen, and the sensitized lymphocytes can be fused with human myeloma cells, such as U266, to obtain a desired human antibody having binding activity to the antigen (see Japanese Patent Publication No. 1-59878). Also, a desired human antibody can be obtained by immunizing a transgenic animal having a full repertoire of human antibody genes with an antigen (see WO 93 / 12227, WO 92 / 03918, WO 94 / 02602, WO 94 / 25585, WO 96 / 34096, and WO 96 / 33735). Furthermore, a technique for obtaining a human antibody by panning using a human antibody library is also known. For example, the variable region of a human antibody can be expressed on the surface of a phage as a single chain antibody (scFv) by phage display, and a phage that binds to the antigen can be selected. By analyzing the genes of the selected phage, the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined. Once the DNA sequence of the scFv that binds to the antigen is known, an appropriate expression vector containing the sequence can be constructed to obtain a human antibody. These methods are already well known, and reference can be made to WO 92 / 01047, WO 92 / 20791, WO 93 / 06213, WO 93 / 11236, WO 93 / 19172, WO 95 / 01438, and WO 95 / 15388. In one aspect of the present invention, the antibody used also includes such a human antibody.

[0328] When the antibody gene is isolated and then introduced into a suitable host to produce the antibody, a suitable combination of host and expression vector can be used. When eukaryotic cells are used as hosts, animal cells, plant cells, and fungal cells can be used. Known animal cells include (1) mammalian cells, such as CHO, COS, myeloma, BHK (baby hamster kidney), HeLa, and Vero, (2) amphibian cells, such as Xenopus oocytes, and (3) insect cells, such as sf9, sf21, and Tn5. Known plant cells include cells derived from the genus Nicotiana, such as Nicotiana tabacum, which can be cultured as callus. Known fungal cells include yeasts such as Saccharomyces, e.g., Saccharomyces cerevisiae, and filamentous fungi such as Aspergillus, e.g., Aspergillus niger. When using prokaryotic cells, there are production systems using bacterial cells. Known examples of bacterial cells include E. coli and Bacillus subtilis. Antibodies can be obtained by introducing the desired antibody gene into these cells by transformation and culturing the transformed cells in vitro.

[0329] Furthermore, the antibodies used in pharmaceutical preparations include modified antibodies. For example, antibodies conjugated with various molecules such as polyethylene glycol (PEG) or cytotoxic drugs 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 the antibodies. These methods have already been established in this field.

[0330] In one aspect of the present invention, the antibody of the present disclosure may be a chimeric antibody. Chimeric antibodies are described, for example, in US Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). Chimeric antibodies may contain non-human variable regions (e.g., variable regions derived from a non-human primate such as a monkey, or a mouse, rat, hamster, or rabbit, etc.) and human constant regions.

[0331] In one aspect of the present invention, the antibody of the present disclosure may be a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity in humans while maintaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody comprises one or more variable regions, in which there are HVRs, e.g., CDRs (or portions thereof) derived from a non-human antibody, and FRs (or portions thereof) derived from a human antibody sequence. The humanized antibody may optionally comprise at least a portion of a human constant region. In one embodiment, amino acid residues of FRs in a humanized antibody may be substituted with corresponding amino acid residues of a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to maintain or improve the specificity or affinity of the antibody.

[0332] Humanized antibodies and methods for making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US 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" approach to FR shuffling).

[0333] In one aspect of the invention, the human frameworks to be used for humanization may include, for example, frameworks selected using the "best-fit" method (Sims et al. J. Immunol. 151:2296 (1993)), frameworks derived from consensus sequences 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)), and framework regions derived from screening of FR libraries (Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0334] In one aspect of the invention, the antibody of the present disclosure may be a human antibody. Human antibodies can be produced by a variety of techniques. Human antibodies are reviewed, for example, in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-374 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008). Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been engineered to produce fully human antibodies or complete antibodies with human variable regions in response to an antigen. Such animals typically contain all or a portion of a human immunoglobulin locus, which either replaces an endogenous immunoglobulin locus or is present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are usually inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., US Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; US Patent No. 5,770,429, which describes HUMAB® technology; US Patent No. 7,041,870, which describes KM MOUSE® technology; and US 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies produced by such animals may be further modified, e.g., by combining with different human constant regions.

[0335] In another aspect of the invention, human antibodies can also be produced by hybridoma-based methods. Human myeloma cells and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies are described below (e.g., Kozbor J. Immunol., 133: 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 via human B-cell hybridoma technology are described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Other methods may include, for example, US Patent No. 7,189,826 (describing the production 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).

[0336] In another aspect of the invention, human antibodies can be generated by isolating Fv clone variable domain sequences selected from a human-derived phage display library. Such variable region sequences can then be combined with the desired human constant regions. See below for techniques for selecting human antibodies from antibody libraries.

[0337] In one aspect of the invention, antibodies of this disclosure may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. Methods for generating phage display libraries and screening such libraries for antibodies with the desired binding characteristics are known in the art. Such methods are reviewed by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described in, e.g., 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).

[0338] In a particular phage display method in one aspect of the invention, VH and VL repertoires 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 display binding fragments of antibodies, e.g., scFv or Fab. Libraries from immunized sources can provide high affinity antibodies to immunogens without the need to construct hybridomas. In another embodiment, naive repertoires can be cloned (e.g., from humans) without immunization to provide single-origin antibodies to a broad range of non-self or self antigens, as described in Griffiths et al., EMBO J, 12: 725-734 (1993). In yet another embodiment, the naive library can be synthetically generated by cloning unrearranged V-gene segments from stem cells and using PCR primers that encode the hypervariable region CDR3 and contain random sequences to achieve rearrangement in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent documents describing human antibody phage libraries include, for example, US Patent Nos. 5,750,373, US2005 / 0079574, US2005 / 0119455, US2005 / 0266000, US2007 / 0117126, US2007 / 0160598, US2007 / 0237764, US2007 / 0292936, and US2009 / 0002360.

[0339] Antibodies or binding fragments thereof isolated from a human antibody library are considered herein to be human antibodies or binding fragments of human antibodies. In one aspect of the present invention, the antibody of this disclosure is a multispecific antibody (e.g., a bispecific antibody). A multispecific antibody is an antibody (e.g., a monoclonal antibody) that has binding specificities at at least two different sites. In one embodiment, one of the binding specificities is for an antigen and the other is for another antigen. In another embodiment, a bispecific antibody may bind to two different epitopes of an antigen. Bispecific antibodies may be used to localize cytotoxic agents to cells expressing the antigen. Bispecific antibodies may be prepared as full length antibodies or as binding fragments of antibodies.

[0340] Techniques for producing multispecific antibodies include, but are not limited to, recombinant coexpression 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. Patent No. 5,731,168). Multispecific antibodies can be made by manipulating electrostatic steering effects to create Fc heterodimeric molecules (e.g., WO2009 / 089004A1); cross-linking two or more antibodies or binding fragments thereof (e.g., US Patent No. 4,676,980 and Brennan et al., Science, 229: 81(1985)); using leucine zippers to generate antibodies with two specificities (e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "diabody" technology to create 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 (1993)); (1994)); by preparing trispecific antibodies (e.g., Tutt et al. J. Immunol. 147: 60 (1991)). Additionally, antibodies may be engineered to have three or more functional antigen binding sites, including "octopus antibodies" (e.g., US2006 / 0025576).

[0341] In one aspect of the invention, an antibody or binding fragment thereof in this disclosure may be a "dual-acting Fab" or "DAF" that contains one antigen-binding site that binds to an antigen and another distinct antigen (e.g., US2008 / 0069820).

[0342] In one aspect of the present invention, modified (variant) amino acid sequences of antibodies of the present disclosure may be prepared by introducing appropriate modifications into a nucleic acid encoding the antibody molecule or by synthesizing a peptide. Such modifications may be made by any one or more appropriate combinations of deletion, insertion, and substitution of any amino acid (residue) into the amino acid sequence. Any combination of deletion, insertion, and substitution may be used as long as the final construct has the desired characteristics (e.g., antigen binding).

[0343] In one aspect of the present invention, when an antibody variant (mutant) with one or more amino acid substitutions is provided, target sites for substitutional mutagenesis may include HVRs and FRs. Examples of antibodies used in pharmaceutical preparations include, but are not limited to, 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 surrogate antibodies, anti-IL31 receptor antibodies, anti-HLA antibodies, anti-AXL antibodies, anti-CXCR4 antibodies, anti-NR10 antibodies, and bispecific antibodies of Factor IX and Factor X.

[0344] Preferred reshaped humanized antibodies for use in pharmaceutical preparations include humanized anti-interleukin 6 (IL-6) receptor antibody (tocilizumab, hPM-1 or MRA, see WO92 / 19759), humanized anti-HM1.24 antigen monoclonal antibody (see WO98 / 14580), humanized anti-parathyroid hormone-related peptide antibody (anti-PTHrP antibody) (see WO98 / 13388), humanized anti-tissue factor antibody (see WO99 / 51743), anti-glypican-3 humanized IgG1κ antibody (codrituzumab, GC33, see WO2006 / 006693), anti-NR10 humanized antibody (see WO2009 / 072604), and bispecific humanized antibody of Factor IX and Factor X (ACE910, see WO2012 / 067176). In one aspect of the present invention, the active ingredient contained in the solution filled in the syringe is an antibody selected from emicizumab, tocilizumab, and satralizumab. Emicizumab, tocilizumab, and satralizumab are antibodies contained as active ingredients in, for example, Hemlibra (registered trademark), Actemra (registered trademark), and Enspryng (registered trademark), respectively, and their respective amino acid sequences are publicly known. In this specification, antibodies specified by the terms emicizumab, tocilizumab, and satralizumab include antibodies that have substantially the same amino acid sequence as these antibodies and have the same pharmaceutical effect.

[0345] In one aspect of the present invention, the pharmaceutical preparation can be prepared as a solution preparation by mixing with an appropriate pharma- ceutically acceptable carrier, vehicle, etc., as necessary. The solvent of the solution preparation is water or a pharma- ceutically acceptable organic solvent. Examples of such organic solvents include propylene glycol (1,2-propanediol), polyethylene glycol 300, polyethylene glycol 400, ethanol, glycerol, and acetic acid. Examples of suitable pharma- ceutically acceptable carriers and vehicles include sterilized water, physiological saline, stabilizers, antioxidants (ascorbic acid, etc.), buffers (phosphate, citric acid, histidine, other organic acids, etc.), preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.), and binders. It may also contain other low molecular weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulin, amino acids such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, sugars and carbohydrates such as polysaccharides and monosaccharides, and sugar alcohols such as mannitol and sorbitol. When used as a solution for injection, examples include physiological saline, isotonic solutions containing glucose and other auxiliary drugs, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with appropriate solubilizing agents such as alcohol (ethanol, etc.), polyalcohols (propylene glycol, PEG, etc.), nonionic surfactants (polysorbate 80, polysorbate 20, poloxamer 188, HCO-50), etc.

[0346] In one aspect of the present invention, the buffer used in the solution formulation is prepared using a substance for maintaining the pH of the solution. In one aspect of the present invention, in a high-concentration antibody-containing solution formulation, the pH of the solution is preferably 4.5 to 7.5, more preferably 5.0 to 7.0, and even more preferably 5.5 to 6.5. In one aspect of the present invention, a buffer that can be used is one that can adjust the pH to this range and is medicamentally acceptable. Such buffers are known to those skilled in the art in the field of solution formulation, and examples of such buffers include inorganic salts such as phosphate (sodium or potassium) and sodium bicarbonate; organic acid salts such as citrate (sodium or potassium), sodium acetate, and sodium succinate; and acids such as phosphoric acid, carbonic acid, citric acid, succinic acid, malic acid, and gluconic acid. Furthermore, Good's buffers such as Tris, MES, MOPS, and HEPES, histidine (e.g., histidine hydrochloride), and glycine may be used.

[0347] The concentration of the buffer is generally 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 of histidine, and more preferably 10 to 20 mmol / L of histidine.

[0348] In one aspect of the present invention, the high-concentration antibody-containing solution formulation is preferably stabilized by adding a stabilizer appropriate for the antibody, which is the active ingredient. In one aspect of the present invention, a "stable" high-concentration antibody-containing solution formulation shows no significant change at least 12 months, preferably 2 years, more preferably 3 years, at refrigerated temperature (2-8°C); or at least 3 months, preferably 6 months, more preferably 1 year, at room temperature (22-28°C). For example, the total amount of dimer and decomposition product after storage at 5°C for 2 years is 5.0% or less, preferably 2% or less, more preferably 1.5% or less, or the total amount of dimer and decomposition product after storage at 25°C for 6 months is 5.0% or less, preferably 2% or less, more preferably 1.5% or less.

[0349] In one aspect of the present invention, the surfactant may be a nonionic surfactant, for example, a sorbitan fatty acid ester such as sorbitan monocaprylate, sorbitan monolaurate, or sorbitan monopalmitate; glycerin monocaprylate; Glycerol Monomyristate, glycerin fatty acid esters such as glycerin monostearate; polyglycerin fatty acid esters such as decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbit tetrastearate, polyoxyethylene sorbit tetraoleate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monostearate; polyethylene glycol fatty acid esters such as polyethylene glycol distearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene polyoxypropylene glycol ethers, poly polyoxyethylene polyoxypropylene alkyl ethers such as oxyethylene polyoxypropylene propyl ether and polyoxyethylene polyoxypropylene cetyl ether; polyoxyethylene alkyl phenyl ethers such as polyoxyethylene nonylphenyl ether; polyoxyethylene hydrogenated castor oils such as polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogen castor oil); 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 the like, which have an HLB of 6 to 18; anionic surfactants, for example, alkyl sulfates having an alkyl group having 10 to 18 carbon atoms such as sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, and the like; polyoxyethylene alkyl ether sulfates having an average added mole number of ethylene oxide of 2 to 4 and an alkyl group having 10 to 18 carbon atoms such as polyoxyethylene sodium lauryl sulfate;Typical examples include alkyl sulfosuccinate salts in which the alkyl group has 8 to 18 carbon atoms, such as sodium lauryl sulfosuccinate; natural surfactants, such as lecithin, glycerophospholipids; phingophospholipids such as sphingomyelin; and sucrose fatty acid esters of fatty acids having 12 to 18 carbon atoms. In one aspect of the present invention, one or more of these surfactants can be added to the formulation.

[0350] Preferred surfactants are polyoxyethylene sorbitan fatty acid esters and polyoxyethylene polyoxypropylene alkyl ethers, particularly preferred are polysorbates 20, 21, 40, 60, 65, 80, 81, 85 and Pluronic® type surfactants, most preferred are polysorbate 20, 80 and Pluronic F-68 (Poloxamer 188).

[0351] In one aspect of the present invention, the amount of surfactant added to an antibody formulation is generally 0.0001 to 10% (mg / mL), preferably 0.001 to 5%, and more preferably 0.005 to 3%.

[0352] Furthermore, cryoprotectants, suspending agents, solubilizing agents, isotonicity agents, preservatives, adsorption inhibitors, diluents, excipients, pH adjusters, soothing agents, sulfur-containing reducing agents, antioxidants and the like can be appropriately added to the formulations of the present invention, as necessary.

[0353] Examples of cryoprotectants include sugars such as trehalose, sucrose, and sorbitol. Solubilizing Agent Examples of such fatty acids include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, magurogol, and castor oil fatty acid ethyl esters.

[0354] Examples of the isotonic agent include sodium chloride, potassium chloride, calcium chloride, and the like. Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0355] Examples of anti-adsorption agents include human serum albumin, lecithin, dextran, ethylene oxide-propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, and polyethylene glycol.

[0356] Examples of sulfur-containing reducing agents include those having a sulfhydryl group, such as N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having 1 to 7 carbon atoms.

[0357] Examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium hydrogen sulfite, sodium sulfite, triamyl gallate, propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0358] In one aspect of the invention, the pharmaceutical preparation is for the treatment of autoimmune diseases, immune diseases, infectious diseases, inflammatory diseases, nervous system diseases, and tumor and neoplastic diseases, including cancer. In a particular embodiment, the pharmaceutical use 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; bone loss; Paget's disease, giant cell tumor of bone; breast cancer; disuse bone loss; malnutrition, periodontal disease, Gaucher's disease, Langerhans cell histiocytosis, spinal cord injury, acute septic arthritis, osteomalacia, Cushing's syndrome, monostotic fibroids, Bone dysplasia, polyostotic fibrous dysplasia, periodontal remodeling, and fractures; sarcoidosis; melanoma, prostate cancer, pancreatic cancer, osteolytic bone cancer, breast cancer, lung cancer, gastric cancer, renal cancer, and rectal cancer; bone metastases, bone pain management, and humoral malignant hypercalcemia, ankylosing spondylitis, and other spondyloarthropathies; transplant rejection, viral infections, hematological neoplasms, and neoplastic-like conditions, such as Hodgkin's lymphoma; non-Hodgkin's lymphoma (Burkitt's lymphoma, small lymphocytic lymphoma / chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, hairy cell leukemia, and lymphoplasmacytic leukemia), neoplasms of lymphoid precursor cells, including B-cell acute lymphoblastic leukemia / lymphoma and T-cell acute lymphoblastic leukemia / lymphoma, neoplasms of mature T cells and mature NK cells, including thymoma, peripheral T-cell leukemia, adult T-cell leukemia / T-cell lymphoma, and large granular lymphocytic leukemia, Langerhans cell histiocytosis, AML with maturation and without differentiation Myeloid neoplasms such as acute myeloid leukemia, including AML, acute promyelocytic leukemia, acute myelomonocytic leukemia, and acute monocytic leukemia, myelodysplastic syndromes, and chronic myeloproliferative disorders, including chronic myeloid leukemia, tumors of the central nervous system, such as brain tumors (glioma, neuroblastoma, astrocytoma, medulloblastoma, ependymoma, and retinoblastoma), solid tumors (nasopharyngeal carcinoma, basal cell carcinoma, pancreatic cancer, cholangiocarcinoma, Kaposi's sarcoma, testicular cancer, uterine cancer, vaginal cancer, or cervical cancer, ovarian cancer, primary liver cancer, or endometrial cancer )and tumors of the vascular system (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 graft rejection, hematological malignancies such as multiple myeloma (MM), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML), inflammation associated with tumors, peripheral nerve injury, or demyelinating diseases. In certain embodiments, 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, treatment-induced bone loss, bone metastases, multiple myeloma, Alzheimer's disease, glaucoma, Sjogren's disease, Still's disease, multiple sclerosis, hyperglobulinemia, anemia, mesangial proliferative nephritis, and asthma.

[0359] In one aspect of the invention, the antigen to which the antibody has specific binding affinity 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; lipoproteins; alpha-1-antitrypsin; insulin A chain; insulin B chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors, such as factor VIIIC, factor IX, tissue factor (TF), and von Willebrand factor; anticoagulants, such as protein C; atrial natriuretic factor; pulmonary surfactant; plasminogen activators, such as urokinase or human urinary or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hematopoietic growth factors; tumor necrosis factor-alpha and -beta; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted);human macrophage inflammatory protein (MIP-1-α);serum albumin such as human serum albumin;Müllerian inhibitory substance;relaxin A chain;relaxin B chain;prorelaxin;mouse gonadotropin-related peptide;microbial proteins such as beta-lactamase;DNAse;IgE;cytotoxic T-lymphocyte-associated antigen (CTLA) such as CTLA-4;inhibin;activin;vascular endothelial growth factor (VEGF);hormone or growth factor receptors;protein A or D;rheumatoid factor;neurotrophic factors, e.g. bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5 , or -6 (NT-3, NT-4, NT-5, or NT-6), or nerve growth factors, e.g., NGF-b; platelet-derived growth factor (PDGF); fibroblast growth factors, such as aFGF and bFGF; epidermal growth factor (EGF); transforming growth factors (TGFs), such as TGF-α and TGF-β, including TGF-b1, TGF-b2, TGF-b3, TGF-b4, or TGF-b5; tumor necrosis factors (TNFs), such as TNF-α or TNF-β; insulin-like growth factors-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; bone morphogenetic 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; interleukins (ILs) 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 receptors; surface membrane proteins; decay accelerating factors; viral antigens such as parts of the AIDS envelope; transport proteins; homing receptors; addressins; regulatory proteins; integrins such as CD11a, CD11b, CD11c, CD18, ICAM, VLA-4 and VCAM; tumor associated antigens such as the HER2, HER3 or HER4 receptor; and fragments of any of the above listed polypeptides. ;

[0360] In one aspect of the invention, exemplary molecular targets of encompassed antibodies include CD proteins, such as CD3, CD4, CD8, CD19, CD20, CD22, CD34, and CD40; members of the ErbB receptor family, such as the EGF receptor, HER2, HER3, or HER4 receptor; B cell surface antigens, such as CD20 or BR3; members of the tumor necrosis receptor superfamily, including DR5; prostate stem cell antigen (PSCA); LFA-1, Mac1, p150.95, VLA-4, ICAM-1, VCAM, alpha These include cell adhesion molecules such as αv / β3 integrin, including α4 / β7 integrin and either its α or β subunits (e.g., anti-CD11a, anti-CD18 or anti-CD11b antibodies); 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, and the like.

[0361] (4) Particles In one aspect of the present invention, "removing visually detectable particles" refers to removing visually detectable particles from a pharmaceutical formulation solution in which visually detectable particles are generated under certain conditions by pouring the solution through a filter provided in the barrel when the solution is poured out from a syringe. In one aspect of the present invention, the number of visually detectable particles in the poured solution is zero. The size and number of particles can be measured by light shielding particle counting method, microscopic particle counting method, flow site particle image analysis method, visual inspection, or by isolating particles and then subjecting them to microscopic infrared spectroscopy (IR) measurement or microscopic Raman spectroscopy measurement, and preferably by a combination of visual inspection and microscopic infrared spectroscopy or microscopic Raman spectroscopy measurement.

[0362] (5) Particles detectable by visual inspection In this specification, visually detectable particles are particles that can be visually detected at high illuminance and have a particle size of 40 μm or more. Among them, particles that can be visually detected at standard illuminance (about 2,000-3,000 lx) specified in the Pharmacopoeia are called "visible particles" or "insoluble visible particles". Visible particles generally have a particle size larger than 100 μm (Non-Patent Document 1). Particles that are smaller than visible particles and cannot be seen with the eye at standard illuminance (about 2,000-3,000 lx) specified in the Pharmacopoeia but can be visually detected by increasing the illuminance or lengthening the observation time are "particles that can be visually detected only at high illuminance" and have a particle size of 40 μm to 100 μm. Visible particles are confirmed by visual inspection with the naked eye for 5 seconds or more under illumination at standard illuminance (about 2,000-3,000 lx) by gently rotating or inverting a container in front of a black or white background. Particles that are only visually detectable under high light intensity are identified by visual inspection with the naked eye for 30 seconds or more under lighting and high light intensity (6,000 lx or greater) while gently swirling or inverting the container in front of a black background. Visible particles are also visible under high light intensity inspection.

[0363] As used herein, "protein-derived particles" or "particles derived from a component of a solution" refers to visually detectable particles generated from proteins, including particles consisting of only proteins and particles consisting of a complex of proteins and polydimethylsiloxane (PDMS). The fact that the particles are protein molecules can be confirmed by microscopic Raman spectroscopy. The only protein contained in the solution is the active pharmaceutical ingredient (API), and the visually detectable particles are generated from the API. The number of visually detectable particles can be measured by light-shielding particle counting method, microscopic particle counting method, flow cytometer particle image analysis method, visual inspection, or by isolating the particles and then subjecting them to microscopic infrared spectroscopy (IR) measurement or microscopic Raman spectroscopy measurement, and is preferably measured by a combination of visual inspection and microscopic infrared spectroscopy or microscopic Raman spectroscopy measurement.

[0364] As used herein, the terms "exogenous particles" or "particles originating from other than components of the solution" refer to visually detectable particles other than those mentioned above. As used herein, "aggregates" refer to relatively high molecular weight protein species resulting from the assembly of multiple denatured proteins and are used interchangeably with the terms "high molecular weight species" and "HMWS". Protein aggregates can generally differ in size (small (dimers) to large (microscopic or even visible particles) aggregates with diameters ranging from nanometers to micrometers), morphology (roughly spherical to fibrous), protein structure (native vs. non-native / denatured), type of intermolecular bonds (covalent vs. non-covalent), reversibility, and solubility. Soluble aggregates cover a size range of approximately 1-100 nm, while protein particles cover the microscopic (approximately 0.1-100 μm) and visible (>100 μm) ranges. All of the aforementioned types of protein aggregates are generally encompassed by the term. Thus, the term "(protein) aggregate" refers to any kind of non-native species in which two or more protein monomers are physically associated or chemically linked.

[0365] In one aspect of the present invention, the term "prefilled syringe" refers to a syringe in which a liquid composition is filled in the syringe as a container. In one embodiment, the prefilled syringe is filled with a pharmaceutical composition for administration to a patient. Here, the syringe may be capped with a syringe closure, for example, but not limited to, a stopper. In one embodiment, the composition is placed in the syringe at a manufacturing filling facility. In one embodiment, the syringe is sterilized before placing the composition in the syringe. In one embodiment, 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 administration of the composition to a patient. In one embodiment, the prefilled syringe keeps the solution in the syringe out of contact with the filter even when a level of stress normally expected during manufacturing or distribution is applied. EXAMPLES

[0366] Example 1: Selection of filter material with high particulate removal capacity The antibody solution (satralizumab (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 dispensed into a regular COP syringe (1 mL size) with a 27G needle and into a syringe made of different materials (polyethersulfone (PES) (Supor®; Nippon Pall Co., Ltd.), polyvinylidene fluoride (PVDF) (Durapore®; Merck Ltd.), polyethylene terephthalate (PET), nylon, polysulfone (Asymmetric Super Micron Six types of COP syringes (1 mL standard) with 27G needles, each of which had a built-in filter with a pore size of 5 μm made of polysulfone (Nihon Pall Co., Ltd.) or hydrophobic acrylic copolymer (VERSAPOR®; Nihon Pall Co., Ltd.), were filled with 1.0 mL of the solution and sealed with a stopper. The antibody solution was stored at 25°C and 40°C to intentionally increase the amount of fine particles in the formulation before being used for testing. The antibody solution was in contact with the filter. For the filled and sealed samples, the antibody solution in the syringe was discharged into a clean, washed and sterilized glass vial at a speed of 210 mm / min or 100 mm / min using an autograph (model number: AG-1, Shimadzu Corporation). Phosphate buffered saline was added to the discharged solution or the original solution at an appropriate ratio, and then the solution was mixed by inverting 20 times and left to stand for 2 hours. The solution was slowly inverted 3 times just before measurement. In trials 1 and 2, a microflow imaging device (model number: DPA4100, manufactured by Bright Well) was used to measure the number of microparticles in the solution, and in trial 3, a microflow imaging device (model number: MFI5200, manufactured by Protein Simple) was used to measure the number of microparticles in the solution.

[0367] [Evaluation Results] Table 1 shows the number of particles of 10 μm or more and 25 μm or more in the solution after ejection from a normal COP syringe with a 27 G needle and a COP syringe with a 27 G needle equipped with various filters.

[0368] As a result, it was found that the amount of fine particles in the antibody solution could be significantly reduced when the solution was discharged from a syringe with a PES, PVDF, polysulfone, or hydrophobic acrylic copolymer filter built in, whereas the reduction in the amount of fine particles in the solution was insufficient when the solution was discharged from a syringe with a PET or nylon filter built in. These differences were thought to be due to the fact that the PES, PVDF, polysulfone, and hydrophobic acrylic copolymer filters are all membrane filters, whereas the PET and nylon filters are net filters, a type of depth filter.

[0369] [Table 1]

[0370] Example 2: Selection of optimal filter pore size The antibody solution (satralizumab (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 1.2 μm or 5 μm pore size PES filter punched into a 47 mm diameter circle, and collected in a clean plastic container. Phosphate buffered saline was added to the collected solution or undiluted solution at an appropriate ratio, then mixed by inversion 20 times and left to stand for 2 hours. Just before measurement, the solution was slowly inverted three times and mixed, and the number of particles in the solution was measured using a microflow imaging device (model number: MFI5200, Protein Simple). As in Example 1, the antibody solutions were stored at 25° C. and 40° C. to intentionally increase the amount of fine particles in the formulation before use in the test.

[0371] [Evaluation Results] Table 2 shows the number of particles larger than 25 μm and larger than 70 μm in the original solution and in the sample solution filtered through a filter with a pore size of 1.2 μm or 5 μm.

[0372] As a result, it was found that there was no significant difference in the particle reduction capacity in the solution when filtered through a filter with a pore size of 1.2 μm and a filter with a pore size of 5 μm, and that a pore size of about 5 μm was sufficient. In addition, the water flow rate at a pressure of 70 kPa was 315 mL / min / cm for a pore size of 1.2 μm. 2 and 778 mL / min / cm for a 5 μm pore size. 2 Therefore, the pouring resistance associated with the introduction of a filter with a pore size of 1.2 μm is approximately 2.5 times that of a filter with a pore size of 5 μm. Considering the balance between the particle reduction performance to be achieved and the increase in pouring resistance, we determined that a pore size of 5 μm is optimal.

[0373] In addition, 1.0 mL of sucrose solution (viscosity 7 cP) was filled into a COP syringe (1 mL standard) with a 27G needle incorporating a hydrophobic acrylic copolymer (pore size 5 μm) filter, and the syringe was stoppered with a stopper. The sucrose solution was maintained in a state of non-contact with the filter. For the filled and stoppered samples, the sucrose solution in the syringe was discharged into an appropriate container at a speed of 100 mm / min or 210 mm / min using an autograph (model number: AG-1, manufactured by Shimadzu Corporation). The average sliding resistance values ​​from 10 mm to 25 mm are shown in Table 3. The average sliding resistance values ​​were calculated based on the data obtained by the autograph.

[0374] As a result, it was found that the average sliding resistance of the syringe with the built-in filter was within 1.3 times that of a normal syringe, and was kept sufficiently low despite the presence of the filter.

[0375] [Table 2]

[0376] [Table 3]

[0377] Example 3 Evaluation of filter durability Three types of sucrose solutions (viscosity 10 cP, 15 cP, 20 cP) were filled in 1.0 mL into a COP syringe (1 mL standard) with a 27 G needle and a hydrophobic acrylic copolymer (pore size 5 μm) filter, and then sealed with a stopper. In addition, the drug solution was discharged from Cimzia (registered trademark): Autoclicks for subcutaneous injection 200 mg, and filled in 1.0 mL into a COP syringe (1 mL standard) with a 27 G needle and a hydrophobic acrylic copolymer (pore size 5 μm) filter, and then sealed with a stopper. The viscosity of the Cimzia solution was measured with an EMS viscometer (model: EMS-1000, Kyoto Electronics Manufacturing Co., Ltd.) and was 96.4 cP at 25°C. The sucrose solution and Cimzia solution were maintained in a state of non-contact with the filter. For the filled and stoppered samples, the sucrose solution in the syringe was discharged into a suitable container at a speed of 1000 mm / min using an autograph (model number: AG-1, manufactured by Shimadzu Corporation). The Cimzia solution in the syringe was also discharged manually (N=10). The discharge time was measured with a stopwatch, and the speed was calculated. After discharge, the filter unit was removed from the syringe and the presence or absence of damage to the filter was confirmed.

[0378] [Evaluation Results] The maximum load when discharging sucrose solution with a viscosity of 10-20 cP at a speed of 1000 mm / min and the presence or absence of damage to the filter after discharging were measured. Table 4 The figure shows the discharge speed when discharging a 96.4 cP viscosity Cimzia solution according to the manual, and whether or not the filter was damaged after discharging. Table 5 Also shown are examples of a normal and a damaged filter. Fig. 22 The evaluation results showed that no damage was observed in the filters of any of the samples, and that the filters had sufficient durability and could be used with a wide range of drugs.

[0379] [Table 4]

[0380] [Table 5]

[0381] Example 4 Evaluation of proteinaceous foreign matter removal ability Three pharmaceutical formulations were evaluated: [Formulation 1] Actemra (registered trademark) (active ingredient: tocilizumab): subcutaneous injection 162 mg; [Formulation 2] Hemlibra (registered trademark) (active ingredient: emicizumab): subcutaneous injection 150 mg; [Formulation 3] Enspryng (registered trademark) (active ingredient: satralizumab): subcutaneous injection 120 mg.

[0382] After each formulation was discharged into a plastic container, 1.0 mL was filled into a COP syringe (1 mL standard) with a 27G needle equipped with a hydrophobic acrylic copolymer (pore size 5 μm) filter, and then the syringe was sealed with a stopper. For formulation 1, a sample was used after buffer replacement with the same buffer components as those for formulations 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). This sample was stored at 40°C to intentionally generate proteinaceous foreign matter inside the syringe. Samples (N=5) containing proteinaceous foreign matter were prepared for each formulation, and before discharging the solution, the syringe was gently rotated or inverted in front of a black background at a position of brightness of about 10,000 lx directly under a white light source, and visual inspection was performed with the naked eye for about 30 seconds to confirm the presence or absence of foreign matter in the solution filled in the syringe and the number of foreign matter if any. In addition, even at an illumination of about 3,000 lx, the syringe was gently rotated or inverted in front of a black and white background, and visual inspection was performed with the naked eye for about 30 seconds to confirm the presence or absence of foreign matter in the solution filled in the syringe and the number of foreign matter if any. The number of proteinaceous foreign matter inside the syringe was confirmed at a low illumination of about 10,000 lx in samples with a low illumination of 10,000 lx and at a high of 10 or more. In addition, the number was 0 to 4 at an illumination of about 3,000 lx. The filled and stoppered samples were manually discharged into clean glass vials that had been washed and sterilized. After discharging, the presence or absence of foreign matter inside the vial and the number of foreign matter, if any, were confirmed at illumination intensities of approximately 10,000 lx and 3,000 lx.

[0383] [Evaluation Results] The rate of proteinaceous foreign matter and the number of proteinaceous foreign matter particles after discharge from a COP syringe with a 27G needle and a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter were measured. Tables 6 and 7 As a result, it was confirmed that all 10 types of proteinaceous foreign matter could be adequately removed by discharging the solution using a syringe equipped with a hydrophobic acrylic copolymer filter with a pore size of 5 μm.

[0384] [Table 6]

[0385] [Table 7]

[0386] Similar tests were also conducted on five other prefilled syringe or vial formulations that were already on the market, other than the three above. Three of these were administered subcutaneously, and two were administered intravenously. After the samples were discharged from the containers, they were stored in plastic tubes at 40°C to intentionally generate proteinaceous foreign matter. 1.0 mL of this solution was filled into COP syringes (1 mL standard) with 27G needles and hydrophobic acrylic copolymer (pore size 5 μm) filters, and the syringes were sealed with stoppers. The test results for these five formulations showed that 13 to 31 proteinaceous foreign matter could be removed at an observation illuminance of 10,000 lx, and 4 to 7 proteinaceous foreign matter could be removed at an observation illuminance of 3,000 lx.

[0387] Example 5 Evaluation of ability to remove foreign bodies A 1.0 mL volume of sucrose solution with a viscosity of 7 cP was filled into a COP syringe (1 mL standard) with a 27G needle and a built-in hydrophobic acrylic copolymer (pore size 5 μm). Five types of exogenous foreign bodies (size: approximately 700 μm to 6000 μm, material: glass, SUS, rubber stopper, plastic, fiber) were added to different syringes using tweezers, and then the syringes were sealed with stoppers. N=3 samples containing each exogenous foreign body were prepared, and the presence of foreign bodies inside the syringe was confirmed at an illuminance of approximately 3,000 lx before the solution was discharged from the syringe. After assembling the plunger rod and removing the Rigid Needle Shield (RNS), the solution in the syringe was manually discharged into a clean glass vial that had been washed and sterilized. The presence or absence of foreign bodies was confirmed for the solution discharged into the vial at an illuminance of approximately 3,000 lx.

[0388] [Evaluation Results] 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 was measured. 8 The results of this test confirmed that all five types of exogenous foreign bodies could be adequately removed by discharging a solution containing the exogenous foreign bodies from a syringe equipped with a hydrophobic acrylic copolymer filter with a pore size of 5 μm.

[0389] [Table 8]

[0390] Example 6 Drug Solution and Stability Formulation 2 was filled in 1.0 mL into a normal COP syringe with a 27G needle (1 mL standard) and a COP syringe with a 27G needle with a built-in hydrophobic acrylic copolymer (pore size 5 μm) filter (1 mL standard), and then stoppered. The filled and stoppered samples were stored at 5°C for 12 months or at 25°C for 6 months, and then size exclusion chromatography (SE-HPLC), UV measurement (model number: UV-2700i, Shimadzu Corporation), and PX188 concentration measurement were performed under the following conditions. In the size exclusion chromatography measurement, the main peak detected was defined as the Main Peak, the sum of the peaks detected before the Main Peak was defined as the High Molecular Weight (HMW), and the sum of the peaks detected after the Main Peak was defined as the 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 in a normal COP syringe or a COP syringe with a built-in filter, almost no change in physical properties was observed in any of the samples. From the above, it was confirmed that this COP syringe with built-in filter is highly compatible with medicinal liquids.

[0391] [Table 9]

[0392] Size Exclusion Chromatography -Size exclusion chromatography device: Waters "2695 or e2695" -Detector: UV spectrophotometer -Measurement wavelength: 280nm -Column: TSKgel G3000SWXL (Tosoh) -Column temperature: 25℃ -Mobile phase: Phosphate buffer (pH 7.0) -Flow rate: 0.5mL / min -Injection volume: 60μL ·PX188 concentration measurement -PX188 Concentration Measuring Device: Waters 2690, 2695, e2795 or e2695 -Detector: Differential refractometer (2414 Refractive Index Detector) -Column: TSKgel SuperSW2000 (Tosoh) -Column temperature: 25℃ -Mobile phase: 40% acetonitrile solution containing 30mmol / L sodium chloride -Flow rate: 0.3mL / min -Injection volume: 20μL [Explanation of symbols]

[0393] 1...prefilled syringe, 2...syringe, 3...piston, 4...injection needle, 5...cap, 6...barrel, 7...partition means, 8...housing, 9...internal plug portion, 30...rod portion, 31...gasket, 32...operation portion, 33...tip surface, 60...tip portion, 61...base end portion, 62...cylindrical portion, 63...flange portion, 64...dispensing hole, 80...filter, 81...closed engagement portion, 82...inner circumferential surface, 83...mounting portion, 84...main body portion, 85...extension portion, 86...filter member, 90...closed engagement portion, 91...regulating means, 92...lid portion, 93...step engagement portion, 94...leg portion, 95...projection portion, 96...annular portion, 97...lid recess, 98...abutment face, 600…Base end side end face, 800…Outer peripheral face, 801…Base end outer peripheral face portion, 802…Tip end outer peripheral face portion, 810…Step face, 821…Base end inner peripheral face portion, 822…Tip end inner peripheral face portion, 830…Tip end face, 901…Engaged portion when closed at the base end side, 902…Engaged portion when closed at the tip end side, 920…Outer peripheral portion, 921…Inner peripheral portion, 922…Cover leg portion, S…Space, S1…Base end side space, S2…Tip end side space, S21 Tip end side space, S22…Second tip end side space, S3…Third tip end side space, S4…Fourth tip end side space 、C 8…Liquid flow path, C9…Plug flow path, C91…Axial flow path, C92…Communication flow path, ML…Liquid agent, MS…Solid agent, MM…Mixed agent 80…Filter, 10…Holding member,, 34…Adhesive portion, 35…Protruding portion,, 65…Inner peripheral face, 71…Tip end side auxiliary space, 72…Base end side auxiliary space, 110…Base end side portion, 111…Flow path, 112…Mounting site, 113…Leg portion, 600…Base end side end face, 601…Base end side edge, 200…Contact face (base end side end face), 201…Base end side contact face, 201a…First base end side contact face, 201b…Second base end side contact face, 202…Tip end side contact face, 203…Connection contact face, 203a…First connection contact face, 203b…Second connection contact face, 203c…Second connection contact face, 204…Tip end face, 220…Mounting outer peripheral portion, 221…Mounting inner peripheral portion, 222…Outer peripheral tip end face, 223…Inner peripheral tip end face, 224…Shoulder portion, 225…Protrusion portion, 226…Mounting inner peripheral face, 230…Base face

Claims

1. An injectable preparation in which the solution is filled into a syringe, The syringe A barrel formed in a cylindrical shape having a tip and a base, with a pouring hole provided at the tip for pouring out a solution contained inside, The barrel comprises a filter positioned at the base end of the dispensing hole, The filter is provided such that the solution flows through the filter from the base end to the tip end. An injectable formulation wherein the filter is a membrane, and its material comprises one or more selected from polyethersulfone (PES), polypyrinidene fluoride (PVDF), polysulfone (PS), and acrylic copolymer.

2. The injectable formulation according to claim 1, wherein, when the solution is discharged, particles that can be visually detected can be removed from the discharged solution.

3. The injectable formulation according to claim 1 or 2, wherein the material of the membrane is an acrylic copolymer.

4. The injectable formulation according to claim 3, wherein the acrylic copolymer is hydrophobic.

5. The injectable formulation according to claim 1 or 2, wherein the filter has a pore size of 5 μm or less.

6. An injectable preparation according to claim 1 or 2, wherein a tip-side subspace is provided on the tip side of the filter, and a proximal-side subspace is provided on the proximal-side of the filter, and when viewed from the axial direction of the barrel, the area of ​​the dispensing hole is smaller than the area of ​​the proximal-side subspace and smaller than the area of ​​the tip-side subspace.

7. The syringe is equipped with a partitioning means that divides the space inside the barrel into a base end space and a tip end space. picture, The partition means comprises a cylindrical housing positioned to be in liquid-tight contact with the inner surface of the barrel, and an internal stopper positioned to be openable and closable within the housing such that the base end space and the tip end space communicate or not communicate through the inside of the housing. The housing has a closed engagement portion, and the material of the housing is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE). The aforementioned plug portion has a closed-engaged portion that engages with the closed-engaged portion from the base end side, The partition means is configured such that when a pressing force is applied from the base end side by a piston inserted into the barrel from the base end side, one of the closed engaging portion and the closed engaged portion overcomes the other, disengaging the closed engaging portion and the closed engaged portion, opening the inner plug portion to the inside of the housing, and allowing the base end side space and the tip end side space to communicate. The injectable formulation according to claim 1 or 2, wherein the filter is held in the tip portion of the housing.

8. The injectable preparation according to claim 7, wherein one of the closed engaging portion and the closed engaged portion is positioned on the tip side and the proximal end side with respect to the other of the closed engaging portion and the closed engaged portion.

9. The injectable preparation according to claim 7, wherein the material of the stopper is linear low-density polyethylene (LLDPE) or low-density polyethylene (LDPE).

10. The syringe is equipped with a partitioning means that divides the space inside the barrel into a base end space and a tip end space. The partition means comprises a cylindrical housing positioned to be in liquid-tight contact with the inner surface of the barrel, The injectable formulation according to claim 1 or 2, wherein the filter is held in the tip portion of the housing.

11. The partition means has a volume of 150 mm³ in the space at the tip of the barrel. ３ The injectable preparation according to claim 7, arranged as follows:

12. The injectable formulation according to claim 1 or 2, wherein the active ingredient compound contained in the solution is a low-molecular-weight compound, a medium-molecular-weight compound, or a protein.

13. The injectable formulation according to claim 1 or 2, wherein the solution contains emicizumab as an active ingredient.

14. A method for removing visually detectable particles contained in an injectable preparation, The injectable preparation is a solution and is filled in a syringe. The syringe is formed in a cylindrical shape having a tip and a base, and comprises a barrel with an injection hole at the tip for dispensing an injectable preparation contained inside, and a filter located inside the barrel on the base side of the injection hole, wherein the filter is provided so that the solution flows through the filter from the base side to the tip side of the filter. A method comprising discharging a solution filled in a syringe through a filter, wherein the filter is a membrane and its material comprises one or more selected from polyethersulfone (PES), polypyrinidene fluoride (PVDF), polysulfone (PS), and acrylic copolymer.

15. The method according to claim 14, wherein the active ingredient compound contained in the solution 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 comprises emicizumab as an active ingredient.

17. The injectable preparation according to claim 1 or 2, wherein the syringe is attached to an autoinjector.

18. The method according to claim 14 or 15, wherein the syringe is attached to an auto-injector.

Images