Patent Publication Number: US-2022218910-A1

Title: Syringe barrel, prefilled syringe, and methods for manufacturing the same

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of U.S. patent application Ser. No. 15/982,833, filed on May 17, 2018, which is a Bypass Continuation of International Patent Application No. PCT/JP2016/084025, filed on Nov. 17, 2016, which claims priority to Japanese Application No. 2015-226646 filed on Nov. 19, 2015. The contents of these applications are hereby incorporated by reference in their entireties. 
    
    
     BACKGROUND 
     The present disclosure relates to a syringe barrel, a prefilled syringe, and methods for manufacturing these. 
     A typical syringe includes a hollow barrel, a gasket formed of an elastic body slidably inserted in the barrel, and a pusher connected to the gasket, and is configured to dispense a drug solution filled in the barrel with operation of the pusher in the axial direction. In addition, it is conventionally known to spray a silicone oil to be applied to the barrel inner surface so as to suppress the sliding resistance of the gasket in the barrel. 
     In order to effectively reduce the sliding resistance of the gasket in the barrel, it is effective to uniformly apply the silicone oil to the barrel inner surface. For this reason, for example, JP 2002-143300 A applies a silicone oil by spraying the oil toward the barrel inner surface and then spreading and smoothing the oil with a tool such as a squeegee so as to uniformly apply the silicone oil. 
     SUMMARY 
     In the case of spreading and smoothing the silicone oil applied to the barrel inner surface with a tool as disclosed in JP 2002-143300 A, the barrel inner surface is rubbed with the tool, leading to a possibility of generation of a scratch or adhesion of foreign matter on the barrel inner surface. 
     Certain embodiments described in the present application have been made in view of this problem, and aim to provide a syringe barrel and prefilled syringe having the silicone oil uniformly applied without generation of scratches or adhesion of foreign matter on the barrel inner surface, and methods for manufacturing the same. 
     According to one embodiment, a method for manufacturing a syringe barrel includes: a providing step of providing a syringe barrel including a hollow body portion and being configured that a gasket sliding on an inner surface of the body portion is inserted therein; an application step of applying a non-reactive silicone oil having a viscosity of 3000 cps to 30000 cps to the inner surface by spraying with a coating amount rate of 0.02 mg/cm 2  to 0.2 mg/cm 2 ; and a heating step of heating the silicone oil applied to the inner surface without spreading or smoothing the silicone oil applied to the inner surface in a state in which a liquid is not filled in the syringe barrel. 
     With this method for manufacturing a syringe barrel, the non-reactive silicone oil applied to the barrel inner surface is heated to reduce the viscosity, so as to allow the silicone oil to spread out in a direction of the barrel inner surface and the direction of gravity. This increases uniformity of the silicone oil distribution, making it possible to suppress the sliding resistance of the gasket inserted into the syringe barrel. In addition, application of the silicone oil having the above-described viscosity makes it possible to suitably reduce the viscosity at the time of heating and effectively uniformize the silicone oil distribution. Furthermore, application of the silicone oil at the above-described coating amount rate enables the silicone oil to uniformly spread over the barrel inner surface without causing excessive application. In addition, because the silicone oil applied to the barrel inner surface is not spread and smoothed with a tool such as a squeegee to achieve uniformity in the silicone oil distribution, it is possible to obtain a syringe barrel on which the silicone oil is uniformly applied without generation of scratches or adhesion of foreign matter on the barrel inner surface. 
     In the method for manufacturing a syringe barrel as described above, in the heating step, the silicone oil may be heated by performing autoclave sterilization on the syringe barrel. 
     With this method, the silicone oil is heated at the time of autoclave sterilization for the syringe barrel, making it possible to efficiently manufacture the syringe barrel without a need to provide a dedicated step for heating the silicone oil. In addition, autoclave sterilization can suppress degradation of the syringe barrel as compared with other sterilization treatments such as electron beam sterilization, making it possible to suppress adverse effects on the drug solution filled in the syringe barrel. 
     In the above-described method for manufacturing a syringe barrel, the heating step may be performed in a state in which an axis of the syringe barrel is substantially vertical. 
     This enables the silicone oil to spread out in a barrel axial direction due to gravity at the time of heating, leading to achievement of higher uniformity in the silicone oil distribution. 
     In the above-described method for manufacturing a syringe barrel, in the application step, the silicone oil may be applied to the inner surface by spraying the silicone oil from a first side toward a second end side of the syringe barrel, and the heating step may be performed in a state in which the second end side faces downward. 
     With this method, heating is performed with the side opposite to the spraying side facing downward, allowing the mass of the silicone oil to spread out from the first end side of the barrel toward the second end side due to gravity. This makes it possible to effectively achieve higher uniformity in the silicone oil distribution. 
     In the above-described method for manufacturing a syringe barrel, in the application step, the silicone oil may be sprayed from the first end side toward the second end side of the syringe barrel, while aspirating air within the syringe barrel from the second end side. 
     This can suppress unevenness in spraying of silicone oil and achieve application of the silicone oil with higher uniformity. 
     In the above-described method for manufacturing a syringe barrel, the syringe barrel may include: an opening portion for inserting the gasket at the first end side; and a nozzle having an inner diameter smaller than the inner diameter of the body portion at the second end side. 
     In this manner, the inner diameter of the nozzle provided on the side opposite to the opening portion of the barrel is smaller than the body portion. Accordingly, the air inside the barrel is not likely to escape from the nozzle side (the second end side) when the silicone oil is sprayed from the opening portion (first end side) of the barrel, making it difficult to allow the sprayed silicone oil to reach the nozzle side (second end side). This makes it more important to spray the silicone oil while aspirating the air from the nozzle side (the second end side). 
     According to another embodiment, a method for manufacturing a prefilled syringe includes: a preparation step of preparing the syringe barrel manufactured by any of the methods for manufacturing a syringe barrel; a filling step of filling the prepared syringe barrel with a drug solution; and a plugging step of plugging the gasket into the syringe barrel filled with the drug solution. 
     With this method, a prefilled syringe in which silicone oil is uniformly applied to the barrel inner surface is provided. 
     In the above-described method for manufacturing a prefilled syringe, the drug solution may be a protein preparation. 
     The silicone oil is uniformly applied with this method, leading to suppression of outflow of the silicone oil into the drug solution, making it possible to suppress the aggregation of the protein caused by the outflow of the silicone oil. 
     According to another embodiment, a syringe barrel include: a hollow body portion; a shoulder portion reduced in diameter from a distal end of the body portion; a nozzle protruding in a distal end direction from the shoulder portion; and an opening portion that opens at a proximal end of the body portion, the syringe barrel being configured that a gasket sliding on an inner surface of the body portion is inserted therein, in which a non-reactive silicone oil having a viscosity of 3000 cps to 30000 cps is applied on the inner surface at least from an insertion position configured for the gasket being inserted thereat, up to a position closer to the shoulder portion than the insertion position, and a coverage as a ratio of the area of the silicone oil present as droplets to the area of the inner surface is 20% or less at each of sections where a region applied with the silicone oil in the inner surface is partitioned with a predetermined width in the axial direction, and a droplet structure of the silicone oil is present on the inner surface. 
     With the syringe barrel configured as described above, it is possible to suppress the sliding resistance of the gasket because the silicone oil distribution is uniformized. In addition, because the silicone oil applied to the barrel inner surface is not spread or smoothed with a tool such as a squeegee to achieve uniformity of the silicone oil, it is possible to provide a syringe barrel that has suppressed generation of scratches or adhesion of foreign matter on the barrel inner surface. 
     In the syringe barrel described above, the silicone oil may have been applied from a vicinity of the opening portion beyond the insertion position to the position closer to the shoulder portion. 
     With this configuration, the silicone oil has been applied up to a vicinity of the opening portion, making it possible to plug the gasket quickly and reliably up to the insertion position at the time of vacuum plugging. 
     In the syringe barrel described above, the silicone oil may have been applied up to a vicinity of the shoulder portion. 
     With this configuration, the silicone oil has been applied to substantially an entire region of the barrel inner surface on which the gasket slides before discharging the drug, making it possible to suppress the sliding resistance of the gasket up to the end. 
     In the above-described syringe barrel, an average value of the coverage from a vicinity of the shoulder portion to the insertion position may be 10% or less. 
     This makes it possible to further suppress the sliding resistance of the gasket. 
     According to another embodiment, a prefilled syringe includes any of the above-described syringe barrels, the gasket, and a drug solution filled in the syringe barrel. 
     In the above-described prefilled syringe, the drug solution may be a protein preparation. 
     According to certain embodiments describe in the present application, there is provided a syringe barrel, a prefilled syringe, having the silicone oil uniformly applied without generation of scratches or adhesion of foreign matter on the barrel inner surface, and methods for manufacturing the same. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view of a syringe including a syringe barrel according to one embodiment. 
         FIG. 2  is a cross-sectional view of the syringe illustrated in  FIG. 1 . 
         FIG. 3  is a cross-sectional view of a barrel constituting the syringe illustrated in  FIG. 1 . 
         FIG. 4  is a cross-sectional view of a medical package. 
         FIG. 5A  is an illustration of a step of providing a barrel.  FIG. 5B  is an illustration of a step of applying a silicone oil to a barrel inner surface.  FIG. 5C  is an illustration of a step of attaching a cap to the barrel. 
         FIG. 6A  is a cross-sectional view of a storage container storing a barrel.  FIG. 6B  is a cross-sectional view of a sterilization bag storing the storage container. 
         FIG. 7A  is a graph illustrating the silicone oil distribution before sterilization of a sample A 1  not filled with water.  FIG. 7B  is a graph illustrating the silicone oil distribution before sterilization of a sample A 2  not filled with water.  FIG. 7C  is a graph illustrating the silicone oil distribution before sterilization of a sample A 3  not filled with water.  FIG. 7D  is a graph illustrating the silicone oil distribution before sterilization of a sample A 4  not filled with water. 
         FIG. 8A  is a graph illustrating the silicone oil distribution after sterilization of the sample A 1  not filled with water.  FIG. 8B  is a graph illustrating the silicone oil distribution after sterilization of the sample A 2  not filled with water.  FIG. 8C  is a graph illustrating the silicone oil distribution after sterilization of the sample A 3  not filled with water.  FIG. 8D  is a graph illustrating the silicone oil distribution after sterilization of the sample A 4  not filled with water. 
         FIG. 9A  is a graph illustrating the silicone oil distribution before sterilization of a sample B 1  filled with water.  FIG. 9B  is a graph illustrating the silicone oil distribution before sterilization of a sample B 2  filled with water.  FIG. 9C  is a graph illustrating the silicone oil distribution before sterilization of a sample B 3  filled with water.  FIG. 9D  is a graph illustrating the silicone oil distribution before sterilization of a sample B 4  filled with water. 
         FIG. 10A  is a graph illustrating the silicone oil distribution after sterilization of the sample B 1  filled with water.  FIG. 10B  is a graph illustrating the silicone oil distribution after sterilization of the sample B 2  filled with water.  FIG. 10C  is a graph illustrating the silicone oil distribution after sterilization of the sample B 3  filled with water.  FIG. 10D  is a graph illustrating the silicone oil distribution after sterilization of the sample B 4  filled with water. 
     
    
    
     DETAILED DESCRIPTION 
     Embodiments of a syringe barrel, a prefilled syringe and methods for manufacturing the same will be described below with reference to the accompanying drawings. 
     In  FIGS. 1 and 2 , a syringe  10  includes a syringe barrel  12  (hereinafter simply referred to as a “barrel  12 ”), a cap  14  for sealing a distal end opening  12   a  (refer to  FIG. 3 ) of the barrel  12 , a gasket  16  inserted into the barrel  12  in a liquid-tight slidable manner, and a drug M filled in a filling chamber  13  formed in the barrel  12 . The syringe  10  is configured as a prefilled syringe  10 A prefilled with the drug M. 
     In using the syringe  10 , another prefilled syringe having a male luer and filled with a medical liquid (diluting or dissolving liquid) is connected to the syringe  10 . Subsequently, in the connected state, the drug M in the syringe  10  is aspirated into the other prefilled syringe filled with the medical liquid to mix the drug M with the medical liquid in the other prefilled syringe to prepare a desired drug solution. 
     As illustrated in  FIGS. 2 and 3 , the barrel  12  includes a hollow body portion  18  constituting a main portion of the barrel  12 , a shoulder portion  19  reduced in diameter from a distal end of the body portion  18 , a hollow nozzle  20  protruding in a distal end direction from the shoulder portion  19 , and a proximal end opening portion  21  that opens at a proximal end of the body portion  18 . 
     The body portion  18  is a hollow cylindrical portion in which the gasket  16  is slidably inserted. A flange  23  protruding outward in the radial direction is formed on the outer circumferential portion of the proximal end of the body portion  18 . 
     In order to enhance the slidability of the gasket  16  against the inner surface of the body portion  18  (hereinafter referred to as a “barrel inner surface  18   a ”), a non-reactive silicone oil  27  having a viscosity of 3000 cps to 30000 cps is applied as a lubricant to the barrel inner surface  18   a . Unlike the reactive silicone oil that is crosslinked and cured by heat or the like, the non-reactive silicone oil  27  is not crosslinked and cured even when it is heated. An example of this non-reactive silicone oil  27  is dimethylpolysiloxane. Hereinafter, the non-reactive silicone oil  27  is simply referred to as the “silicone oil  27 ”. 
     As illustrated in  FIG. 3 , the silicone oil  27  is applied at least to a portion from an insertion position P, where the gasket  16  is inserted, up to a position closer to the shoulder portion  19  than the insertion position P. Note that the insertion position P is an initial position of the gasket  16  in the syringe  10 . 
     In the present embodiment, the silicone oil  27  is applied to a portion from the vicinity of the proximal end opening portion  21  beyond the insertion position P up to the position closer to the shoulder portion  19 , as indicated by an application range with arrow A in  FIG. 3 . In addition, in the present embodiment, the silicone oil  27  is applied up to the vicinity of the shoulder portion  19 . Therefore, in the case of the present embodiment, the silicone oil  27  is applied to substantially an entire region of the barrel inner surface  18   a  on which the gasket  16  slides before discharging the drug. Note that the vicinity of the proximal end opening portion  21  indicates a region extending in approximately 0 mm to 10 mm from the proximal end opening portion  21  toward the distal end, for example. The vicinity of the shoulder portion  19  indicates a region extending in 0 mm to 10 mm from a boundary portion between the body portion  18  and the shoulder portion  19  (portion where the inner diameter starts to be reduced) toward the proximal end, for example. 
     As will be described below, the silicone oil  27  provided on the barrel inner surface  18   a  is first applied to the barrel inner surface  18   a  and then broadened in a direction of the barrel inner surface  18   a  and the direction of gravity with reduced viscosity due to the heat generated at autoclave sterilization, without being spread or smoothed by a tool such as a squeegee in a state in which the barrel  12  is not filled with the drug solution. This uniformizes the silicone oil distribution on the barrel inner surface  18   a.    
     Specifically, a coverage as a ratio of the area of the silicone oil  27  present as droplets to the area of the barrel inner surface  18   a  is 20% or less in each of sections obtained by dividing a region (region indicated by arrow A in  FIG. 3 ) on the barrel inner surface  18   a  to which the silicone oil  27  is applied, at a predetermined width in an axial direction. Each of sections is an annular section. In addition, in the present embodiment, an average value of the coverage at a portion from the vicinity of the shoulder portion  19  up to the insertion position P is 10% or less. 
     An exemplary method of measuring the coverage of the silicone oil  27  includes a scheme of detecting an edge of a transparent fine particle by forming bright and dark light fringes (zebra pattern) on an object to quantify an application state (hereinafter referred to as a “zebra pattern measurement scheme”). Measurement of the coverage using the zebra pattern measurement scheme is specifically implemented by emitting light from a light source (for example, a red light source) via a slit plate having a large number of slits formed at predetermined intervals so as to form bright and dark fringes in which the bright and dark portions alternate in the axial direction with respect to the body portion  18  of the barrel  12 . Next, the barrel is photographed by receiving transmitted light transmitted through the body portion  18  of the barrel  12 , so as to detect a ring-shaped edge from the shading in a photographed image. This photographing and edge detection is performed on the entire circumference of the barrel  12  by rotating the barrel  12  by a predetermined angle. Subsequently, the droplet of the silicone oil  27  is specified from the edge, and a proportion (%) of the total area of the droplet to the image area is defined as the coverage. More specifically, the region on the barrel inner surface  18   a  to which the silicone oil  27  is applied is divided into sections (annular bands) having a predetermined width in the axial direction, so as to calculate the coverage for each of the sections. In this case, the predetermined width of the section is set to 1 mm to 3 mm, for example. 
     In the case of the barrel  12 , the silicone oil  27  applied to the barrel inner surface  18   a  is not spread or smoothed after being sprayed onto the barrel inner surface  18   a , and thus, a droplet structure of the silicone oil  27  exists on the barrel inner surface  18   a . The droplet structure of the silicone oil  27  is a raised structure or an uneven structure formed by the droplet of the applied silicone oil  27  not spreading out completely even by heating. In contrast, the droplet structure of the silicone oil  27  would not exist on the barrel inner surface  18   a  in a case where the silicone oil  27  is spread and smoothed with a tool such as a squeegee after the silicone oil  27  is applied to the barrel inner surface  18   a  as in the above-described conventional technique. 
     The nozzle  20  is reduced in diameter with respect to the body portion  18  from the distal end portion of the body portion  18  and protrudes in the distal end direction. The nozzle  20  includes a female luer to which the male luer can be inserted and connected, and has a tapered inner surface with an inner diameter increasing toward the distal end direction. 
     In  FIG. 2 , the outer circumferential portion of the distal end of the nozzle  20  includes a fixing portion  24  for detachably fixing the cap  14 . In the present embodiment, the fixing portion  24  is constituted by two engaging projections  25  protruding in directions opposite to each other about an axis of the barrel  12  as a reference and capable of being screwed with the cap  14 . 
     Examples of the constituent material of the barrel  12  include various resins such as polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly-(4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyester such as polyethylene terephthalate, cyclic olefin polymer, and cyclic olefin copolymer. Among them, resins such as polypropylene, cyclic olefin polymer and cyclic olefin copolymer are preferable because of their excellent moldability and heat resistance. Moreover, as will be described below, the silicone oil  27  tends to spread out with higher uniformity by heat during thermal treatment (autoclave sterilization) in the case of the cyclic olefin polymer than the polypropylene or the like, and thus, it is more preferable that the barrel  12  be formed of cyclic olefin polymer. 
     The cap  14  includes a sealing member  28  formed of an elastic member for sealing the distal end opening  12   a  of the barrel  12 , and a tubular main body portion  30  supporting the sealing member  28 . The inner circumferential portion of the main body portion  30  includes a female screw  31  to be screwed into the fixing portion  24  (engaging projection  25 ) on the nozzle  20 . In a pre-use state in which the cap  14  is attached to the nozzle  20 , the distal end opening  12   a  is sealed liquid-tight by the cap  14  so as to suppress leakage of the drug M from the distal end opening  12   a.    
     The outer circumferential portion of the gasket  16  includes a plurality of ring-shaped sealing projections  17  formed at intervals in the axial direction. With the gasket  16  inserted in the barrel  12 , the sealing projection  17  comes into close contact with the barrel inner surface  18   a . This enables the gasket  16  to slide within the barrel  12  in a liquid-tight manner in the axial direction. 
     The gasket  16  includes a fitting recess  34  opening to the proximal end side and having a female screw  32  formed in the inner circumferential portion. The fitting recess  34  can be screwed with the distal end portion of a pusher (not illustrated) as necessary. 
     Examples of the constituent material of the gasket  16  include various rubber materials such as natural rubber, butyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, and silicone rubber, or various types of thermoplastic elastomer such as polyurethane type, polyester type, polyamide type, olefin type, and styrene type, or a mixture of these. 
     The drug M may be any of a powdered drug, a lyophilized drug, a solid drug, a liquid drug, or the like. Examples of the drug include protein preparations, antitumor agents, vitamins (multivitamin), various amino acids, antithrombotics such as heparin, insulin, antibiotics, analgesics, cardiotonics, intravenous anesthetics, medical narcotics, antiparkinson agents, ulcer therapeutic agents, adrenocortical hormone agents, and arrhythmia agents. 
     Note that the syringe  10  includes, at the proximal end portion (flange  23 ) of the barrel  12 , a detachable gasket stopper  36  that prevents the gasket  16  from dropping from the barrel  12  in the proximal end direction. 
     The medical package  40  illustrated in  FIG. 4  includes one or more syringe assemblies  42 , a storage container  44  for storing the syringe assembly  42 , a sterilization bag  46  for storing the storage container  44 , and outer wrap  48  for storing the sterilization bag  46 . The syringe assembly  42  is an assembly constituting a portion of the syringe  10  (prefilled syringe  10 A) described above. Specifically, the syringe assembly  42  includes the barrel  12  having the silicone oil  27  being applied to the barrel inner surface  18   a , and the cap  14  attached to the distal end portion of the barrel  12 . The barrel  12  of the syringe assembly  42  is not filled with the drug M (refer to  FIG. 2 ). 
     The storage container  44  includes a container main body  50  (tub), a holding member  52  (nest), and a sheet material  54 . The container main body  50  is formed in a box shape including a bottom portion  56  forming a bottom wall, a side portion  58  forming a circumferential wall, and a flange portion  62  surrounding an opening portion  60  formed at an upper end portion of the side portion  58 . A sheet material  54  is releasably fixed (bonded) to an upper surface of the flange portion  62 . 
     The holding member  52  is mounted on a step  51  formed in the container main body  50 , so as to hold a plurality of syringe assemblies  42  flush with each other. The holding member  52  includes a plurality of hollow cylindrical protrusion holders  64 . The flange  23  provided at the proximal end of the barrel  12  is caught on the upper end of the protrusion holder  64  so as to hold the syringe assembly  42  in a substantially vertically suspended state. 
     The sheet material  54  is a lid member to seal the opening portion  60  of the container main body  50 , and is formed of a material having gas permeability and bacteria impermeability. Accordingly, the sheet material  54  is permeable to water vapor used as a sterilizing gas at the time of autoclave sterilization (high-pressure steam sterilization) in the step of manufacturing the medical package  40 . Examples of the constituent material of the sheet material  54  include a plastic nonwoven fabric and a plastic porous film. An example of the plastic nonwoven fabric is nonwoven polyolefin. 
     The sterilization bag  46  is a bag having at least partial gas permeability and bacteria impermeability. In the present embodiment, the sterilization bag  46  includes a first sheet  66  having gas permeability and bacteria impermeability, and a second sheet  68  formed of a material having gas impermeability and bacteria impermeability (for example, polyethylene). Peripheral edges of the first sheet  66  and the second sheet  68  are fusion bonded to each other. 
     The outer wrap  48  is a bag formed of a material having gas impermeability and bacteria impermeability (for example, polyethylene), being formed to be larger than the sterilization bag  46  so as to be able to store the sterilization bag  46  storing the storage container  44 . As will be described below, after the sterilization bag  46  storing the storage container  44  is wrapped in the outer wrap  48  in the manufacturing step, a mouth portion of the outer wrap  48  is sealed by a sealing apparatus to achieve outer wrap of the sterilization bag  46 . 
     The medical package  40  thus configured is shipped in a box and unsealed by a pharmaceutical manufacturer, for example, and the syringe assembly  42  is taken out. Subsequently, the drug M is filled in the barrel  12  of the syringe assembly  42 , then, the gasket  16  is inserted into the barrel  12 , so as to complete the prefilled syringe  10 A illustrated in  FIG. 1 . The method for manufacturing the prefilled syringe  10 A according to the present embodiment includes a preparation step of preparing the barrel  12 , a filling step of filling the prepared liquid barrel  12  with a drug solution, and a plugging step of plugging the gasket  16  into the barrel  12  filled with the drug solution. 
     The medical package  40  configured as described above can be manufactured by a manufacturing method including, for example, the following steps. In the present embodiment, the method for manufacturing the barrel  12  having the silicone oil  27  uniformly applied to the barrel inner surface  18   a  includes a providing step, an application step, and a heating step as described below, the method constituting a portion of the manufacturing method of the medical package  40 . 
     As illustrated in  FIG. 5A , the barrel  12  is provided (providing step). The barrel  12  can be manufactured by an injection molding method, for example. 
     Next, as illustrated in  FIG. 5B , the silicone oil  27  having a viscosity of 3000 cps to 30000 cps is applied to the barrel inner surface  18   a  by spraying with a coating amount rate of 0.02 mg/cm 2  to 0.2 mg/cm 2  (application step). The coating amount rate is a value obtained by dividing the weight of the silicone oil  27  dispensed from a spray nozzle  70  by the area of the barrel inner surface  18   a.    
     Specifically, in the application step, the barrel  12  is held with the proximal end opening portion  21  facing upward (with the cap  14  downward), and the spray nozzle  70  is arranged to face the proximal end opening portion  21 . Subsequently, the silicone oil  27  is dispensed from the spray nozzle  70  in a form of mist and sprayed onto the barrel inner surface  18   a . That is, the silicone oil  27  is sprayed from the proximal end opening portion  21  of the barrel  12  toward the nozzle  20  side onto the barrel inner surface  18   a . This operation applies the silicone oil  27  to the barrel inner surface  18   a . In the present embodiment, the silicone oil  27  is applied to a portion from the vicinity of the proximal end opening portion  21  of the barrel  12  up to the vicinity of the shoulder portion  19 . 
     In addition, as illustrated in  FIG. 5B , in the present embodiment, air B is aspirated from the nozzle  20  side when the silicone oil  27  is applied by spraying. With a method of spraying the silicone oil  27  while aspirating the air B from the nozzle  20  side in this manner, the silicone oil  27  can be reliably applied up to the vicinity of the shoulder portion  19 . Moreover, it is possible to reduce unevenness of spraying and apply the silicone oil  27  with higher uniformity. 
     Next, as illustrated in  FIG. 5C , the cap  14  is provided and the cap  14  is then attached to the nozzle  20  of the barrel  12  with the silicone oil  27  applied, so as to seal the distal end opening  12   a  of the barrel  12 . 
     Next, a step of obtaining the storage container  44  illustrated in  FIG. 6A  is performed. In this step, one or more syringe assemblies  42  obtained as described above are first stored in the container main body  50 . Specifically, the syringe assembly  42  is inserted into each of the protrusion holders  64  of the holding member  52  with the distal end side facing downward. Next, the plurality of syringe assemblies  42  are suspended by the holding member  52 , and thereafter, the holding member  52  is mounted on the inside of the container main body  50 . 
     Next, the opening portion  60  of the container main body  50  is sealed with the sheet material  54 . Specifically, the sheet material  54  is releasably fixed to the flange portion  62  of the container main body  50 , so as to seal the opening portion  60  of the container main body  50 . In this case, it is allowable to use fixation with an adhesive in addition to thermal fusion bonding, as a fixing means. The opening portion  60  of the container main body  50  storing the syringe assembly  42  is sealed with the sheet material  54 . With this processing, the storage container  44  storing the syringe assembly  42  not filled with the drug M is obtained as illustrated in  FIG. 6A . 
     Next, a step of obtaining a package  72  illustrated in  FIG. 6B  is performed. In this step, the storage container  44  (container main body  50  in which the syringe assembly  42  is stored and the opening portion  60  is sealed with the sheet material  54 ) is first packaged by the sterilization bag  46 . Specifically, the storage container  44  is stored in the sterilization bag  46  with its mouth portion open, and thereafter, the mouth portion of the sterilization bag  46  is sealed. This processing achieves acquisition of the package  72 , in which the opening portion  60  of the container main body  50  is sealed with the sheet material  54 , the syringe assembly  42  is stored in the storage container  44 , and the storage container  44  is stored in the sterilization bag  46 . 
     Next, the package  72  undergoes sterilization treatment. In the present embodiment, autoclave sterilization is performed as the sterilization treatment. In autoclave sterilization, water vapor as a sterilizing gas permeates through the sterilization bag  46 , so as to allow the syringe assembly  42  in the storage container  44  to be sterilized. In addition, the silicone oil  27  applied to the barrel inner surface  18   a  has a reduced viscosity due to the heat generated at autoclave sterilization. That is, in the present embodiment, the autoclave sterilization also serves as a heating step of heating the silicone oil  27  applied to the barrel inner surface  18   a  to reduce its viscosity in a state in which the barrel  12  is not filled with liquid. 
     At this time, because the drug solution is not filled in the barrel  12 , the silicone oil  27  with reduced viscosity is greatly influenced by surface tension and gravity. This allows the silicone oil  27  to spread out in a direction of a wall surface (barrel inner surface  18   a ) and the direction of gravity, leading to uniformization of the silicone oil distribution on the barrel inner surface  18   a.    
     After completion of sterilization of the package  72 , the package  72  is stored in the outer wrap  48  with its mouth portion open, and then, the mouth portion of the outer wrap  48  is sealed, so as to store the package  72  in the outer wrap  48 . This achieves acquisition of the medical package  40  illustrated in  FIG. 4 . 
     Note that while the above example is a case where autoclave sterilization is performed as a sterilization treatment, and the silicone oil  27  applied to the barrel inner surface  18   a  is heated by the heat generated at autoclave sterilization so as to reduce the viscosity, the heating of the silicone oil  27  may be performed by thermal treatment other than autoclave sterilization. In this case, the sterilization treatment may be ethylene oxide sterilization, electron beam sterilization, or the like. 
     As described above, according to the present embodiment, the silicone oil  27  applied to the barrel inner surface  18   a  is heated to reduce the viscosity, so as to allow the silicone oil  27  to spread out in a direction of the barrel inner surface  18   a  and the direction of gravity. This uniformizes the silicone oil distribution on the barrel inner surface  18   a , making it possible to suppress the sliding resistance of the gasket  16  inserted into the barrel  12 . 
     In this case, excessively high viscosity of the silicone oil  27  applied to the barrel inner surface  18   a  would lead to difficulty in reducing the viscosity even by the heat generated at heat treatment and in achieving uniformity in the silicone oil  27 . Conversely, excessively low viscosity of the silicone oil  27  would allow the silicone oil  27  to flow excessively in the direction of gravity during the heat treatment. In the present embodiment, the silicone oil  27  having a viscosity of 3000 cps to 30000 cps is applied to suitably reduce the viscosity of the silicone oil  27  at the time of heat treatment, so as to achieve effective uniformization of the silicone oil distribution. 
     Furthermore, in the present embodiment, the silicone oil  27  is applied to the barrel inner surface  18   a  with a coating amount rate of 0.02 mg/cm 2  to 0.2 mg/cm 2 , making it possible to allow the silicone oil  27  to uniformly spread over the barrel inner surface  18   a  without excessively applying the silicone oil  27 . 
     In addition, because it is possible to avoid excessive application of the silicone oil  27  and the silicone oil  27  is not formed as large particles, outflow of the silicone oil  27  into the drug solution in the prefilled syringe  10 A is expected to be suppressed. Because the silicone oil  27  flowing out into the drug solution would cause aggregation of the protein preparation, it is particularly preferable to suppress outflow of the silicone oil  27  into the drug solution in a case of filling the protein preparation. Moreover, because the particles of the silicone oil  27  are greatly reduced, it is possible to prevent bubbles generated at the time of filling the drug in the filling chamber  13  of the barrel  12  from being caught on the barrel inner surface  18   a . This makes it possible to suppress false detection of foreign matter due to bubbles at the time of foreign matter inspection of the prefilled syringe  10 A. 
     In addition, because the silicone oil  27  applied to the barrel inner surface  18   a  is not spread or smoothed with a tool such as a squeegee to achieve uniformity in the silicone oil distribution, it is possible to obtain the barrel  12  on which the silicone oil  27  is uniformly applied without generation of scratches or adhesion of foreign matter on the barrel inner surface  18   a.    
     With the present embodiment, the silicone oil  27  is heated at the time of autoclave sterilization for the barrel  12 , making it possible to omit providing a dedicated step for heating the silicone oil  27 . Therefore, it is possible to efficiently manufacture the barrel  12  with the silicone oil  27  applied with high uniformity. In addition, autoclave sterilization can suppress degradation of the barrel  12  as compared with other sterilization treatments such as electron beam sterilization, making it possible to suppress adverse effects on the drug solution filled in the barrel  12 . 
     In the present embodiment, the heating step is performed in a state in which the barrel  12  faces up and down directions. This allows the silicone oil  27  to spread out in a barrel  12  axial direction due to gravity at the time of heating, leading to higher uniformity in the silicone oil distribution. 
     When the silicone oil  27  is applied to the barrel inner surface  18   a  by spraying, the coating amount rate of the silicone oil  27  is increased toward the side closer to the spray nozzle  70  (refer to  FIG. 5B ), and the mass of the silicone oil  27  is likely to be formed. In the present embodiment, the application step is performed such that the silicone oil  27  is sprayed from the first end side (proximal end opening portion  21  side) of the barrel  12  toward the second end side (nozzle  20  side) to allow the silicone oil  27  to be applied to the barrel inner surface  18   a , while the heating step is performed with the second end side facing downward. With this method, heating is performed with the side opposite to the spraying side facing downward, allowing the mass of the silicone oil  27  to spread out from the first end side of the barrel  12  toward the second end side due to gravity. This makes it possible to effectively achieve higher uniformity in the silicone oil distribution. 
     In the present embodiment, the silicone oil  27  is applied to a portion from the vicinity of the proximal end opening portion  21  beyond the insertion position P up to the position closer to the shoulder portion  19 . With this configuration, the silicone oil  27  is applied up to the vicinity of the proximal end opening portion  21 , making it possible to plug the gasket  16  quickly and reliably up to the insertion position P at the time of vacuum plugging. 
     In particular, in the present embodiment, the silicone oil  27  is applied up to the vicinity of the shoulder portion  19 . With this configuration, the silicone oil  27  is applied to substantially an entire region of the barrel inner surface  18   a  on which the gasket  16  slides before discharging the drug, making it possible to suppress the sliding resistance of the gasket  16  up to the end. 
     In addition, in the present embodiment, the average value of the coverage at a portion from the vicinity of the shoulder portion  19  up to the insertion position P is 10% or less, making it possible to further suppress the sliding resistance of the gasket  16 . 
     In order to confirm the effects of the embodiments described above, the following test was performed. 
     In the test, 0.6 mg of silicone oil was dispensed from a spray nozzle in a form of mist to be applied to the barrel inner surface with the spray nozzle arranged to face the proximal end opening portion of the barrel having a capacity of 2.25 mL. The silicone oil used was DOW CORNING (R) 360 MEDICAL FLUID, 12500 CST (manufactured by Dow Corning Corporation, viscosity: 12500 cst). 
     Ten barrels with the silicone oil applied to the inner surface in this manner were prepared. Among the ten barrels, five barrels (samples A 1  to A 5 ) are each provided with a cap attached and without water filled therein, while the other five barrels (samples B 1  to B 5 ) are each provided with a cap attached and with water filled. Thereafter, the gasket was inserted into the barrels and sealed. 
     Subsequently these samples A 1  to A 5  and B 1  to B 5  underwent autoclave sterilization (121° C., 20 minutes) and are then dried. Autoclave sterilization was performed with the barrel nozzle facing downward and the barrel kept in a substantially vertical posture. For samples B 1  to B 5  filled with water, the water in each of the barrels was removed after sterilization and drying. 
     For each of the samples, silicone oil distribution on the barrel inner surface was measured by the above-described zebra pattern measurement scheme and then evaluated. The measurement instrument used was ZS-S40 Bench Top Silicone Detection System (manufactured by ZEBRASCI). In the measurement, photographing was performed six times while the barrel was rotated by 63° to measure the entire barrel, and then, an overlapping portion (corresponding to 18°) was removed. In addition, the silicone oil application region on the barrel inner surface was divided into 35 sections in the axial direction, and the coverage was measured for each of the sections. From the results obtained, it was investigated how the silicone oil distribution in the barrel changes before and after sterilization. 
       FIGS. 7A to 7D  are graphs illustrating silicone oil distribution before autoclave sterilization of samples A 1  to A 4  that were not filled with water.  FIGS. 8A to 8D  are graphs illustrating silicone oil distribution after autoclave sterilization of samples A 1  to A 4  that were not filled with water. In each of the graphs, the horizontal axis indicates the section number corresponding to the position of the barrel in the axial direction (left side is the shoulder portion side and the right side is the proximal end opening portion side), while the vertical axis indicates the coverage in each of the positions (sections). From the graphs of  FIGS. 7A to 7D , it is observed that the coverage is high on the proximal end side of the barrel close to the spray nozzle (oil dispense portion) before autoclave sterilization, and that the silicone oil distribution is not uniform. 
     In contrast, it is observed from the graphs of  FIGS. 8A to 8D  that, after autoclave sterilization of the samples A 1  to A 4  that were not filled with water, the coverage was 20% or less even at maximum, and that the silicone oil distribution is uniform. In addition, the average coverage after autoclave sterilization was 10% or less in each of the samples. Note that, although not illustrated here, it was observed from the images before and after sterilization of each of sample A 1  to A 4  that mass of silicone oil has spread out to the cap side by sterilization. 
       FIGS. 9A to 9D  are graphs illustrating silicone oil distribution before autoclave sterilization of samples B 1  to B 4  that were filled with water.  FIGS. 10A to 10D  are graphs illustrating silicone oil distribution after autoclave sterilization of samples B 1  to B 4  that were filled with water. From these graphs, it was observed that sterilization increases the coverage. In addition, although not illustrated here, the mass of silicone oil did not seem to have spread out before and after sterilization on the basis of an image before and after sterilization of each of samples B 1  to B 4 . This coverage increase by sterilization is presumed to be caused by aggregation of the silicone oil during sterilization due to water pressure. Note that the excessively high coverage in a region on the proximal end opening portion side in the graph after sterilization of the sample filled with water (particularly,  FIGS. 10B to 10D ) is presumed to be caused by extrusion of the silicone oil on the proximal end opening portion side at the time of insertion of the gasket into the barrel. For this reason, this region was excluded from the evaluation target. 
     The difference in silicone oil distribution due to the presence or absence of water filling as described above can be considered and explained as follows. That is, in the barrels (samples A 1  to A 4 ) not filled with water, the viscosity of the silicone oil is reduced by heat generated at sterilization, and the oil is greatly influenced by surface tension and gravity. As a result, the silicone oil spreads out in the direction of the wall surface and the direction of gravity. In contrast, in the barrels filled with water (samples B 1  to B 4 ), the silicone oil is greatly influenced by water pressure at this time although the viscosity of the silicone oil is reduced by the heat during sterilization. As a result, the silicone oil is aggregated. 
     From the above test results, it was observed that the silicone oil applied to the barrel not filled with water achieves higher uniformity by heat treatment. In contrast, it was observed that the silicone oil applied to the barrel filled with water hardly moved or even aggregated after heat treatment. 
     As described above, in a case where heat treatment (for example, autoclave sterilization) is performed without the drug solution filled, the distribution of the silicone oil  27  applied to the barrel inner surface  18   a  achieves higher uniformity as compared with the case where the heat treatment is performed with the drug solution filled. This characteristic contributes to enhancement of the slidability of the gasket  16  inserted into the barrel  12 . 
     Note that, while, in the above-described embodiment, the barrel  12  is configured as a barrel for the prefilled syringe  10 A prefilled with the drug M, the concepts described herein can also be applied to a syringe barrel not prefilled with the drug M. 
     In addition, the nozzle  20  is not particularly limited as long as it has a shape capable of discharging the drug M in the barrel  12 , and thus, may have a shape of a male luer that can be inserted and connected to a female luer, a shape having a lock adapter around the male luer, and a shape in which an injection needle is directly fixed inside the nozzle. Alternatively, the barrel  12  may have a cylindrical shape having no nozzle and having a distal end opening portion at the second end opposite to the proximal end opening portion  21 . In this case, a sealing member for sealing the distal end opening portion would be attached to the second end (distal end) of the barrel  12  and used together with a needle hub or the like having a double-ended needle. 
     The present invention is not limited to the above-described embodiments, and various modifications are possible without departing from the scope and spirit of the present invention.