JP2020074855A - Syringe, and prefilled syringe using the same - Google Patents

Abstract

To provide a syringe capable of achieving both airtightness and slidability between a stopper and an inner surface of a syringe barrel without using a lubricant such as silicone oil, and to provide a prefilled syringe capable of preventing denaturation of a liquid chemical by using the syringe.SOLUTION: A syringe comprises: a syringe barrel (10) having a spout part and an opening; a stopper (20) having a contact part in contact with the inner surface of the syringe barrel and inserted from the opening of the syringe barrel; a plunger (30) attached to the stopper; and a cap (40) attached to the spout part of the syringe barrel. The syringe barrel has a laminated structure, a surface roughness of the inner surface of 4nm-30nm at an arithmetic average roughness (Ra). The stopper comprises a body composed of an elastic body, and a laminate film laminated on the body, and has in the contact part a groove disposed along the circumferential direction of the stopper, and a surface roughness of the contact part of 20nm-100nm at an arithmetic average roughness (Ra).SELECTED DRAWING: Figure 1

Description

  The present invention relates to a syringe and a prefilled syringe using the syringe.

  2. Description of the Related Art Conventionally, a glass prefilled syringe has been used as a medical packaging container for filling and storing a drug solution in a hermetically sealed state at a medical site or the like. The prefilled syringe has a medical solution necessary for treatment filled in advance in the syringe, and removes the cap fitted to the barrel tip of the syringe barrel (hereinafter referred to as “pouring part”) from which the medical solution is poured out during use. It is a syringe configured to attach an injection needle to a dispensing portion. The prefilled syringe does not require the operation of once sucking the drug solution stored in the ampoule or the vial with the syringe. Therefore, the use of the prefilled syringe can be expected to prevent foreign substances from being mixed into the drug solution, improve the efficiency of medical work, and prevent medical accidents such as erroneous administration of the drug solution. Conventionally, glass has been used for syringe barrels and the like used for prefilled syringes.

  However, in the case of a glass prefilled syringe, sodium ions etc. elute in the content liquid in the container during storage, a minute substance called flakes is generated, and when using a light-shielding glass container colored with metal, There are problems that the coloring metal is mixed in the contents, and that the metal easily breaks due to an impact such as dropping. Further, since glass has a relatively large specific gravity, there is a problem that the prefilled syringe becomes heavy.

  In order to solve the above problems, as a glass substitute used for a syringe barrel, a technique using a plastic lighter than glass is being studied. As a prefilled syringe using such a plastic, a container for a prefilled syringe having a laminated structure of a resin layer and an oxygen barrier layer and having an excellent oxygen barrier property has been proposed (for example, refer to Patent Document 1 below).

  Further, when using a syringe, it is required that the stopper slides smoothly. In many syringes, silicone oil or the like is applied as a lubricant to the sliding contact portion on the outer surface of the stopper or the inner surface of the syringe in order to smoothly slide the stopper. However, it is known that some chemicals interact with the lubricant such as silicone oil. It is also known that among such chemicals, if the chemicals are stored for a long period of time after filling, the chemicals will be deteriorated due to the interaction. For this reason, it is difficult to prefill some drugs.

  In particular, in a prefilled syringe that is stored for a long period of time in a state filled with a drug solution, a lubricant-free one that can maintain the stability of the drug solution is desired. Therefore, as a solution to the above problem, it has been proposed to coat the surface of the stopper with a fluorine-based resin having a low friction coefficient (for example, refer to Patent Document 2 below).

JP, 2016-019619, A US Patent No. 7111848

  Although the prefilled syringe of Patent Document 1 improves the oxygen barrier property of the thermoplastic resin container, it requires a lubricant such as silicone oil in order to smoothly slide the stopper, so that the chemical solution by interaction with the silicone oil It was difficult to prevent alteration.

  Moreover, the effect of lowering the sliding resistance is recognized by using the laminate stopper of Patent Document 2. However, not applying a lubricant such as silicone oil has a problem that the airtightness between the stopper and the inner surface of the syringe barrel is lowered, and the chemical liquid is deteriorated.

  In order to solve the above problems, the present invention uses a syringe that does not use a lubricant such as silicone oil and can achieve both airtightness and slidability between a stopper and an inner surface of a syringe barrel, and the syringe. An object of the present invention is to provide a prefilled syringe capable of preventing the deterioration of a drug solution.

  The inventors of the present invention provided a groove on the stopper surface laminated with a film, and when the surface roughness of the inner surface of the syringe barrel and the sliding contact portion of the stopper were within a certain range, excellent sealing performance against liquid and gas was obtained. The present invention has been completed by finding that it is possible to provide a prefilled syringe capable of exhibiting excellent slidability with respect to a stopper while exhibiting the above-mentioned effects.

That is, the present invention is as shown below.
<1> A syringe barrel having a spout and an opening, a stopper having a sliding contact portion in contact with the inner surface of the syringe barrel and inserted from the opening of the syringe barrel, and a plunger attached to the stopper. And a cap attached to the pouring part of the syringe barrel,
The syringe barrel has a laminated structure, and the surface roughness of the inner surface is 4 nm to 30 nm in terms of arithmetic average roughness (Ra),
The stopper includes a main body made of an elastic body, and a laminate film laminated on the main body, and the slide contact portion has a groove arranged along a circumferential direction of the stopper, and A syringe having a surface roughness of the sliding contact portion of 20 nm to 100 nm in terms of arithmetic average roughness (Ra).
<2> The laminated structure of the syringe barrel includes, from the outer surface of the syringe barrel, a first resin layer containing a cyclic polyolefin, a second resin layer containing a polyester having a structural unit containing a tetralin ring, and a cyclic polyolefin. The syringe according to <1>, which includes at least three layers of a third resin layer in this order.
<3> The syringe according to <2>, wherein the second resin layer contains a transition metal catalyst.
<4> The syringe according to any one of <1> to <3>, wherein the depth of the groove of the stopper is 1 μm to 50 μm, and the width of the groove is 1 μm to 100 μm.
<5> The syringe according to any one of <1> to <4>, wherein the laminated film has a thickness of 10 μm to 100 μm.
<6> The syringe according to any one of <1> to <5>, in which the laminate film contains a fluororesin.
<7> The syringe according to <6>, wherein the fluororesin is polytetrafluoroethylene.
<8> A prefilled syringe obtained by filling the syringe according to any one of <1> to <7> with a drug.

  According to the present invention, without using a lubricant such as silicone oil, a syringe capable of achieving both airtightness and slidability between a stopper and an inner surface of a syringe barrel, and prevention of alteration of a chemical solution using the syringe. It is possible to provide a prefilled syringe that can be used.

It is a schematic diagram showing composition at the time of storage of a syringe of this embodiment. It is a schematic diagram for explaining a laminated structure of a cylindrical body. 3A is a plan view of the stopper 20 in FIG. 3B as viewed from above in the drawing, and FIG. 3B is a sectional view of the stopper 20 taken along the sliding direction. It is a schematic diagram for explaining a groove provided in a sliding contact portion. 5 is an atomic force microscope observation image of the inner surface of the syringe barrel in Example 1. 6 is an atomic force microscope observation image of the inner surface of the syringe barrel in Comparative Example 1.

  Hereinafter, modes for carrying out the present invention (hereinafter, simply referred to as “the present embodiment”) will be described in detail. The following embodiments are examples for explaining the present invention, and are not intended to limit the present invention to the following contents. The present invention can be appropriately modified and implemented within the scope of the gist.

<Structure of syringe>
The configuration of the syringe of this embodiment will be described. The following configuration is one mode showing the syringe of the present embodiment, and the syringe of the present invention is not limited to the configuration below.

  FIG. 1 is a schematic diagram showing the configuration of the syringe of this embodiment during storage. As shown in FIG. 1, the syringe 100 includes a syringe barrel 10, a stopper 20, a plunger 30, and a cap 40. The syringe 100 is a so-called prefilled syringe that accommodates the drug solution 18 in a sealed state.

  The syringe barrel 10 has a cylindrical main body 12 as shown in FIG. 1, and a drug solution 18 is contained therein. The cylindrical main body 12 is a syringe barrel having the same diameter along the same direction with the XX 'line in FIG. 1 as the central axis. Further, the tubular main body 12 has a pouring portion 14 for pouring (discharging) the chemical liquid 18 at the tip, and has an opening 16 into which the stopper 20 is inserted at the other end.

  As shown in FIG. 2, the tubular body 12 has a laminated structure. FIG. 2 is a schematic diagram for explaining the laminated structure of the tubular main body 12. The tubular main body 12 in the present embodiment has a three-layer structure in which the oxygen barrier layer A1 is laminated between the resin layers B1 and B2 (skin layers) so that the oxygen barrier layer A1 serves as an intermediate layer (core layer). Although materials used for the resin layers and the oxygen barrier layer will be described later, it is preferable that at least the resin layer B1 forming the inner surface (innermost layer) of the tubular body 12 contains a cycloolefin polymer. The syringe 100 of the present embodiment has excellent gas barrier properties because the syringe barrel 10 has the oxygen barrier layer A1.

  Next, as shown in FIG. 1, a cap 40 is fitted to the pouring portion 14 of the tubular body 12 when the syringe 100 is stored. When the syringe 100 is used, the cap 40 is removed and the injection portion 14 is fitted with an injection needle. The spout 14 is formed of a portion having a diameter smaller than that of the cylindrical main body 12, and may be formed in a tapered shape.

  The stopper 20 is attached to one end of the plunger 30, and is installed so as to be slidable in the syringe barrel 10 along the line XX 'in FIG. As described above, the stopper 20 is inserted through the opening 16 of the syringe barrel 10, and is pushed and moved in the direction from the opening 16 toward the pouring portion 14 (that is, the direction of arrow P in FIG. 1) when the syringe 100 is used. Be done. When the stopper 20 slides in the direction of arrow P, the drug solution 18 in the syringe barrel 10 receives the pressure in the same direction. As described above, when the syringe 100 is used, the injection needle (not shown) is connected to the ejection portion 14, and the drug solution 18 that has received pressure from the stopper 20 is ejected from the injection needle via the ejection portion 14. Be poured out. Although not shown in FIG. 1, a groove arranged in the circumferential direction of the stopper 20 is provided in the sliding contact portion of the stopper 20.

  Next, the surface roughness of the inner surface of the cylindrical main body 12 of the syringe barrel 10 will be described with reference to FIG. In the present embodiment, the surface roughness of the inner surface of the cylindrical main body 12 (in FIG. 2, they are referred to as the inner surface 12A, the inner surface 12B, and the inner surface 12C in order from the tip end side provided with the pouring portion 14 toward the opening side). The arithmetic mean roughness (Ra) is 4 nm to 30 nm. When the surface roughness of the inner surface of the cylindrical body 12 is less than 4 nm in terms of arithmetic average roughness (Ra), the slidability of the stopper 20 with respect to the inner surface of the cylindrical body 12 is poor (that is, when sliding). The load required to push in the plunger becomes large). Further, when the surface roughness of the inner surface of the tubular body 12 exceeds 30 nm in terms of arithmetic average roughness (Ra), the sealing property of the liquid and gas sealed in the syringe barrel 10 is deteriorated. From the viewpoint of further improving (lowering) the slidability between the inner surface of the cylindrical body 12 and the sliding contact portion 24 (see FIG. 3) of the stopper 20 described later, the surface roughness (arithmetic calculation) of the inner surface of the cylindrical body 12 is calculated. The average roughness (Ra) is more preferably 4 nm to 20 nm, particularly preferably 5 nm to 10 nm. The arithmetic mean roughness (Ra) of the inner surface of the cylindrical main body 12 of the syringe barrel 10 described above is measured, for example, using a device such as a surface shape measuring instrument, a laser microscope, an atomic force microscope, and then JIS. It can be calculated by the formula described in B 0601. Specifically, it can be calculated by the method shown in Examples described later. The method of controlling the surface roughness of the inner surface of the tubular body 12 is not particularly limited, but for example, the surface roughness of the mold used to mold the tubular body 12 is set to a desired range, and the tubular body 12 is molded. There is a method of controlling the surface roughness of the inner surface to fall within a desired range. Examples of the method for controlling the surface roughness of the die include a method of adjusting the material of the abrasive, the grain size of the abrasive grains, the polishing load, and the polishing time in the step of polishing the die.

  The inner surface of the cylindrical main body 12 may have at least a surface roughness of a portion in contact with the sliding contact portion 24 of the stopper 20 in a range of arithmetic average roughness (Ra) of 4 nm to 30 nm, but the surface roughness of the entire inner surface is the same. It may be a range. The surface roughness of the inner surface of the tubular body 12 may be uniform in the circumferential direction or the longitudinal direction (the direction of arrow P in FIG. 1), or in the range of arithmetic average roughness (Ra) 4 nm to 30 nm. A difference may be provided. For example, the difference in surface roughness between the inner surface 12A on the pouring portion side, the inner surface 12B on the central portion, and the inner surface 12C on the opening side of the tubular body 12 is about ± 1 to 10 nm in terms of arithmetic average roughness (Ra). There may be a difference.

  Hereinafter, each member will be described.

<Syringe barrel>
The cylindrical main body that constitutes the syringe barrel of the present embodiment has a laminated structure. Although not particularly limited, the laminated structure has at least one layer of an oxygen barrier layer containing a thermoplastic resin (a) (hereinafter, may be simply referred to as “layer A”) and at least one layer of heat. It is preferable to have a resin layer containing the plastic resin (b) (hereinafter, may be simply referred to as “layer B”). The layer structure of the tubular body is not particularly limited, and the number and types of layers A and B are not particularly limited. The layer A may be referred to as a core layer and the layer B may be referred to as a skin layer. For example, a layer (layer B) containing at least two layers of the thermoplastic resin (b), and the oxygen barrier layer (layer A) containing two layers of the thermoplastic resin (b) (layer B). It may be a three-layer structure arranged between the two (B / A / B structure). That is, the tubular body in the present embodiment may have an A / B structure composed of one layer A and one layer B as described above, and may include one layer A and two layers B. The B / A / B structure may have a three-layer structure. Further, it may have a five-layer structure of B1 / B2 / A / B2 / B1 consisting of one layer A and layer B1 and layer B2 of two kinds and four layers. Furthermore, the tubular body in the present embodiment may include an optional layer such as an adhesive layer (layer AD) as necessary, and for example, has a seven-layer structure of B1 / AD / B2 / A / B2 / AD / B1. May be The layer structure of the tubular body preferably has at least three layers such as a B / A / B structure. More specifically, it is preferable that the tubular body has a laminated structure of three or more layers, and that an intermediate layer containing polyester having a tetralin skeleton is provided as an oxygen barrier layer.

<Oxygen barrier layer (layer A)>
For the oxygen barrier layer (layer A), as the thermoplastic resin (a), an oxygen barrier resin in a narrow sense (so-called passive barrier resin) having a property of simply not permeating oxygen may be used, or it may have oxygen absorbability. An oxygen-absorbing resin composition (so-called active barrier resin composition) that can prevent oxygen permeation into the inside by absorbing oxygen that permeates from the outside may be used. For example, the oxygen-barrier resin may be polyester or polyamide, and the oxygen-absorbing resin composition may be a composition containing polyester having a unit structure containing a tetralin ring and a transition metal catalyst.

The glass transition temperature (Tg ¹ ) of the thermoplastic resin (a) is preferably 50 ° C to 160 ° C, more preferably 55 ° C to 140 ° C, and further preferably 60 ° C to 120 ° C. .. When the glass transition temperature (Tg ¹ ) of the thermoplastic resin (a) is within the above temperature range, a good syringe barrel can be manufactured from the viewpoint of heat resistance and moldability.

(Composition containing polyester and transition metal catalyst)
The polyester is not particularly limited, and examples thereof include those having a structural unit containing a tetralin ring. It is also possible to use a polyester having a structural unit containing a tetralin ring that does not contain a transition metal catalyst as the oxygen barrier resin.

-Tetralin ring-containing polyester compound-
When the oxygen barrier layer (layer A) contains a composition containing polyester and a transition metal catalyst, it can be formed using, for example, a composition containing a polyester compound having a tetralin ring as a constituent unit. As the composition containing the polyester compound (a1) having a tetralin ring as a constituent unit and a transition metal catalyst, the composition described in International Publication No. 2013/077436 may be used.

  The polyester compound and the transition metal catalyst can be mixed by a known method, but preferably, they are kneaded by an extruder. This makes it possible to obtain an oxygen-barrier resin composition having good dispersibility. Further, in the oxygen barrier resin composition, a drying agent, a pigment, a dye, an antioxidant, a slip agent, an antistatic agent, a stabilizer; calcium carbonate, clay, mica, Other additives such as a filler such as silica and a deodorant may be added, but various materials can be mixed without being limited to those shown above.

(Other)
The oxygen barrier layer (layer A) may further contain a radical generator or a photoinitiator in order to enhance the oxygen barrier performance. Further, the oxygen-barrier resin composition can be kneaded with a thermoplastic resin other than the above-mentioned thermoplastic resin in an extruder as long as the object of the present embodiment is not impaired. Known materials can be used as these radical generator, photoinitiator, and other thermoplastic resins. Examples of the radical generator include N-hydroxyimide compounds such as N-hydroxysuccinimide and N-hydroxymaleimide. Examples of the photoinitiator include benzophenone and its derivative, thiazine dye, metalloporphyrin derivative, and anthraquinone derivative. Examples of other thermoplastic resins include polyolefins typified by polyethylene, ethylene-vinyl compound copolymers, styrene resins, polyvinyl compounds, polyamides, polyesters and polycarbonates.

  The content of the polyester or the composition containing the polyester and the transition metal catalyst in the oxygen barrier layer (layer A) is not particularly limited, but is preferably 50% by mass or more, more preferably 70% by mass or more, and 90% by mass or more, respectively. A mass% or more is particularly preferable. In the case of the above range, the oxygen barrier performance can be further enhanced as compared with the case of less than 50% by mass.

The thickness of the oxygen barrier layer (layer A) is not particularly limited, but is preferably 10 to 1000 μm, more preferably 20 to 800 μm, and further preferably 50 to 700 μm. By controlling the thickness of the layer A within the above range, the oxygen barrier property of the layer A can be further enhanced and the economical efficiency can be prevented from being impaired. The oxygen permeability coefficient of the oxygen barrier layer (layer A) is preferably 0.5 mL / (mm · m ² · day · atm) or less, which is obtained by a method based on JIS K 7126.

<Layer containing thermoplastic resin (b) (Layer B)>
In this embodiment, the layer B is a layer containing the thermoplastic resin (b). Unless otherwise specified, the layers B1 and B2 are collectively referred to as "layer B". Similarly, when the thermoplastic resins (b1) and (b2) are shown, these are collectively referred to as "thermoplastic resin (b)". The thermoplastic resin (b) is a thermoplastic resin other than the thermoplastic resin (a). The content of the thermoplastic resin (b) in the layer B is not particularly limited, but is preferably 70 to 100% by mass, more preferably 80 to 100% by mass, and further preferably 90 to 100% by mass. In the case where there are a plurality of layers containing the thermoplastic resin (b), such as the layers B1 and B2, the content of the thermoplastic resin (b) in the layer B here means the heat of each layer. It means the content of the plastic resin (b).

  The syringe barrel of this embodiment may have a plurality of layers B as described above. When a plurality of layers B are provided, the configurations of the layers B may be the same or different from each other. The thickness of the layer B can be appropriately determined depending on the application. Usually, from the viewpoint of securing various physical properties such as strength required for the syringe barrel such as drop resistance, the thickness of one layer B is preferably 30 μm to 1000 μm, more preferably 50 μm to 800 μm, More preferably, it is 100 μm to 500 μm.

  As the thermoplastic resin (b), any thermoplastic resin other than the thermoplastic resin (a) can be used and is not particularly limited. Specific examples of the thermoplastic resin (b) include known polyolefins, polyesters, polyamides, ethylene-vinyl alcohol copolymers, plant-derived resins and chlorine-based resins. The thermoplastic resin (b) preferably contains at least one selected from the group consisting of these resins. Of these, polyolefin is preferred. As a more specific preferred example, a cyclic polyolefin is preferable, for example, a copolymer of norbornene and an olefin such as ethylene as a raw material; a cycloolefin that is a copolymer of tetracyclododecene and an olefin such as ethylene as a raw material. A copolymer (COC) etc. are mentioned. Further, cycloolefin polymer (COP) which is a polymer obtained by ring-opening polymerization of norbornene and hydrogenation is also particularly preferable. As such COC and COP, those described in, for example, JP-A-5-300939 and JP-A-5-317411 can be used.

  A commercially available product can be used as the COC. For example, Apel (registered trademark) manufactured by Mitsui Chemicals, Inc. is commercially available. A commercially available product can be used as the COP. For example, it is commercially available as ZEONEX (registered trademark) manufactured by ZEON CORPORATION. COC and COP show chemical characteristics such as heat resistance and light resistance and chemical resistance as characteristics of a polyolefin resin, and physical characteristics such as mechanical characteristics, melting, flow characteristics, and dimensional accuracy as amorphous resins. It is a particularly preferable material because of its characteristics.

The glass transition temperature (Tg ² ) of the thermoplastic resin (b) is preferably −10 to + 20 ° C., and −5 to + 15 ° C. with respect to the glass transition temperature (Tg ¹ ) of the thermoplastic resin (a). More preferably, it is more preferably ± 0 to + 10 ° C. When the glass transition temperature (Tg ² ) of the thermoplastic resin (b) is within the above temperature range with respect to the glass transition temperature (Tg ¹ ) of the thermoplastic resin (a), in the multilayer molding with the thermoplastic resin (a). A molded article having a good appearance can be produced.

<Other>
In addition to the oxygen barrier layer (layer A) and the layer containing the thermoplastic resin (b) (layer B), the tubular body of the syringe barrel may further include any layer depending on desired performance and the like. Good. Examples of such an optional layer include an adhesive layer (layer AD). For example, in the case where the layer B is formed on the layer A, even if the layer B is formed on the layer A via the layer AD (layer A / layer AD / layer B) Good.

  In the tubular body of the syringe barrel, when practical interlayer adhesive strength cannot be obtained between two adjacent layers, an adhesive layer (layer AD) can be provided between the two layers. The adhesive layer preferably contains a thermoplastic resin having adhesiveness. As the thermoplastic resin having adhesiveness, for example, a polyolefin resin such as polyethylene or polypropylene is modified with an unsaturated carboxylic acid such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, fumaric acid or itaconic acid. Polyolefin resin: A polyester-based thermoplastic elastomer containing a polyester-based block copolymer as a main component, and the like. From the viewpoint of adhesiveness, it is preferable to use, as the adhesive layer, a modified resin of the same kind as the thermoplastic resin used as the layer B. The thickness of the adhesive layer is preferably 2 to 100 μm, more preferably 5 to 90 μm, and further preferably 10 to 80 μm from the viewpoint of ensuring molding processability while exhibiting practical adhesive strength. ..

  The manufacturing method of the syringe barrel in the present embodiment is not particularly limited, and it can be manufactured by a normal injection molding method. For example, by using a molding machine equipped with two or more injection machines and an injection mold, the material forming the layer A and the material forming the layer B are passed through the mold hot runners from the respective injection cylinders and then the inside of the cavity. Then, a syringe barrel corresponding to the shape of the injection mold can be manufactured.

Further, first, the material forming the layer B is injected from an injection cylinder, then the material forming the layer A is injected from another injection cylinder at the same time as the resin forming the layer B, and then the resin forming the layer B. A syringe barrel having a three-layer structure B / A / B can be manufactured by injecting a necessary amount of the above to fill the cavity.
Examples of such a configuration include, from the outer surface of the syringe barrel 10, a first resin layer containing a cyclic polyolefin, a second resin layer containing a polyester having a structural unit containing a tetralin ring, and a third resin layer containing a cyclic polyolefin. A laminated structure including at least three resin layers in this order may be mentioned.

  Further, first, by injecting the material forming the layer B, then injecting the material forming the layer A alone, and finally injecting the necessary amount of the material forming the layer B to fill the mold cavity, A syringe barrel having a five-layer structure B / A / B / A / B can be manufactured.

  Further, first, the material forming the layer B1 is injected from an injection cylinder, then the material forming the layer B2 is injected from another injection cylinder at the same time as the resin forming the layer B1, and then the resin forming the layer A. Is injected at the same time as the resin forming the layers B1 and B2, and then the required amount of the resin forming the layer B1 is injected to fill the cavity, whereby a syringe barrel having a five-layer structure B1 / B2 / A / B2 / B1. Can be manufactured.

<Stopper>
The stopper in this embodiment includes a main body made of an elastic body and a laminate film laminated on the surface. Further, the stopper has a sliding contact portion on its surface, which is in contact with the inner surface of the syringe barrel. Further, as shown in FIG. 3, the sliding contact portion 24 is provided with a groove 25 arranged along the circumferential direction of the stopper 20. The syringe 100 has good air-tightness, liquid-tightness and liquid-tightness by combining a syringe barrel 10 having an inner surface having a prescribed surface roughness and a stopper 20 having a groove formed in a sliding contact portion and having a prescribed surface roughness. The slidability can be exhibited.

  The structure of the stopper 20 will be described with reference to FIG. FIG. 3 shows the structure of the stopper 20 in the present embodiment, FIG. 3a is a plan view of the stopper 20 in FIG. 3b observed from the upper side of the drawing, and FIG. 3b is a sectional view of the stopper 20 along the sliding direction. is there. Although not shown in FIG. 3b, the stopper 20 is attached to the tip of the plunger 30 as shown in FIG. 1, and the user of the syringe 100 moves the plunger 30 to the arrow in FIG. The stopper 20 is configured to slide while being in contact with the inner surface of the syringe barrel 10 by being pushed in the P direction. The stopper 20 has a liquid contact portion 22 at the tip (the end surface of the stopper 20 in the upward direction of the paper surface in FIG. 3B), and is in contact with the drug solution 18 in the syringe barrel 10. Further, as shown in FIG. 3, the stopper 20 has a sliding contact portion 24 having an annular rib structure. The sliding contact portion 24 of the stopper 20 is in close contact with the inner surface of the syringe barrel 10, so that the chemical solution 18 can be hermetically stored in the syringe barrel 10. Although not shown, a laminate film containing polytetrafluoroethylene or the like is laminated on the surfaces of the liquid contacting portion 22 and the sliding contact portion 24 of the stopper 20. Further, the liquid contacting portion 22 of the stopper 20 may be provided with a protrusion 26.

  As shown in FIG. 3B, the surface of the sliding contact portion 24 of the stopper 20 is arranged in the circumferential direction (the direction of the water surface of the paper in FIG. 3B (the direction along the arrow S about the XX ′ axis)). An arranged groove 25 is provided. By providing the groove 25 in the sliding contact portion 24 along the circumferential direction of the stopper 20, a uniform effect can be obtained in terms of chemical liquid sealing. This is because the compressive stress in the injection cylinder is increased in the peripheral portion of the groove 25, and therefore, it is presumed that by providing the groove 25 in the circumferential direction, the compressive stress is increased over the entire sliding contact portion, and a uniform sealing effect can be obtained. To be done. In the present embodiment, a continuous annular groove 25 is provided over the entire circumference of the sliding contact portion 24. However, the groove 25 may be a groove that is discontinuous in the circumferential direction as long as the effect of the present invention is not affected. Furthermore, in the stopper shown in FIG. 3, there is one groove 25 continuous in the circumferential direction, but the number of grooves 25 is not limited and two or more grooves may be formed. The groove 25 is preferably provided so as to be substantially perpendicular to the XX 'axis in FIG. As long as the groove 25 is provided on the surface of the sliding contact portion 24, its position (position in the direction along the XX 'axis (position in the vertical direction on the paper surface in FIG. 3)) is not particularly limited.

The cross-sectional shape of the groove 25 and its width and depth will be described with reference to FIG. FIG. 4 is a schematic diagram for explaining the groove 25 provided in the sliding contact portion 24. The cross-sectional shape of the groove 25 is not particularly limited, but from the viewpoint of productivity, a simple concave shape having a rectangular groove cross section or a rounded concave shape having a U-shaped groove cross section is preferable. The width of the groove 25 is preferably 1 to 100 μm, more preferably 5 to 50 μm. Here, the “groove width” means the distance indicated by W in FIG. Note that W is in a direction parallel to the XX 'axis in FIG. Further, when the width of the groove 25 varies along the depth direction of the groove 25 (the direction indicated by the arrow D in FIG. 4), the “groove width” is the value when W is measured at any three points. Means its average value in.
The depth of the groove 25 is preferably 1 μm to 50 μm, more preferably 5 μm to 15 μm. Here, the “groove depth” means the distance indicated by D in FIG. 4, and is the distance from the bottom surface of the groove 25 to the surface flush with the surface of the sliding contact portion. Note that D is a direction perpendicular to the XX 'axis in FIG. Further, when the depth of the groove 25 varies along the width direction of the groove 25 (the direction indicated by the arrow W in FIG. 4), the “groove depth” is measured at three arbitrary points with respect to D. It means the average value at the time. By setting the width and the depth of the groove 25 within the above ranges, it is possible to achieve both the airtightness and the slidability of the syringe 100.

  The method of forming the groove 25 is not particularly limited, and a conventionally known method such as cutting with a blade, cutting with a laser beam, cutting with an ultrasonic wave can be used. Among them, cutting with a laser beam is preferable because it can easily form a fine groove structure and has little influence on the periphery of the groove.

As the elastic body that constitutes the main body of the stopper, for example, a rubber composite can be used. The rubber used as the raw material of the rubber composite includes butyl rubber, isoprene rubber, butadiene rubber, styrene butadiene rubber, natural rubber, chloroprene rubber, nitrile rubber such as acrylonitrile butadiene rubber, hydrogenated nitrile rubber, norbornene rubber, ethylene. Propylene rubber, ethylene-propylene-diene rubber, acrylic rubber, ethylene / acrylate rubber, fluororubber, chlorosulphonated polyethylene rubber, epichlorohydrin rubber, silicone rubber, urethane rubber, polysulfide rubber, phosphansen rubber or 1,2- Polybutadiene or the like is used.
These may be used individually by 1 type and may be used in combination of 2 or more type.

  The rubber used in the rubber composite is not limited to the above materials, but butyl rubber is preferable because it is excellent in gas permeation resistance and water vapor permeation resistance. A known compound may be used as the butyl rubber, and examples thereof include isobutylene-isoprene copolymer rubber, halogenated isobutylene-isoprene copolymer rubber (hereinafter referred to as "halogenated butyl rubber"), or a modified product thereof. Examples of the modified product include a bromide of a copolymer of isobutylene and p-methylstyrene. Of these, halogenated butyl rubber is more preferable, and chlorinated butyl rubber or brominated butyl rubber is still more preferable, because it is easily crosslinked.

  The laminate film preferably contains a fluororesin. The fluororesin is not particularly limited, but from the viewpoint of obtaining good chemical resistance, polytetrafluoroethylene (PTFE), modified polytetrafluoroethylene (modified PTFE; 4F monomer and a trace amount of perfluoroalkoxide are used. Copolymer), tetrafluoroethylene / ethylene copolymer (ETFE)), tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA), and polychlorotetrafluoroethylene (PCTFE). Fluorine-based resins and / or olefin-based resins are preferable, and polytetrafluoroethylene (PTFE) is particularly preferable.

  The thickness of the laminate film laminated on the body of the stopper is preferably thin from the viewpoint of obtaining elasticity of the stopper, but if it is excessively thin, tearing occurs during molding, so 10 μm to 100 μm is preferable, and 20 μm to 50 μm is preferable. More preferable.

The stopper 20 may have only one annular rib serving as the sliding contact portion 24, or may have a plurality of annular ribs. For example, the stopper 20 shown in FIG. 3 has two annular ribs, and has a front annular rib and a rear annular rib. The number of annular ribs may be one, or may be three or more.
The shape of the sliding contact portion 24 is not particularly limited. When a plurality of annular ribs are provided as the sliding contact portion 24, the length of the sliding contact portion of the entire stopper with respect to the length of the sliding contact portion of the tip annular rib is not particularly limited, and the radius of curvature of the tip corner portion of the tip annular rib is not limited. The radius of curvature of the rear end corner is not particularly limited. The cross section of the sliding contact portion of the tip annular rib may be expanded substantially linearly or may be reduced in diameter along the length direction of the stopper, or the diameter may not be changed. The diameter of the tip annular rib may be larger, smaller, or substantially the same as the diameter of the annular rib other than the tip.

The compressibility of the annular rib is preferably 2 to 8% with respect to the syringe inner diameter, and more preferably 3 to 7%. If it is less than 2%, the liquid tightness and airtightness are inferior, and if it exceeds 8%, it is difficult to plug the barrel, and wrinkles occur on the film on the surface of the annular rib, resulting in poor liquid tightness and high sliding resistance. There is a tendency to become. The compression rate is calculated by the following formula. The compression rate may be uniform along the longitudinal direction of the tubular body 12 (direction of arrow P in FIG. 1) or may be different. For example, the compression rate may be designed to gradually decrease from the opening side toward the pouring side.

Compressibility (%) = ((annular rib diameter)-(barrel inner diameter)) / (annular rib diameter) x 100

It is also possible to polish the surface of the laminated film in the circumferential direction after forming the laminated stopper into the shape of the stopper. By polishing the film surface after molding in the circumferential direction, it is possible to eliminate fine scratches in the sliding direction that occur during molding and demolding, and contribute to the improvement of airtightness and liquid tightness. Examples of the method of polishing include a method of rubbing with a polymer cloth and a method of polishing with a substrate using fine abrasive particles. Examples of the polymer cloth include cotton cloth and rayon cloth. Examples of the fine abrasive particles include alumina, silicon carbide, diamond and the like. The polishing direction is preferably the circumferential direction. When the stopper has a plurality of annular rib structures, it is preferable to polish at least the entire tip annular rib. The degree of polishing depends on the ratio of the arithmetic mean roughness Ra // of the stopper surface to the arithmetic mean roughness Ra⊥ of the sliding direction, the maximum circumferential height Ry // of the stopper surface and the maximum sliding direction. The difference in height Ry⊥ can be used as an index.
The average arithmetic roughness (Ra) of the surface of the sliding contact portion of the stopper is from 20 nm to 100 nm, more preferably from 30 to 90 nm, particularly preferably from 40 nm to 70 nm, from the viewpoint of slidability and sealing property with the inner surface of the syringe barrel. ..

  The above-mentioned example is an example of a conventionally known stopper that is preferably used in the syringe barrel of the present embodiment, but the stopper preferably used in the syringe barrel of the present embodiment is not limited to the above example.

<Cap>
The cap in the present embodiment is attached to the spout of the syringe barrel. As a material for forming the cap, it is preferable to use a material having an oxygen permeability coefficient of 300 mL · mm / (m ² · day · atm) or less. Further, the oxygen permeability coefficient of the material forming the cap is preferably 200 mL · mm / (m ² · day · atm) or less, more preferably 150 mL · mm / (m ² · day · atm) or less, and 100 mL · mm / ( m ² · day · atm) or less is particularly preferable. Examples thereof include butyl rubber composed of a copolymer of isobutylene and a small amount of isoprene, bromobutyl rubber and chlorobutyl rubber obtained by halogenating butyl rubber, and bromobutyl rubber and chlorobutyl rubber are preferable. From the viewpoint of oxygen barrier performance, the thickness of the cap at the portion in contact with the pouring portion of the syringe barrel is preferably 300 to 20000 μm, more preferably 500 to 10000 μm, and particularly preferably 1000 to 5000 μm. From the viewpoint of oxygen barrier performance, the thickness of the cap that covers the opening of the injection portion of the syringe barrel is preferably 500 to 30,000 μm, more preferably 1,000 to 20,000 μm, and particularly preferably 2,000 to 10,000 μm.

<Plunger>
The plunger in this embodiment is attached to the stopper, and the stopper is moved by pressing the plunger. As the plunger, a plunger used in a general syringe can be used, and the structure and material thereof are not limited.

<Prefilled syringe>
As one aspect of the prefilled syringe, a syringe equipped with the above-mentioned syringe barrel, stopper, cap, and plunger is configured to store a drug solution or the like, and the tip side of the barrel is opened at the time of use to attach an injection needle. Examples include a syringe.

  The drug solution is not particularly limited, but from the viewpoint of the effect of the present embodiment, for example, vitamin agents such as vitamin A, vitamin B2, vitamin B12, vitamin C, vitamin D, vitamin E and vitamin K, alkaloids such as atropine, Hormonal agents such as adrenaline and insulin, sugars such as glucose and maltose, antibiotics such as ceftriaxone, cephalosporin and cyclosporine, hormone agents such as insulin and adrenaline, benzodiazepines such as oxazolam, flunitrazepam, clotiazepam, clobazam, etc. Is mentioned. The syringe of the present embodiment can suppress deterioration due to oxidation when containing a drug solution containing these compounds.

[Sterilization treatment]
Before and after containing these chemicals, the container and the chemicals can be sterilized in a form suitable for the chemicals. Examples of the sterilization method include heat sterilization such as hot water treatment at 100 ° C. or lower, pressurized hot water treatment at 100 ° C. or higher, and ultra-high temperature heat treatment at 130 ° C. or higher; electromagnetic sterilization of ultraviolet rays, microwaves, gamma rays, etc .; Examples include gas treatment with ethylene oxide and the like; chemical sterilization with hydrogen peroxide, hypochlorous acid and the like.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The NMR measurement was performed at room temperature unless otherwise specified.

<Production of syringe>
(Example of monomer synthesis)
An autoclave having an internal volume of 18 L was charged with 2.20 kg of dimethyl naphthalene-2,6-dicarboxylate, 11.0 kg of 2-propanol, and 350 g of a catalyst having 5% palladium supported on activated carbon (50% by mass hydrous product). Next, the air in the autoclave was replaced with nitrogen, the nitrogen was replaced with hydrogen, and then hydrogen was supplied until the pressure in the autoclave reached 0.8 mPa. Next, the stirrer was started, the rotation speed was adjusted to 500 rpm, the internal temperature was raised to 100 ° C. over 30 minutes, and then hydrogen was further supplied to adjust the pressure to 1 mPa. Then, according to the pressure drop due to the progress of the reaction, hydrogen was continuously supplied so as to maintain 1 mPa. After 7 hours, there was no decrease in pressure, so the autoclave was cooled, unreacted residual hydrogen was released, and then the reaction solution was taken out from the autoclave. After the reaction solution was filtered to remove the catalyst, 2-propanol was evaporated from the separated filtrate with an evaporator. To the obtained crude product, 4.40 kg of 2-propanol was added and purified by recrystallization to obtain dimethyl tetralin-2,6-dicarboxylate in a yield of 80%. The melting point of purified dimethyl tetralin-2,6-dicarboxylate was 77 ° C. The NMR analysis results are as follows. 1H-NMR (400 mhz cdcl3) δ 7.76-7.96 (2H m), 7.15 (1H d), 3.89 (3H s), 3.70 (3H s), 2.70-3.09 (5Hm), 2.19-2.26 (1Hm), 1.80-1.95 (1Hm).

(Example of polymer synthesis)
In a polyester resin manufacturing apparatus equipped with a packed column type rectification column, a partial condenser, a total condenser, a cold trap, a stirrer, a heating device and a nitrogen introducing pipe, the tetralin-2,6- 504 g of dimethyl dicarboxylate, 227 g of ethylene glycol, 0.027 g of tetrabutyl titanate, and 0.043 g of zinc acetate were charged, and the mixture in the apparatus was heated to 230 ° C. under a nitrogen atmosphere to carry out a transesterification reaction. After the reaction conversion rate of the dicarboxylic acid component is 90% or more, the temperature is raised and the pressure is reduced gradually over 90 minutes, polycondensation is performed at 275 ° C. and 133 Pa or less for 1 hour, and the tetralin ring-containing polyester compound (1) is used. (Hereinafter, also referred to as “polyester compound”). The polystyrene equivalent weight average molecular weight of the obtained polyester compound was 2.8 × 10 ⁴ , the number average molecular weight was 2.8 × 10 ⁴ , the glass transition temperature was 69 ° C., and the melting point was not recognized because it was amorphous. The intrinsic viscosity was 0.92 dl / g.

(Production Example of Resin Composition)
A mixture obtained by dry blending 100 parts by mass of the polyester compound obtained above with cobalt (II) stearate so that the amount of cobalt is 0.0002 parts by mass has two screws each having a diameter of 37 mm. The oxygen-absorbing resin composition is obtained by supplying the mixture to a shaft extruder at a rate of 12 kg / h, performing melt-kneading at a cylinder temperature of 210 ° C., extruding strands from the extruder head, cooling and pelletizing. It was

(Example of manufacturing a syringe barrel)
The material forming the skin layer (layer B) is injected from an injection cylinder under the following conditions, and then the material forming the core layer (layer A) is injected from another injection cylinder into a resin forming the skin layer (layer B). At the same time, a syringe barrel having a three-layer construction of B / A / B was manufactured by injecting at the same time, and then injecting a required amount of resin constituting the skin layer (layer B) to fill the cavity in the injection mold. At this time, the surface roughness of the inner surface of the syringe barrel was adjusted by adjusting the degree of polishing of the die contacting the inner surface of the syringe barrel. Cycloolefin polymer (manufactured by Nippon Zeon Co., Ltd., trade name: ZEONEX 5000, glass transition temperature 68 ° C.) was used as a resin constituting the skin layer (layer B). An oxygen-absorbing resin composition was used as the resin forming the core layer (layer A). The gate after molding was cut with an ultrasonic fusing machine at a position where the diameter at a position of 0.75 mm from the cut end had a specified value according to ISO80369-7 (φ4.021 ± 0.051 mm).

(Shape of syringe barrel)
The content was 1 ml (Long) according to ISO11040-6. An injection molding machine (Model: GL-150 manufactured by Sodick Co., Ltd.) was used for manufacturing the syringe.

-Syringe barrel molding conditions-
Injection cylinder temperature for skin layer (layer B): 315 ° C
Injection cylinder temperature for core layer (layer A): 280 ° C
Injection mold resin flow path temperature: 300 ° C
Mold temperature: 30 ℃

(stopper)
[Manufacturing conditions]
An unvulcanized rubber sheet containing chlorinated butyl rubber and PTFE were bonded together and molded by vulcanization adhesion at 175 ° C. for 10 minutes by a vacuum press to obtain a molded sheet having a stopper shape. Unnecessary portions were cut off from the obtained molded sheet to obtain stoppers. The obtained stopper was washed and sterilized and dried to obtain a predetermined sterilized stopper. The thickness of the molded sheet was 20 μm.
[Product shape]
The shape shown in FIG. 3 (3 b) was used, and the diameter of the sliding contact portion was φ6.65 mm.
[Groove processing]
The formation of the groove was performed after obtaining the product shape. The groove was formed by using the following laser beam processing.
Equipment: Keyence Corporation 3-Axis CO ₂ LaserMarker ML-Z9550T
Processing was performed by irradiating a laser beam having a wavelength of 9300 nm.
[Groove dimension measurement]
The product (sample) after the formation of the groove was measured for the surface shape of the groove using a laser micro microscope (VK-X100, manufactured by Keyence Corporation) and an objective lens with a magnification of 50 times. In the measurement, the maximum depth of the groove and the width portion were selected from the screen to obtain numerical values. In addition, for each measured value, three arbitrary points on the sample were measured and the arithmetic mean thereof was shown. The results are shown in Tables 1 and 2.
[Surface roughness]
The cut stopper was sampled and the surface shape of the sliding contact portion was measured. An atomic force microscope (MFP-3D-SA-J manufactured by Oxford Instruments) was used for the measurement. The arithmetic average roughness Ra was calculated from the obtained surface shape. The results are shown in Tables 1 and 2.

(Syringe performance evaluation)
The performance test of the obtained syringe was measured and evaluated according to the following methods and criteria.

[Sliding property test]
A stopper was attached to the syringe barrel so that the internal volume became the nominal volume of the syringe, pure water was charged in an amount equal to the nominal volume of the syringe, and the mixture was allowed to stand in a thermostatic chamber at 23 ° C. for 12 hours. After that, the needle and the plunger were attached, the barrel tip and the stopper were fixed to a thermostatic bending tensile tester (INSTRON (registered trademark) 5267), and the load required to push the plunger at a speed of 200 mm / min was measured. The needle used was a standard needle of 25 G × 1 inch.
An average load with a sliding distance of 10 mm to 25 mm was calculated as an average sliding resistance value, and a value of 10 N or less was determined as "good" and a value of more than 10 N was determined as "defective". The results are shown in Table 1.

[Liquid seal test]
A stopper was attached to the nominal volume position of the syringe, the test liquid was filled to the nominal volume, and a cap was attached to the pouring portion. After storage at 5 ° C or 25 ° C for 1 month, the presence or absence of liquid leakage was visually measured. By observing 10 products, if the test liquid exceeds the sliding contact side of the stopper, it is judged as a liquid leak, and if no liquid leak has occurred, "good," if liquid leak has occurred It was judged to be "poor". The test solution used was water containing 0.1 mg / g of dye Neucoccin (manufactured by Kanto Chemical Co., Inc.) and 1 mg / g of a surfactant Tween 80 (manufactured by Tokyo Chemical Industry Co., Ltd.).

[Surface roughness]
A section of the cut syringe barrel was taken and the surface shape of the inner surface of the barrel was measured. An atomic force microscope (MFP-3D-SA-J manufactured by Oxford Instruments) was used for the measurement. Atomic force microscope observation images of Example 1 and Comparative Example 1 are shown in FIGS. 5 and 6, respectively. The arithmetic average roughness Ra was calculated from the obtained surface shape. The surface shape is measured at each of three points of the flange portion (see inner surface 12C in FIG. 2), the central portion (see inner surface 12B in FIG. 2), and the tip portion (see inner surface 12A in FIG. 2) of the syringe barrel, each 20 μm. A region of × 20 μm was measured. The results are shown in Tables 1 and 2.

  As can be seen from the comparison between the example of Table 1 and the comparative example 1, it can be seen that when the surface roughness of the inner surface of the syringe barrel is less than 4 nm in terms of arithmetic average roughness (Ra), the slidability is poor. Further, as can be seen from the comparison between the example and the comparative example 3, it can be seen that when the surface roughness of the inner surface of the syringe barrel exceeds 30 nm in terms of arithmetic average roughness (Ra), the liquid sealing property deteriorates. Further, in Comparative Example 2 in which the groove was not formed, liquid leakage occurred, whereas in Example, liquid leakage did not occur, resulting in compatibility of slidability and liquid sealing property. .. Further, Comparative Examples 4 and 5 in which the surface roughness of the sliding contact portion of the stopper exceeded 100 nm or less than 20 nm, respectively, were inferior in liquid sealing property or slidability.

10 ... Syringe barrel, 12 ... Cylindrical main body, 12A-12C ... Inner surface, 14 ... Pour-out part, 16 ... Opening part, 20 ... Stopper, 22 ... Liquid contact part, 24 ... Sliding contact part, 25 ... Groove, 26 ... Protrusion, 30 ... Plunger, 40 ... Cap, 100 ... Syringe

Claims (8)

A syringe barrel having a pouring portion and an opening portion, a stopper having a sliding contact portion in contact with the inner surface of the syringe barrel and inserted from the opening portion of the syringe barrel, a plunger attached to the stopper, and A syringe equipped with a cap to be attached to a dispensing portion of a syringe barrel,
The syringe barrel has a laminated structure, and the surface roughness of the inner surface is 4 nm to 30 nm in terms of arithmetic average roughness (Ra),
The stopper includes a main body made of an elastic body, and a laminate film laminated on the main body, and the slide contact portion has a groove arranged along a circumferential direction of the stopper, and A syringe having a surface roughness of the sliding contact portion of 20 nm to 100 nm in terms of arithmetic average roughness (Ra).   The laminated structure of the syringe barrel includes, from the outer surface of the syringe barrel, a first resin layer containing a cyclic polyolefin, a second resin layer containing a polyester having a structural unit containing a tetralin ring, and a third resin layer containing a cyclic polyolefin. The syringe according to claim 1, comprising at least three resin layers in this order.   The syringe according to claim 2, wherein the second resin layer contains a transition metal catalyst.   The syringe according to any one of claims 1 to 3, wherein the depth of the groove of the stopper is 1 µm to 50 µm, and the width of the groove is 1 µm to 100 µm.   The syringe according to any one of claims 1 to 4, wherein the laminate film has a thickness of 10 µm to 100 µm.   The syringe according to any one of claims 1 to 5, wherein the laminate film contains a fluororesin.   The syringe according to claim 6, wherein the fluororesin is polytetrafluoroethylene.   A prefilled syringe in which the syringe according to any one of claims 1 to 7 is filled with a drug.