Patent Application
20150273155
The present invention relates to a gasket for a prefilled syringe, and a production method therefor.
In recent years, syringes prefilled with a liquid drug have been increasingly used because of their handling ease and their capability of preventing medical accidents such as administration of a wrong drug (see Patent Document 1). A distal end of such a prefilled syringe to which an injection needle is attached is sealed with a cap. For administration of the liquid drug, the injection needle is attached to the distal end, and a plunger rod is pushed toward the distal end to slide a gasket of the prefilled syringe. Thus, the liquid drug is administered through the injection needle.
Since rubber members such as the gasket and the cap used in the prefilled syringe are kept in direct contact with the liquid drug for a long period of time, butyl rubber materials excellent in chemical resistance, gas permeation resistance, water vapor permeation resistance and anti-aging property are often used for the rubber members.
However, bioengineered drugs and the like are liable to be adversely affected by the gasket and the nozzle cap through interactions between the drug and a raw rubber and other ingredients of a rubber material leached from the gasket and the cap and a coating separated from the gasket and the cap.
Particularly, a distal end face of the gasket directly contacts the liquid drug contained in a barrel of the syringe, so that the raw rubber and other ingredients of the rubber material are liable to be leached into the liquid drug from a body of the gasket.
A sliding portion of the gasket kept in contact with an inner peripheral surface of the syringe barrel is less liable to be brought into direct contact with the liquid drug, but is coated with an oil type silicone lubricant or a cured type silicone lubricant in order to improve the slidability of the gasket with respect to the inner peripheral surface of the barrel when the gasket is fitted in the barrel or when the plunger is pushed for injection of the liquid drug. Therefore, the liquid drug is liable to be contaminated with the silicone as foreign matter, so that the quality of the liquid drug is adversely affected by the silicone depending on the type of the liquid drug. Particularly, the inner peripheral surface of the syringe barrel is coated with a greater amount of the silicone coating agent than the gasket, and has a greater area of contact with the liquid drug contained in the syringe barrel. This significantly influences the liquid drug.
In order to ensure the stability of the drug, a laminated gasket product has recently been developed, which includes a gasket body of an elastic material such as a butyl rubber laminated with a fluororesin film having an excellent chemical resistance. It has been proposed to use the laminated gasket for glass syringes and prefilled resin syringes.
According to the proposal, the rubber component is prevented from being leached into the liquid drug from the distal end face of the gasket kept in direct contact with the liquid drug, and the sliding resistance of the side surface (circumferential surface) of the gasket kept in contact with the inner surface of the syringe barrel is reduced. This obviates the need for coating the inner surface of the syringe barrel with a great amount of the silicone coating agent, thereby preventing the contamination of the liquid drug due to separation of the silicone coating from the inner surface of the barrel. That is, the safety of the liquid drug contained in the syringe is enhanced by laminating at least the outer surface of the gasket body with the fluororesin film.
Further, it is possible to obviate the step of coating the inner surface of the syringe barrel with a great amount of silicone, thereby advantageously reducing the costs for the assembling of the syringe.
PATENT DOCUMENT 1: JP2005-185747-A
The chemical resistance can be improved by providing an inert film such as of the fluororesin on the surface of the gasket (by laminating the gasket with the inert film). However, the inert film is liable to be scratched in a film production process or a laminated gasket production process. If the gasket laminated with the scratched film is used, the liquid drug is liable to leak through the scratch. Particularly, where the scratch extends parallel to a gasket sliding direction, the leakage of the liquid drug is more liable to occur.
To solve the problem described above, it is a principal object of the present invention to provide a gasket for a prefilled syringe and a method for producing the gasket, which ensure that a sliding portion of the laminated gasket (a portion of the laminated gasket to be kept in contact with a syringe barrel) is substantially free from a scratch or an existing scratch of the laminated gasket is substantially eliminated.
According to an invention aspect, there is provided a method for producing a prefilled syringe gasket including a liquid contact portion and a sliding portion to be kept in contact with an inner surface of a syringe barrel, the method including the steps of forming the gasket, and rubbing a surface of the sliding portion of the formed gasket against a predetermined base, wherein a rubbing direction in which the surface of the sliding portion is rubbed in the rubbing step extends circumferentially of the sliding portion.
According to another inventive aspect, there is provided a prefilled syringe gasket, which includes a liquid contact portion, and a sliding portion to be kept in contact with an inner surface of a syringe barrel, wherein the sliding portion of the gasket has an arithmetic average roughness Ra// as measured in a circumferential direction thereof and an arithmetic average roughness Ra⊥ as measured in a direction perpendicular to the circumferential direction thereof (in a sliding direction), and the ratio (Ra⊥/Ra//) of the arithmetic average roughness Ra⊥ to the arithmetic average roughness Ra// is not less than 1.00.
According to further another inventive aspect, there is provided a prefilled syringe gasket, which includes a liquid contact portion, and a sliding portion to be kept in contact with an inner surface of a syringe barrel, and is produced through the steps of forming the gasket, and rubbing a surface of the sliding portion of the formed gasket against a predetermined base circumferentially of the sliding portion.
According to still another inventive aspect, there is provided a medical syringe, which includes a hollow cylindrical syringe barrel, a plunger combined with the syringe barrel and movable in the syringe barrel, and a prefilled syringe gasket attached to a distal end of the plunger.
The present invention provides a laminated gasket which is free from leakage of a liquid drug contained in a prefilled syringe.
With reference to the attached drawings, one embodiment of the present invention will hereinafter be described specifically.
Referring to
The plunger 12 is a resin plate piece, for example, having a cross shape as seen in section, and includes a head 18 provided at its distal end to which the gasket 13 is attached. The head 18 is an integral part of the plunger 12 made of a resin and shaped in a male screw.
The gasket 13 has a generally cylindrical shape having a short axis. The gasket 13 has a distal end face, for example, having a conical center portion projecting at an obtuse angle, and a rear end face axially recessed into an engagement recess 21 shaped in a female screw. The head 18 of the plunger 12 is screwed into the engagement recess 21 of the gasket 13, whereby the gasket 13 is attached to the distal end of the plunger 12.
Referring to
The gasket 13 includes the main body 14, and the lamination film 15 provided on the surface of the main body 14. The main body 14 is formed from a rubber (elastic material).
The type of the lamination film 15 provided on the surface of the main body 14 is not particularly limited, as long as the lamination film 15 can prevent migration of components from a crosslinked rubber (main body 14) and is more slidable than the rubber, i.e., has a smaller friction coefficient than the rubber.
Exemplary materials for the main body 14 and the lamination film 15 are shown below.
<Rubber>
Examples of the rubber as the material for the main body 14 include butyl rubbers, isoprene rubbers, butadiene rubbers, styrene-butadiene rubbers, natural rubbers, chloroprene rubbers, nitrile rubbers such as acrylonitrile-butadiene rubbers, hydrogenated nitrile rubbers, norbornene rubbers, ethylene-propylene rubbers, ethylene-propylene-diene rubbers, acryl rubbers, ethylene-acrylate rubbers, fluororubbers, chlorosulfonated polyethylene rubbers, epichlorohydrin rubbers, silicone rubbers, urethane rubbers, polysulfide rubbers, phosphazene rubbers and 1,2-polybutadiene rubbers.
These rubbers may be used either alone or in combination. The rubber to be used for the main body 14 is not limited to the aforementioned rubbers, but is preferably a butyl rubber and/or an ethylene-propylene-diene rubber (hereinafter referred to as EPDM rubber).
The butyl rubber is preferred because of its excellent gas permeation resistance and water vapor permeation resistance.
A known butyl rubber compound may be used as the butyl rubber, but other examples of the butyl rubber include an isobutylene-isoprene copolymer rubber, a halogenated isobutylene-isoprene copolymer rubber (hereinafter referred to as halogenated butyl rubber), and modification products of any of these rubbers. Examples of the modification products include bromination products of copolymers of isobutylene and p-methylstyrene. Particularly, the halogenated butyl rubber is more preferable, and a chlorinated butyl rubber and a brominated butyl rubber are further more preferable for easy crosslinking.
The EPDM rubber is preferred because of its excellent processability. The EPDM rubber includes a non-oil extension type EPDM rubber containing only a rubber component and an oil extension type EPDM rubber containing a rubber component and an extension oil. In the present invention, either type of the EPDM rubbers may be used. Examples of a diene monomer for the EPDM rubber include dicyclopentadiene, methylene norbornene, ethylidene norbornene, 1,4-hexadiene and cyclooctadiene.
The halogenated butyl rubber and the EPDM rubber are advantageously used in combination because the resulting rubber is excellent in gas permeation resistance, water vapor permeation resistance and processability.
In this embodiment, the main body 14 is of the syringe gasket as a medical rubber product and, therefore, a butyl rubber having a lower gas permeability is preferably used as a principal rubber component. A triazine derivative crosslinking agent is preferably used as a crosslinking agent for cleanliness.
<Lamination Film 15>
The lamination film 15 is not particularly limited, but may be an inert film. At least one fluororesin selected from the group consisting of a polytetrafluoroethylene (PTFE), a modified polytetrafluoroethylene (modified PTFE, which is a copolymer of a 4F-monomer and a very small amount of a perfluoroalkoxide), a tetrafluoroethylene ethylene copolymer (ETFE), a tetrafluorothylene perfluoroalkyl vinyl ether copolymer (PFA) and a polychlorotetrafluoroethylene (PCTFE), and/or an olefin resin is preferred for the lamination film 15 to provide excellent chemical resistance.
<Step of Forming Laminated Gasket 13>
The laminated gasket 13 according to this embodiment is produced by kneading ingredients blended in a predetermined blend radio by means of a sealed kneader, an open roll kneader or the like, forming the resulting kneaded product into an unvulcanized rubber sheet by means of a calender or a sheet forming machine, placing the unvulcanized rubber sheet and the inert film each having a predetermined weight and size in superposition in a die, and press-forming the unvulcanized rubber sheet and the inert film into a laminated gasket sheet by means of a vacuum press.
Conditions for the forming are not particularly limited, but may be properly determined. The forming temperature is preferably 155° C. to 200° C., more preferably 165° C. to 180° C. The forming period is preferably 1 to 20 minutes, more preferably 3 to 15 minutes, further more preferably 5 to 10 minutes. The die to be used for the forming preferably has a sliding surface forming portion having a smooth die surface mirror-finished so as to have an arithmetic average roughness Ra of not greater than 0.03 μm as measured with a cutoff value of 0.08 mm. With the use of this die, the laminated rubber member thus formed can have a smaller surface roughness than the original surface roughness of the inert film. The arithmetic average roughness Ra is preferably not greater than 0.02 μm, more preferably not greater than 0.015 μm.
Thereafter, an unnecessary portion is cut away and removed from the formed gasket sheet. Then, the resulting product is cleaned, sterilized and dried, and then visually inspected. Thus, a primary gasket product is produced.
A feature of the laminated gasket 13 according to this embodiment is that the primary gasket product includes two circumferential portions 17A, 17B as the sliding portion to be kept in gas-tight and liquid-tight contact with the inner peripheral surface 16 of the syringe barrel 11 and a surface of a forward one 17A of the circumferential portions 17A, 17B of the primary gasket product is rubbed against (polished with) a predetermined base in a circumferential direction.
In this embodiment, the two circumferential portions 17A, 17B, i.e., the forward circumferential portion 17A and the rearward circumferential portion 17B, are provided as the sliding portion, but only one circumferential portion 17A may be provided or three or more sliding portions may be provided. The shape of the gasket is not limited to the aforementioned shape of this embodiment.
Next, the step of rubbing the primary gasket product will be described.
<Rubbing Step and Base for Use in Rubbing Step>
The base is not particularly limited, but may be an organic base such as of a natural polymer or a synthetic polymer, an inorganic base such as of a metal or a ceramic material, or an inorganic-organic composite base. More preferably, a fabric formed from a natural polymer or a synthetic polymer or sand paper is preferably used as the base.
The rubbing step is mechanically performed at a constant speed for a predetermined period by means of a rotating rotor.
<Gasket>
An exemplary method for judging if the number of scratches present in the sliding portion and extending in the sliding direction is reduced in the present invention is such that an arithmetic average roughness Ra// as measured in the circumferential direction of the gasket sliding portion and an arithmetic average roughness Ra⊥ as measured in a direction (=the sliding direction) perpendicular to the circumferential direction are determined after the step of rubbing the gasket sliding portion against the base. If the scratches extending in the sliding direction are present, the arithmetic average roughness measured in the circumferential direction is greater than the arithmetic average roughness measured in the sliding direction and, therefore, the ratio (Ra⊥/Ra//) of the arithmetic average roughness measured in the sliding direction to the arithmetic average roughness measured in the circumferential direction is smaller than 1.00. If the number of the scratches extending in the sliding direction is reduced by the present invention, the sliding portion has a smooth surface as observed in the circumferential direction, and has a smaller arithmetic average roughness as measured in the circumferential direction. Therefore, the ratio (Ra⊥/Ra//) of the arithmetic average roughness measured in the sliding direction to the arithmetic average roughness measured in the circumferential direction is not smaller than 1.00.
In the present invention, a difference between a maximum height Ry// as measured in the circumferential direction and a maximum height Ry⊥ as measured in the direction (sliding direction) perpendicular to the circumferential direction (a difference ΔRy=|(Ry//−Ry⊥)| (wherein | | indicates an absolute value and, therefore, ΔRy≧0)) is not greater than 0.100 μm, preferably 0.080 μm, more preferably 0.06 μm.
If ΔRy is greater than 0.100 μm, the gasket does not uniformly contact the barrel and, therefore, leakage of the liquid drug is more liable to occur.
The present invention will hereinafter be described in greater detail byway of examples thereof. It should be understood that the present invention be not limited to the following examples.
<Production Method 1>
An unvulcanized rubber sheet containing a chlorinated butyl rubber was combined with a 100-μm thick inert film, and vulcanized at 175° C. for 10 minutes in a vacuum press to be thereby bonded to the inert film. Thus, the rubber sheet and the inert film were press-formed into a sheet having a plurality of gasket-shaped pieces. The sheet thus formed was stamped, whereby gaskets each having a shape as shown in
<Production Method 2>
The gaskets produced in the production method 1 were each fixed to a distal end of an electric router (mini router available from Proxxon GmbH), and pressed against a cotton fabric (MK0012 available from Taenaka Pile Fabrics Co., Ltd.), whereby the sliding portion of each of the gaskets was rubbed against the cotton fabric in a circumferential direction at a constant speed (8000 rpm) for a predetermined period (5 seconds). The resulting gaskets were immersed in pure water, and cleaned by means of an ultrasonic cleaning machine. Thereafter, the gaskets were sterilized and dried. Thus, gaskets B were produced.
<Production Method 3>
Gaskets C were produced by processing the gaskets in substantially the same manner as in Production Method 2, except that the gaskets were each pressed against the cotton fabric for 30 seconds in Production Method 2.
<Production Method 4>
Gaskets D were produced by processing the gaskets in substantially the same manner as in Production Method 2, except that the gaskets were each pressed against the cotton fabric for 60 seconds in Production Method 2.
<Production Method 5>
Gaskets E were produced by processing the gaskets in substantially the same manner as in Production Method 2, except that a rayon fabric (YA-18-R available from Yoshikawa Chemical Co., Ltd. and having a filament diameter of 2.5 D) was used as the base and the gaskets were each pressed against the rayon fabric for 5 seconds in Production Method 2.
<Production Method 6>
Gaskets F were produced by processing the gaskets in substantially the same manner as in Production Method 2, except that the gaskets were each pressed against the rayon fabric for 30 seconds in Production Method 5.
<Production Method 7>
Gaskets G were produced by processing the gaskets in substantially the same manner as in Production Method 2, except that the gaskets were each pressed against the rayon fabric for 60 seconds in Production Method 5.
The following tests were performed on the gaskets produced by the aforementioned production methods.
<Liquid Drug Sealability Test>
An aqueous solution containing 0.1 wt % of a nonionic surfactant (POLYSOLVATE 80) was prepared as a liquid to be sealed in the prefilled syringe. The gasket was attached to a plastic syringe (of a cyclic olefin polymer) having a volume of 1 mL and an inner diameter of 6.35 mm, and the aqueous solution was injected into the syringe. Then, a distal end of the syringe was capped with a rubber cap, and the resulting syringe sample was allowed to stand in an oven at 40° C. for one week. Thereafter, the sample was taken out of the oven, and a portion of the gasket present between the two sliding portions (hereinafter referred to as “trough” between the circumferential portions 17A and 17B) was visually inspected at a magnification of 50× by means of a video microscope (DVM5000 available from Leica Microsystems GmbH) to see whether the solution reached the trough. Where the solution reached the trough, it was determined that liquid leakage occurred.
<Measurement of Surface Roughnesses of Sliding Portion>
The surface roughnesses of the circumferential portion 17A serving as the gasket sliding portion were measured by means of a laser microscope (VK-X100 available from Keyence Corporation). The measurement was performed at a comprehensive magnification of 1000×, and arithmetic average roughnesses Ra and maximum heights Ry of the sliding portion 17A were measured in a direction perpendicular to a circumferential direction of the sliding portion 17A (in a longitudinal direction) and a direction parallel to the circumferential direction of the sliding portion 17A (in a transverse direction) (in conformity with JIS B06014:1994 with a cutoff of 0.25 mm).
The surface roughnesses of the sliding portion 17A of the gasket C produced in Production Method 3 were measured. As a result, the gasket C had an arithmetic average roughness of 0.077 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.071 μm as measured in the circumferential direction. Further, the gasket C had a maximum height of 0.541 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.532 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets C. As a result, the liquid leakage was not observed.
The surface roughnesses of the sliding portion 17A of the gasket D produced in Production Method 4 were measured. As a result, the gasket D had an arithmetic average roughness of 0.074 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.067 μm as measured in the circumferential direction. Further, the gasket D had a maximum height of 0.536 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.503 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets D. As a result, the liquid leakage was not observed.
The surface roughnesses of the sliding portion 17A of the gasket F produced in Production Method 6 were measured. As a result, the gasket F had an arithmetic average roughness of 0.076 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.071 μm as measured in the circumferential direction. Further, the gasket F had a maximum height of 0.536 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.561 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets F. As a result, the liquid leakage was not observed.
The surface roughnesses of the sliding portion 17A of the gasket G produced in Production Method 7 were measured. As a result, the gasket G had an arithmetic average roughness of 0.072 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.066 μm as measured in the circumferential direction. Further, the gasket G had a maximum height of 0.531 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.558 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets G. As a result, the liquid leakage was not observed.
The surface roughnesses of the sliding portion 17A of the gasket A produced in Production Method 1 were measured. As a result, the gasket A had an arithmetic average roughness of 0.078 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.096 μm as measured in the circumferential direction. Further, the gasket A had a maximum height of 0.537 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.658 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets A. As a result, six of the gaskets A suffered from the liquid leakage.
The surface roughnesses of the sliding portion 17A of the gasket B produced in Production Method 2 were measured. As a result, the gasket B had an arithmetic average roughness of 0.076 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.092 μm as measured in the circumferential direction. Further, the gasket B had a maximum height of 0.536 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.644 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets B. As a result, five of the gaskets B suffered from the liquid leakage.
The surface roughnesses of the sliding portion 17A of the gasket E produced in Production Method 5 were measured. As a result, the gasket E had an arithmetic average roughness of 0.078 μm as measured in the direction perpendicular to the circumferential direction and an arithmetic average roughness of 0.094 μm as measured in the circumferential direction. Further, the gasket E had a maximum height of 0.532 μm as measured in the direction perpendicular to the circumferential direction and a maximum height of 0.644 μm as measured in the circumferential direction. Further, the liquid drug sealability test was performed on 50 such gaskets E. As a result, five of the gaskets E suffered from the liquid leakage.
The results are collectively shown in Table 1.
As shown in Table 1, none of the 50 gaskets of each of Examples 1 to 4 subjected to the liquid drug sealability test suffered from the leakage. On the other hand, 6 to 4 of the 50 gaskets of each of Comparative Examples 1 to 3 suffered from the leakage.
This application corresponds to Japanese Patent Application No. 2014-073761 filed in the Japan Patent Office on Mar. 31, 2014, the disclosure of which is incorporated herein by reference in its entirety.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2014-073761 | Mar 2014 | JP | national |
