Medical rubber composition, medical rubber part, and package of medical rubber part

Abstract

To provide medical rubber parts and a package therefor which can maintain non-elution characteristics after sterilized with gamma rays and which can experience less trouble in a manufacturing process for medical products; and a medical rubber composition for manufacturing the medical rubber parts.SOLUTION: A medical rubber composition of the present invention contains: (a) a base polymer containing halogenated butyl rubber; (b) polyethylene; and (c) a triazine derivative as a crosslinking agent. The content of the triazine derivative is 1 mol%-15 mol% relative to 100 mol% of halogen level of the halogenated butyl rubber.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a medical rubber composition for gamma sterilization, as well as gamma-sterilized medical rubber parts and their packages.

Background Art

[0002] For medical rubber stoppers that seal openings such as syringes and vial bottles, many items such as non-elution, high cleanliness, chemical resistance, needle puncture resistance, self-sealing property, and high slidability are essential. The quality characteristics required for medical rubber stoppers should comply with the infusion rubber stopper test of the 17th revised Japanese Pharmacopoeia for their intended use.

[0003] For example, Patent Document 1 discloses a rubber stopper for a pharmaceutical container, which is obtained by vulcanizing a halogenated butyl rubber containing 5 to 25 parts by weight of ultra-high molecular weight polyethylene fine powder per 100 parts by weight of the halogenated butyl rubber in the absence of a zinc compound using at least one kind of 2-substituted-4,6-dithiol-s-triazine derivative or an organic peroxide.

[0004] The demand for ready-to-use (RTU) medical rubber products (such as syringe gaskets and vial stoppers) provided in a sterilization-guaranteed state is increasing. Sterilization guarantee methods include autoclaving, ethylene oxide gas (EOG) sterilization, and gamma sterilization. Gamma sterilization has the advantage that medical rubber products can be sterilized while being packaged, so they can be supplied without opening the package. EOG sterilization has environmental problems and tends to be switched to gamma sterilization.

[0005] Gamma sterilization ensures sterilization based on the set absorbed dose and the measured value. When multiple medical rubber parts are packed in a packaging bag and gamma sterilized, there may be a bias in the medical rubber parts inside the packaging bag. Therefore, even if the packaging bag is irradiated with gamma rays at a predetermined irradiation dose, variations in the absorbed dose of gamma rays occur inside the packaging bag, resulting in those with a lower absorbed dose of gamma rays and those with a higher absorbed dose of gamma rays. However, it is necessary to ensure the minimum absorbed dose capable of sterilizing each medical rubber part, and the packaging bag needs to be irradiated with gamma rays at a dose not less than the minimum absorbed dose. Therefore, there are medical rubber parts that absorb excessive gamma rays during gamma sterilization inside the packaging bag.

[0006] Patent Document 2 discloses a rubber composition mainly composed of an isobutylene copolymer and having a density of 0.95 or less, a rubber composition for use in a medical rubber stopper or a medical rubber product that is easy to be radiation-treated, or a crosslinked product thereof.

[0007] Patent Document 3 discloses a method for packaging an elastomer part (1) such as a stopper of a pharmaceutical container, including a step of packing the part (1) in a primary bag (10) made of a material that substantially does not allow air to pass through, and a step of applying an atmosphere of at least 80% nitrogen into the primary bag (10), and characterized in that the primary bag (10) is placed in a secondary bag (20), and a vacuum state is created between the primary bag (10) and the secondary bag (20).

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0009] When a medical rubber component is sterilized by irradiating it with gamma rays, the polymer that constitutes the medical rubber component is simultaneously cleaved and crosslinked. When excessive gamma rays are absorbed, the cleavage of the polymer main chain that constitutes the medical rubber component is promoted, generating low molecular components. Therefore, the elution performance of the medical rubber component after gamma sterilization deteriorates. In addition, the cleaved low molecular components bleed out to the surface of the rubber component, and when the medical rubber components adhere to each other, troubles such as clogging of the burt feeder used in the manufacturing process of medical supplies occur.

[0010] In preparation for absorbing excessive gamma rays, it is also conceivable to incorporate an antioxidant into the medical rubber component. However, the addition of an antioxidant raises concerns about a decrease in elution characteristics and adverse effects on drugs.

[0011] The present disclosure has been made in view of the above circumstances, and an object thereof is to provide a medical rubber component and a package of the medical rubber component that maintain non-elution characteristics even after gamma sterilization and have few troubles in the manufacturing process of medical supplies, and a medical rubber composition for manufacturing this medical rubber component.

Means for Solving the Problems

[0012] The medical rubber composition of the present disclosure is (a) a base polymer containing halogenated butyl rubber, (b) polyethylene, (c) a triazine derivative as a crosslinking agent, wherein the content of the triazine derivative is such that the halogen of the (a) halogenated butyl rubber To 100 moles is relative to 1 mole to 15 moles and is characterized by being.

Effects of the Invention

[0013] According to the present disclosure, it is possible to provide a medical rubber part and its package that maintain non-elution characteristics even after gamma sterilization and have few troubles in the manufacturing process of medical supplies. According to the present disclosure, it is possible to provide a medical rubber composition suitable for manufacturing the medical rubber part.

Brief Description of the Drawings

[0014]

Figure 1

Figure 2

Figure 3

Embodiments for Carrying Out the Invention

[0015] The medical rubber composition of the present disclosure contains (a) a base polymer containing halogenated butyl rubber, (b) polyethylene, and (c) a triazine derivative as a crosslinking agent, and the content of the (c) triazine derivative is the halogen of the (a) halogenated butyl rubber To 100 moles relative to 1 mole to 15 moles which is characterized by being

[0016] First, the base polymer containing (a) halogenated butyl rubber used in the present disclosure will be described. Examples of the halogenated butyl rubber include chlorinated butyl rubber, brominated butyl rubber, and brominated copolymers of isobutylene and p-methylstyrene rubber (brominated isobutylene paramethylenestyrene copolymer rubber).

[0017] As the halogenated butyl rubber, chlorinated butyl rubber or brominated butyl rubber is preferred. The chlorinated butyl rubber or brominated butyl rubber is, for example, obtained by adding or substituting chlorine or bromine to the isoprene structural part in butyl rubber, specifically, the double bond and / or the carbon atom adjacent to the double bond. Note that butyl rubber is a copolymer obtained by polymerizing isobutylene and a small amount of isoprene.

[0018] The halogen content in the halogenated butyl rubber is preferably 0.5% by mass or more, preferably 1% by mass or more, more preferably 1.5% by mass or more, preferably 5% by mass or less, more preferably 4% by mass or less, and still more preferably 3% by mass or less.

[0019] Specific examples of the chlorinated butyl rubber include, for example, CHLOROBUTYL 1066 manufactured by Japan Butyl Co., Ltd. [Stabilizer: NS, Halogen content rate: 1.26%, Mooney viscosity: 38 ML 1+8 (125 °C), Specific gravity: 0.92]; at least one such as LANXESS X_BUTYL CB1240 manufactured by LANXESS Co., Ltd.

[0020] Specific examples of the brominated butyl rubber include, for example, BROMOBUTYL 2255 manufactured by Japan Butyl Co., Ltd. [Stabilizer: NS, Halogen content rate: 2.0%, Mooney viscosity: 46 ML 1+8 (125 °C), Specific gravity: 0.93]; at least one such as LANXESS X_BUTYL BBX2 manufactured by LANXESS Co., Ltd.

[0021] The (a) base polymer may contain a rubber component other than halogenated butyl rubber. Examples of other rubber components include, for example, butyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, natural rubber, chloroprene rubber, nitrile rubbers such as acrylonitrile-butadiene rubber, hydrogenated nitrile rubber, norbornene rubber, ethylene-propylene rubber, ethylene-propylene-diene rubber, acrylic rubber, ethylene acrylate rubber, fluororubber, chlorosulfonated polyethylene rubber, epichlorohydrin rubber, silicone rubber, urethane rubber, polysulfide rubber, phosphazen rubber, or 1,2-polybutadiene, etc. These may be used alone or in combination of two or more.

[0022] When using other rubber components, the content of halogenated butyl rubber in the (a) base polymer is preferably 90% by mass or more, more preferably 95% by mass or more, and still more preferably 98% by mass or more. Also, a preferred embodiment is that the (a) base polymer consists only of halogenated butyl rubber.

[0023] The medical rubber composition of the present disclosure contains (b) polyethylene. Polyethylene is more likely to absorb gamma rays than the (a) base polymer and has the effect of preventing the chain breakage of the (a) base polymer by gamma ray irradiation. Also, polyethylene with a low crystallinity has branches and is considered to undergo crosslinking without the main chain being broken even by gamma ray irradiation. As a result, it is considered that the elution performance of the medical rubber composition is improved.

[0024] From such a viewpoint, examples of the (b) polyethylene used in the present disclosure include high-density polyethylene (HDPE) or low-density polyethylene (LDPE). High-density polyethylene (HDPE) and low-density polyethylene (LDPE) may be used alone or in combination.

[0025] When high-density polyethylene (HDPE) and low-density polyethylene (LDPE) are used in combination, the mass ratio of high-density polyethylene (HDPE) to low-density polyethylene (LDPE) (HDPE / LDPE) is preferably 0.3 or more, more preferably 0.5 or more, even more preferably 1.0 or more, preferably 5.0 or less, more preferably 4.0 or less, and even more preferably 3.0 or less. If the mass ratio of high-density polyethylene (HDPE) to low-density polyethylene (LDPE) (HDPE / LDPE) is within the above range, the radical absorption effect during gamma-ray irradiation and the appropriate hardness of the rubber can be ensured.

[0026] (b) The polyethylene preferably contains polyethylene having a crystallinity of 70% or less.

[0027] The crystallinity of high-density polyethylene (HDPE) is preferably 60% to 80%, more preferably 60% to 75%, and even more preferably 60% to 70%. The crystallinity of low-density polyethylene (LDPE) is preferably 30% to 50%, more preferably 30% to 45%, and even more preferably 30% to 40%. If the crystallinity of the polyethylene is within the above range, the radicals generated by gamma-ray irradiation can be effectively absorbed, preventing the cleavage of the polymer main chain.

[0028] (b) The crystallinity of the polyethylene is determined by the following formula. Crystallinity (%) = (Measured heat of fusion (J / g) / Heat of fusion of a perfect crystal (J / g)) × 100 The heat of fusion of a perfect crystal (J / g) is 293 J / g (literature value), which is the heat of fusion of polyethylene at 100% crystallinity. The method for measuring the heat of fusion of polyethylene will be described later.

[0029] (b) As the polyethylene, low-density polyethylene is preferred. The density (g / cm 3 ) of high-density polyethylene is preferably 0.930 to 0.960, and more preferably 0.930 to 0.950. The density (g / cm 3) is not particularly limited, but 0.910 to 0.925 is preferable, and 0.910 to 0.920 is more preferable.

[0030] (b) As the polyethylene, a fine powder form is preferably used. The volume average particle diameter of the polyethylene in fine powder form is preferably 10 μm or more, more preferably 15 μm or more, still more preferably 20 μm or more, preferably 200 μm or less, more preferably 160 μm or less, and still more preferably 120 μm or less. When the average particle diameter of the polyethylene in fine powder form is within the above range, it becomes easier to uniformly mix and disperse in the polymer.

[0031] (b) The blending amount of the polyethylene is preferably 3 parts by mass or more, more preferably 5 parts by mass or more, still more preferably 10 parts by mass or more, preferably 30 parts by mass or less, more preferably 25 parts by mass or less, and still more preferably 20 parts by mass or less with respect to 100 parts by mass of the (a) base polymer. If the blending amount of the (b) polyethylene is within the above range, it can effectively absorb the radicals generated during gamma-ray irradiation and prevent the cleavage of the polymer main chain.

[0032] The medical rubber composition of the present disclosure preferably contains a triazine derivative as the (c) crosslinking agent.

[0033] The triazine derivative acts as a crosslinking agent for the halogenated butyl rubber. Examples of the triazine derivative include compounds represented by the general formula (1).

Chemical formula

[0034] In general formula (1), examples of the alkyl group include alkyl groups having 1 to 12 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, tert-pentyl group, n-hexyl group, 1,1-dimethylpropyl group, octyl group, isooctyl group, 2-ethylhexyl group, decyl group, or dodecyl group. Examples of the alkenyl group include alkenyl groups having 1 to 12 carbon atoms such as vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-butenyl group, 1,3-butadienyl group, or 2-pentenyl group. Examples of the aryl group include monocyclic or condensed polycyclic aromatic hydrocarbon groups, and examples thereof include aryl groups having 6 to 14 carbon atoms such as phenyl group, naphthyl group, anthryl group, phenanthryl group, or acenaphthylenyl group. Examples of the aralkyl group include aralkyl groups having 7 to 19 carbon atoms such as benzyl group, phenethyl group, diphenylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2,2-diphenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 2-biphenylylmethyl group, 3-biphenylylmethyl group, or 4-biphenylylmethyl group. Examples of the alkylaryl group include alkylaryl groups having 7 to 19 carbon atoms such as tolyl group, xylyl group, or octylphenyl group. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 9 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, or cyclononyl group.

[0035] Specific examples of the triazine derivative represented by the general formula (1) include, for example, 2,4,6-trimercapto-s-triazine, 2-methylamino-4,6-dimercapto-s-triazine, 2-(n-butylamino)-4,6-dimercapto-s-triazine, 2-octylamino-4,6-dimercapto-s-triazine, 2-propylamino-4,6-dimercapto-s-triazine, 2-diallylamino-4,6-dimercapto-s-triazine, 2-dimethylamino-4,6-dimercapto-s-triazine, 2-dibutylamino-4,6-dimercapto-s-triazine, 2-di(iso-butylamino)-4,6-dimercapto-s-triazine, 2-dipropylamino-4,6-dimercapto-s-triazine, 2-di(2-ethylhexyl)amino-4,6-dimercapto-s-triazine, 2-dioleylamino-4,6-dimercapto-s-triazine, 2-laurylamino-4,6-dimercapto-s-triazine or 2-anilino-4,6-dimercapto-s-triazine, or sodium salts or disodium salts thereof.

[0036] Among these, 2,4,6-trimercapto-s-triazine, 2-dialkylamino-4,6-dimercapto-s-triazine, and 2-anilino-4,6-dimercapto-s-triazine are preferable, and 2-dibutylamino-4,6-dimercapto-s-triazine is particularly preferable in terms of easy availability.

[0037] Examples of the triazine derivative also include one or more of 6-[bis(2-ethylhexyl)amino]-1,3,5-triazine-2,4-dithiol, 6-diisobutylamino-1,3,5-triazine-2,4-dithiol, 6-dibutylamino-1,3,5-triazine-2,4-dithiol, 6-dibutylamino-1,3,5-triazine-2,4-dithiol monosodium, 6-anilino-1,3,5-triazine-2,4-dithiol, 1,3,5-triazine-2,4,6-trithiol, etc.

[0038] In the present disclosure, as the triazine derivative, one type may be used alone, or two or more types may be used in combination.

[0039] The content of the triazine derivative in the medical rubber composition of the present disclosure is preferably, with respect to the halogen of the (a) halogenated butyl rubber, To 100 moles relative to, Preferably 1 mole or more , 5 moles or more more preferably, 8 moles or more even more preferably, 10 moles or more preferably, 15 moles or less more preferably, 12 moles or less even more preferably. When the content of the triazine derivative is within the above range, no remaining amount of the triazine derivative remains in the rubber composition after vulcanization, and all of it is used for cross-linking bonds, and good rubber physical properties (hardness, tensile strength, Cset) and elution characteristics can be obtained.

[0040] The content of the (c) triazine derivative in the medical rubber composition of the present disclosure is preferably 0.1 part by mass or more, more preferably 0.5 part by mass or more, preferably 1.4 parts by mass or less, and more preferably 1.2 parts by mass or less with respect to 100 parts by mass of the (a) base polymer component. If the content of the (c) triazine derivative is within the above range, a rubber with good rubber physical properties (hardness, tensile strength, Cset) and processability (less scorching) can be obtained.

[0041] The medical rubber composition of the present disclosure preferably does not contain a vulcanization accelerator. This is because the vulcanization accelerator may remain in the final rubber product and dissolve into the chemical solution in the syringe or vial. Examples of the vulcanization accelerator include guanidine-based accelerators (e.g., diphenylguanidine), thiuram-based accelerators (e.g., tetramethylthiuram disulfide, tetramethylthiuram monosulfide), dithiocarbamate-based accelerators (e.g., zinc dimethyldithiocarbamate), thiazole-based accelerators (e.g., 2-mercaptobenzothiazole, dibenzothiazyl disulfide), and sulfenamide-based accelerators (N-cyclohexyl-2-benzothiazole sulfenamide, N-t-butyl-2-benzothiazole sulfenamide).

[0042] The medical rubber composition of the present disclosure may contain hydrotalcite. Hydrotalcite functions as a scorch inhibitor during the crosslinking of butyl rubber halide and also prevents the compression set of medical rubber parts from increasing. Furthermore, hydrotalcite functions as an acid acceptor to absorb chlorine-based gases and bromine-based gases generated during the crosslinking of butyl rubber halide and prevent the occurrence of crosslinking inhibition and the like caused by these gases. Note that the magnesium oxide described above can also function as an acid acceptor.

[0043] Examples of hydrotalcite include Mg 4.5 Al 2 (OH) 13 CO 3 ·3.5H 2 O, Mg 4.5 Al 2 (OH) 13 CO 3 、Mg 4 Al 2 (OH) 12 CO 3 ·3.5H 2 O, Mg 6 Al 2 (OH) 16 CO 3 ·4H 2 O, Mg 5 Al 2 (OH) 14 CO3 ·4H 2 O, Mg 3 Al 2 (OH) 10 CO 3 ·1.7H 2 Examples of the Mg-Al-based hydrotalcite include one or more of Mg-Al-based hydrotalcite such as 3 ·4H 2 O, Mg 3 Al 2 (OH) 10 CO 3 ·1.7H 2 O, etc.

[0044] Specific examples of the hydrotalcite include, for example, DHT-4A (registered trademark)-2 manufactured by Kyowa Chemical Industry Co., Ltd., etc.

[0045] In the medical rubber composition, when using hydrotalcite as an acid acceptor, it is preferably used in combination with MgO. In this case, it is preferable to consider the blending amount of hydrotalcite in terms of the total amount of the acid acceptor (hydrotalcite and MgO). The total content as the acid acceptor (hydrotalcite and MgO) is preferably 0.5 parts by mass or more, more preferably 1 part by mass or more, preferably 15 parts by mass or less, and more preferably 10 parts by mass or less with respect to 100 parts by mass of the base polymer component (a). If the total content of the acid acceptor (hydrotalcite and MgO) is within the above range, the generation of rust on the mold, etc. can be suppressed, and the defect that the raw material itself becomes a white dot foreign matter can be reduced.

[0046] The medical rubber composition of the present disclosure may contain a co-crosslinking agent. The co-crosslinking agent is preferably a polyfunctional (meth)acrylate compound. The polyfunctional (meth)acrylate compound is more preferably a (meth)acrylate-based compound having two or more functional groups, further preferably a (meth)acrylate-based compound having three or more functional groups, preferably an (meth)acrylate-based compound having eight or less functional groups, and preferably an (meth)acrylate-based compound having six or less functional groups. Examples of the (meth)acrylate compound having two or more functional groups include compounds having at least two acryloyl groups and / or methacryloyl groups. Note that "(meth)acrylate" means "acrylate" and / or "methacrylate".

[0047] Examples of the difunctional or higher (meth)acrylate compounds include di(meth)acrylates of polyethylene glycol, 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, 1,9-nonanediol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, trimethylolethane tri(meth)acrylate, pentaerythritol tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, glycerin tri(meth)acrylate, dipentaerythritol tri(meth)acrylate, dipentaerythritol tetra(meth)acrylate, dipentaerythritol penta(meth)acrylate, dipentaerythritol hexa(meth)acrylate, tripentaerythritol tetra(meth)acrylate, tripentaerythritol penta(meth)acrylate, tripentaerythritol hexa(meth)acrylate, tripentaerythritol hepta(meth)acrylate, and the like. The co-crosslinking agent may be used alone or in combination of two or more kinds.

[0048] A filler (d) may be blended in the medical rubber composition of the present disclosure. Examples of the filler (d) include inorganic fillers such as silica, clay, and talc. Clay or talc is more preferable as the filler. The filler functions to adjust the rubber hardness of the medical rubber component and also functions to reduce the production cost of the medical rubber component as a bulking agent.

[0049] Examples of the clay include calcined clay and kaolin clay. Specific examples of the clay include SILLITIN (registered trademark) Z manufactured by HOFFMANN MINERAL, SATINTONE (registered trademark) W manufactured by ENGELHARD, NN kaolin clay manufactured by Tsuchiya Kaolin Industry Co., Ltd., PoleStar200R manufactured by Imerys Specialties Japan Co., Ltd., and the like.

[0050] Specific examples of the talc include, for example, Hytron A manufactured by Takehara Chemical Industry Co., Ltd., MICRO ACE (registered trademark) K-1 manufactured by Nippon Talc Co., Ltd., Mistron (registered trademark) Vapor manufactured by Imerys Specialties Japan Co., Ltd., and the like.

[0051] The medical rubber composition of the present disclosure may further contain a colorant such as titanium oxide or carbon black, a processing aid, polyethylene glycol as a crosslinking activator, a plasticizer (for example, paraffin oil), etc. in appropriate proportions.

[0052] The present disclosure includes a medical rubber part formed by molding the medical rubber composition of the present disclosure. Examples of the medical rubber part of the present disclosure include rubber stoppers and seal members for containers (for example, vial bottles) for various drugs such as liquid preparations, powder preparations, and freeze-dried preparations, rubber stoppers for vacuum blood collection tubes, plunger stoppers for prefilled syringes, or sliding or seal parts such as nozzle caps.

[0053] The medical rubber composition of the present disclosure is obtained by kneading (a) a base polymer containing a halogenated butyl rubber, (b) polyethylene, (c) a triazine derivative as a crosslinking agent, and other compounding materials added as necessary. The kneading can be performed using, for example, an open roll, a closed kneader, etc. The kneaded product is preferably formed into a ribbon shape, a sheet shape, a pellet shape, etc., and more preferably formed into a sheet shape.

[0054] By press-molding the kneaded product in a ribbon shape, a sheet shape, or a pellet shape, a medical rubber part having a desired shape can be obtained. The crosslinking reaction of the medical rubber composition proceeds during pressing. The molding temperature is preferably, for example, 130°C or higher, more preferably 140°C or higher, preferably 200°C or lower, and more preferably 190°C or lower. The molding time is preferably 2 minutes or longer, more preferably 3 minutes or longer, preferably 60 minutes or shorter, and more preferably 30 minutes or shorter. The molding pressure is preferably 0.1 MPa or higher, more preferably 0.2 MPa or higher, preferably 10 MPa or lower, and more preferably 8 MPa or lower.

[0055] From the molded product after press molding, unnecessary portions are cut away and removed to obtain a predetermined shape. The resulting molded product is washed, dried, and packaged to produce medical rubber parts.

[0056] Also, a resin film may be laminated and integrated with the medical rubber parts. Examples of the resin film include films of inert resins such as polytetrafluoroethylene (PTFE), tetrafluoroethylene-ethylene copolymer (ETFE), and modified products thereof, and ultra-high molecular weight polyethylene (UHMWPE).

[0057] The resin film may be integrated with the medical rubber parts formed after press molding by, for example, press molding in a state of being stacked on a rubber composition in the form of a sheet.

[0058] The present disclosure includes a package of medical rubber parts in which a plurality of the medical rubber parts of the present disclosure are housed in a package, and which is characterized by having been subjected to gamma sterilization treatment.

[0059] Examples of the gamma rays include gamma rays emitted from, for example, cobalt 60 or cesium 137, and gamma rays emitted from cobalt 60 are preferred.

[0060] Gamma irradiation is such that the absorbed dose of gamma rays for medical rubber parts is established in the actual sterilization validation procedure. In many ordinary medical devices, 15 kGy is often used as the minimum absorbed dose. The irradiation dose of gamma rays to ensure that the absorbed dose of gamma rays for all medical rubber parts in the package is 15 kGy or more will vary depending on the number and arrangement of medical rubber parts in the package, etc., but generally it is irradiated with a dose in the range of 1.4 times or more and 2.0 times or less of 15 kGy. Similarly, when 20 kGy is used as the minimum absorbed dose, it is irradiated with a dose in the range of 1.4 times or more and 2.0 times or less of 20 kGy, and when 25 kGy is used as the minimum absorbed dose, it is irradiated with a dose in the range of 1.4 times or more and 2.0 times or less of 25 kGy. Incidentally, the absorbed dose of gamma rays can be confirmed by attaching a dosimeter to the irradiated object.

[0061] The oxygen concentration in the package containing medical rubber parts before gamma sterilization treatment is preferably 5% or less, more preferably 3% or less, and even more preferably 1% or less. This is because by setting the oxygen concentration in the package to 5% or less, (a) deterioration of the base polymer due to gamma irradiation can be suppressed.

[0062] Examples of methods for setting the oxygen concentration in the package to 5% or less include a method of replacing the air in the package with an inert gas and a method of containing an oxygen scavenger in the package.

[0063] Examples of the inert gas include noble gases such as helium, neon, argon, or nitrogen gas.

[0064] Examples of the oxygen scavenger include iron-based oxygen scavenger Ageless (commercially available products).

[0065] The package containing medical rubber parts is not particularly limited as long as it can be irradiated with gamma rays. Examples of the package include shapes such as bags and boxes.

[0066] Examples of the packaging bag include those formed from thermoplastic resin films such as polyethylene, polyamide, and polyester. The packaging bag is preferably one that can be sealed. The box is not particularly limited, and examples include cardboard boxes and corrugated boxes.

[0067] Examples of the package include a breathable package and an airtight (gas-sealed) package, and it is also preferable to use them in combination.

[0068] Gamma sterilization of medical rubber parts may be performed, for example, on a plurality of medical rubber parts contained in a primary package (e.g., a packaging bag), and further on a package (e.g., a cardboard box) containing a plurality of primary packages.

[0069] Figure 1 is an explanatory diagram schematically showing an example of a packaging mode for gamma irradiation. In the mode shown in Figure 1, a primary package 3 containing a plurality of medical rubber parts 1 is further contained in a secondary antistatic package 5 and a tertiary antistatic package 7. The primary package 3 preferably has breathability, and the secondary antistatic package 5 and the tertiary antistatic package 7 preferably can seal gas. The secondary antistatic package 5 and the tertiary antistatic package 7 are preferably sealed by heat seals 9 respectively. When using an oxygen absorber 11, it is preferable to arrange the oxygen absorber 11 between the primary package 3 and the secondary package 5 so that the oxygen absorber 11 does not directly contact the medical rubber part 1. By arranging the oxygen absorber 11 in the secondary package 5, the oxygen concentration in the secondary package 5 and the primary package 3 can be made 5% or less. A plurality of the tertiary antistatic packages 7 can be contained in a quaternary package (e.g., a cardboard box) for gamma irradiation.

[0070] FIG. 2 is an explanatory diagram schematically showing another example of a packaging mode for gamma irradiation. In the mode shown in FIG. 2, a primary package 3 containing a plurality of medical rubber parts 1 is further housed in a secondary antistatic package 5 and a tertiary antistatic package 7. The secondary antistatic package 5 and the tertiary antistatic package 7 are preferably sealed by heat seals 9 respectively. As the primary package 3, those having air permeability are preferable, and the secondary antistatic package 5 and the tertiary antistatic package 7 are preferably capable of sealing gas. The secondary package 5 containing the primary package 3 is filled with an inert gas. By filling with an inert gas, the oxygen concentration in the secondary package 5 and the primary package 3 can be made 5% or less. A plurality of the tertiary antistatic packages 7 can be housed in a quaternary package (for example, a cardboard box) and gamma irradiated.

[0071] Note that during gamma irradiation, the package containing a plurality of medical rubber parts is preferably irradiated with gamma rays in a state of being housed in a storage container made of, for example, an aluminum alloy.

Example

[0072] Hereinafter, the present disclosure will be described in detail by way of examples. However, the present disclosure is not limited to the following examples, and any changes and embodiments within the scope not departing from the gist of the present disclosure are all included in the scope of the present disclosure.

[0073] [Preparation of medical rubber composition] Among the components shown in Table 1, the components other than the crosslinking component were blended and kneaded at a filling rate of 75% using a 10 L pressurized sealed kneader. After aging at room temperature, the crosslinking component was added and kneaded on an open roll to prepare a rubber composition.

[0074] [Manufacture of medical rubber stopper] The rubber composition was formed into a sheet, sandwiched between an upper mold and a lower mold, and vacuum press-molded at 180°C for 10 minutes to continuously form a plurality of rubber stoppers for vials of freeze-dried injections, each having a flange diameter of 19.0 mm, a leg diameter of 13.2 mm, and a thickness of the flange puncture portion of 2.5 mm, on one sheet of the above-mentioned sheet. Next, a silicone-based lubricating coating agent was applied to both sides of the sheet, and then the rubber stoppers were manufactured through the steps of appearance inspection, punching, washing, sterilization, drying, and packaging. The manufactured rubber stoppers were used for eluate tests and adhesion tests.

[0075]

Table 1

[0076] The details of the compounding materials used are as follows. Butylated rubber: HT-1066 manufactured by ExxonMobil (chlorine content: 1.26 wt%) Polyethylene 1: Mipelon XM-220 manufactured by Mitsui Chemicals, Inc. (crystallinity 69%) Polyethylene 2: Flocene UF20S manufactured by Sumitomo Seika Chemicals Co., Ltd. (crystallinity 35%) Triazine derivative: Disnet DB manufactured by Sankyo Kasei Co., Ltd. Talc: Mistron Vapor manufactured by Imerys Specialties Silica: Nipseal LP manufactured by Tosoh Silica Corporation Magnesium oxide: Magsurat 150s manufactured by Kyowa Chemical Industry Co., Ltd. Carbon black: Diablack G manufactured by Mitsubishi Chemical Corporation Titanium oxide: KR-380 manufactured by Titanium Industry Co., Ltd. Oil: PW380 manufactured by Idemitsu Kosan Co., Ltd.

[0077] [Evaluation method] (1) Measurement of the heat of fusion of polyethylene The heat of fusion of polyethylene was obtained from the first heating test of differential scanning calorimetry (DSC: Differential Scanning Calorimetry). DSC measurement conditions: 20°C to 200°C, heating rate 10°C / min

[0078] (2) Elution test Measurement sample: The rubber stopper was irradiated with gamma rays so that the absorbed doses were 25 kGy and 50 kGy, respectively, to prepare a rubber stopper after gamma ray irradiation. For the measurement sample, the "elution test" described in the "7.03 Rubber Stopper Test Method for Infusion Solutions" of the 17th Revised Japanese Pharmacopoeia was carried out. The compliance conditions were as follows. Properties of the test solution: Colorless and clear UV transmittance: The transmittance at wavelengths of 430 nm and 650 nm is 99.0% or more with a layer length of 10 mm. Ultraviolet absorption spectrum: The absorbance at wavelengths of 220 nm to 350 nm is 0.20 or less. pH: The difference between the test solution and the blank test solution is 1.0 or less. Zinc: The absorbance of the sample solution is less than or equal to the absorbance of the standard solution. Potassium permanganate reducing substances: 2.0 mL / 100 mL or less (Pharmacopoeia standard) Evaporation residue: 2.0 mg or less If any item was not satisfied, it was regarded as "non-compliant", and if all items were satisfied, it was evaluated as "compliant".

[0079] (3) TOC test For the eluate obtained by performing the elution test in (2), the total organic carbon value TOC (NPOC: TOC by acidification aeration treatment) was measured. Measurement and analysis apparatus: Shimadzu total organic carbon meter TOC-VCSH (combustion oxidation method) Measurement and analysis conditions: Combustion tube temperature 680 degrees, using a high-sensitivity catalyst Carrier gas: High-purity air 150 mL / min Injection volume 200 μL Acid addition concentration 1.5% Aeration treatment time 90 sec

[0080] The elution characteristics before and after gamma ray irradiation were evaluated. Assuming the TOC before gamma ray irradiation as 100%, the TOC after gamma ray irradiation was evaluated with a relative index. The larger the number, the worse the elution performance compared to before gamma ray irradiation. Evaluation Criteria ◎: 100% or less (Improved from before irradiation) 〇: More than 100% and 120% or less (Equivalent to before irradiation) △: More than 120% and 150% or less (Slightly deteriorated from before irradiation) ×: More than 150% (Greatly deteriorated from before irradiation)

[0081] (4) Adhesion Test Using the Shimadzu desktop testing machine EZ-SX, the test was conducted as follows. As shown in Figure 3, the sample 13 was fixed to the lower fixing jig 15, the upper metal probe 17 was pressed onto the sample 13, and after reaching the set pressure, it was held for 10 seconds. Then, the metal probe 17 was raised upward, and the peak value of the adhesion force generated between the metal probe 17 and the sample 13 was taken as the tack value. The measurement was performed 5 times for each sample, and the average value of the 3 measurement values excluding the maximum and minimum values among the obtained results was calculated. Taking the adhesion force of the sample before gamma-ray irradiation as 100, the adhesion force of the sample after gamma-ray irradiation was indexed. The smaller the index, the lower the adhesiveness and the better the result. Measurement Conditions: Pressing speed: 0.5 mm / s Pressing load: 1000 g weight Pressing holding time: 10 seconds Pulling-up speed: 10 mm / s Final pulling-up distance: 3 mm Probe diameter: 10 mm Evaluation Criteria: ◎: 100% or less (Improved from before irradiation) 〇: More than 100% and 120% or less (Equivalent to before irradiation) △: More than 120% and 150% or less (Slightly deteriorated from before irradiation) ×: More than 150% (Greatly deteriorated from before irradiation)

[0082] The results of the eluate test, TOC test, and adhesion test are shown together in Table 1.

[0083] Regarding the suitability of READY TO USE, the judgment was made as follows. When the dissolution test result is compliant, the TOC test result is an evaluation result of Δ or higher, and the adhesion test result is Δ or higher, it is determined that it meets READY TO USE. If any one of the evaluation results is not satisfied, it is considered non-compliant.

[0084] From the results in Table 1, it can be seen that a medical rubber part formed from a medical rubber composition containing (a) a base polymer containing halogenated butyl rubber, (b) polyethylene, and (c) a triazine derivative as a crosslinking agent, and the content ratio of the triazine derivative is 1 mol% to 15 mol% with respect to 100 mol% of the halogen of the (a) halogenated butyl rubber, maintains non-elution characteristics even by gamma sterilization.

Industrial Applicability

[0085] According to the present disclosure, it is possible to provide a medical rubber part and its package that maintain non-elution characteristics even after gamma sterilization and have few troubles in the manufacturing process of medical supplies. According to the present disclosure, it is possible to provide a medical rubber composition suitable for manufacturing the medical rubber part.

Explanation of Symbols

[0086] 1: Medical rubber part, 3: Primary package, 5: Secondary package, 7: Tertiary package, 9: Heat seal, 11: Oxygen absorber, 13: Sample, 15: Fixing jig, 17: Metal probe

[0087] The medical rubber composition of the present disclosure (1) (a) Contains a base polymer containing halogenated butyl rubber, (b) Contains polyethylene, (c) Contains a triazine derivative as a crosslinking agent, It is characterized in that the content ratio of the triazine derivative is 1 mol% to 15 mol% with respect to 100 mol% of the halogen of the (a) halogenated butyl rubber.

[0088] The medical rubber composition of the present disclosure (2) is the medical rubber composition according to the present disclosure (1), wherein the halogenated butyl rubber is at least one selected from the group consisting of chlorinated butyl rubber, brominated butyl rubber, and brominated isobutylene para-methylstyrene copolymer rubber.

[0089] The medical rubber composition of the present disclosure (3) is the medical rubber composition according to the present disclosure (1) or (2), wherein (b) the polyethylene contains polyethylene having a crystallinity of 70% or less.

[0090] The medical rubber composition of the present disclosure (4) is the medical rubber composition according to any one of the present disclosures (1) to (3), wherein (b) the blending amount of the polyethylene is 3 parts by mass to 30 parts by mass with respect to 100 parts by mass of the base polymer.

[0091] The medical rubber composition of the present disclosure (5) is the medical rubber composition according to any one of the present disclosures (1) to (4), wherein (c) the content of the triazine derivative is 0.1 part by mass or more and 1.4 parts by mass or less with respect to 100 parts by mass of the base polymer component.

[0092] The medical rubber part of the present disclosure (6) is a medical rubber part formed by molding the medical rubber composition according to any one of the present disclosures (1) to (5).

[0093] The package of the medical rubber part of the present disclosure (7) is a package of the medical rubber part in which a plurality of the medical rubber parts according to the present disclosure (6) are housed in the package, and is characterized in that gamma sterilization treatment has been performed.

[0094] The package of the medical rubber part of the present disclosure (8) is the package of the medical rubber part according to the present disclosure (7), in which gamma sterilization treatment has been performed so that the absorbed dose of gamma rays is 15 kGy or more.

[0095] The package of the medical rubber part of the present disclosure (9) is the package of the medical rubber part described in the present disclosure (7) or (8) that has been gamma-sterilized so that the absorbed dose of gamma rays is 25 kGy or more.

[0096] The package of the medical rubber part of the present disclosure (10) is the package of the medical rubber part according to any one of the present disclosures (7) to (9) in which the oxygen concentration of the package before gamma sterilization is 5% or less.

[0097] The package of the medical rubber part of the present disclosure (11) is the package of the medical rubber part according to any one of the present disclosures (7) to (10), wherein the medical rubber part is a rubber stopper for a vial, a cap for a syringe, a plunger stopper, or a rubber stopper for a vacuum blood collection tube.

Claims

1. (a) A base polymer containing 90% by mass or more of chlorinated butyl rubber, (b) As fine powder polyethylene, high density polyethylene and low density polyethylene (c) Containing a triazine derivative as a crosslinking agent, A medical rubber composition, wherein the content rate of the triazine derivative is 1 mol to 15 mol with respect to 100 mol of chlorine of the (a) chlorinated butyl rubber.

2. The medical rubber composition according to Claim 1, wherein the mass ratio (HDPE / LDPE) of the high density polyethylene (HDPE) and the low density polyethylene (LDPE) is 0.3 or more and 5.0 or less.

3. (b) The medical rubber composition according to Claim 1 or 2, wherein the fine powder polyethylene contains polyethylene having a crystallinity of 70% or less.

4. (b) The medical rubber composition according to any one of Claims 1 to 3, wherein the blending amount of the fine powder polyethylene is 3 parts by mass to 30 parts by mass with respect to 100 parts by mass of the (a) base polymer.

5. (c) The medical rubber composition according to any one of Claims 1 to 4, wherein the content of the triazine derivative is 0.1 part by mass or more and 1.4 parts by mass or less with respect to 100 parts by mass of the (a) base polymer.

6. A medical rubber part formed by molding the medical rubber composition according to any one of Claims 1 to 5.

7. A package of medical rubber parts, which is formed by accommodating a plurality of the medical rubber parts according to Claim 6 in a package, and is characterized in that gamma sterilization treatment has been performed.

8. The package of medical rubber parts according to Claim 7, wherein gamma sterilization treatment has been performed so that the absorbed dose of gamma rays is 15 kGy or more.

9. The package of medical rubber parts according to Claim 7 or 8, wherein gamma sterilization treatment has been performed so that the absorbed dose of gamma rays is 25 kGy or more.

10. The package of medical rubber parts according to any one of Claims 7 to 9, wherein the oxygen concentration of the package before gamma sterilization treatment is 5% or less.

11. The medical rubber part is a rubber stopper for a vial, a cap for a syringe, a plunger stopper, or a rubber stopper for a vacuum blood collection tube. The package of medical rubber parts according to any one of Claims 7 to 10.

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