JPH05337164A - Plug body for medicine - Google Patents

Abstract

PURPOSE:To provide a plug body for medicine excellent in hygiene with low cost by using a material containing a cyclic olefin compound and/or bridged polycyclic hydrocarbon compound as polymer components and a resin, synthetic rubber or the like having 130 deg.C or more of softening point. CONSTITUTION:A plug body for a medicine implement is formed by using a material containing a cyclic olefin compound and/or bridged polycyclic hydrocarbon compound as polymer components and a resin, synthetic rubber or the like having 130 deg.C or more of softening point. For example, a sliding plug 3 is formed which is slid in an outer tube 2 of an injector by pushing a push rod 5 of the sliding plug. Also, a rubber plug 8, outer plug 20 and inner plug 21 to be mounted on a fixing part 24 of a plastic container 22 for infusion are formed. Thus, the plug body for medicine and medical implement inart to acid, alkali and medicine liquid can be manufactured with low cost.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stopper made of a rubber-like elastic material used as a part of a container for medicines, medical instruments, etc., and a test prescribed in the medical device regulations in the Japanese Pharmacopoeia, Ministry of Health and Welfare Notification, etc. The present invention relates to a stopper for pharmaceuticals which is required to have properties conforming to or conforming to the standard values and standards of the law.

[0002]

2. Description of the Related Art Rubber-like elastic materials that accompany pharmaceutical containers, medical instruments and the like include natural rubber (NR), isoprene rubber (IR), isobutylene / isoprene copolymer (I).
IR), halogenated derivatives thereof (BIIR, CII
R), polybutadiene (BR), thermoplastic elastomer and the like are used. That is, a technique in which a thermoplastic elastomer (a styrene-isoprene or butadiene copolymer and a hydrogenated product thereof) is used as a stopper for a drug container (Japanese Patent Laid-Open No. 6-58242).
1-131746, Japanese Examinations 2-3493, Japanese Examinations-2-
4296, JP-B-57-26782, JP-A-59-28.
965), a technique of using a thermoplastic elastomer and IIR rubber as a stopper (Japanese Patent Laid-Open No. 59-28965),
There is a rubber stopper for pharmaceuticals using a rubber having an isoprene unit content of 20 to 80 mol% (JP-A-2-53843). In order to manufacture rubber products for pharmaceuticals and medical devices, the inventors of the present invention have incorporated a technique of blending ultra-high molecular weight polyethylene with IIR (Japanese Patent Laid-Open No. 60-144346), and then IR, BR, SBR with ultra-high A technique for blending polyethylene having a molecular weight (Japanese Patent Laid-Open No. 1-178261) has already been proposed. Further, a rubber stopper for pharmaceuticals in which a hydrogenated thermoplastic elastomer is mixed with a dynamically partially crosslinked plastic and / or rubber (JP-A-3-68363),
Further, a technique in which a rubber stopper laminated with a thermoplastic resin film is welded to a plastic bag container mouth (Japanese Patent Laid-Open No. 2-12).
No. 75).

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a stopper for pharmaceuticals which is more improved than the above-mentioned conventional products in response to the technology which is advancing in the industrial field. In particular, it not only complies with the standard price described in the official text of the Japanese Pharmacopoeia, but also can handle the most recent new medicines, containers such as antibiotics, tools, etc., and affect unstable chemicals and liquid chemicals. The purpose is to economically supply a rubber elastic body that serves as a plug body that can maintain its quality for a long period of time without giving.

[0004]

Means for Solving the Problems As a means for solving the above problems, the present invention contains a cyclic olefin compound and / or a crosslinked polycyclic hydrocarbon compound as a polymer component and has a softening point of 130 ° C. or higher. Provided is a stopper for a drug, which is made of a material containing a resin and synthetic rubbers. The present invention also contains a cyclic olefin compound and / or a crosslinked polycyclic hydrocarbon compound as a polymer component and has a softening point of 13
There is also provided a stopper for pharmaceuticals made of a material which also contains a resin at 0 ° C. or higher, synthetic rubbers and a crosslinking agent. In the above-mentioned material of the present invention, a softening point 1 containing the cyclic olefin compound and / or the crosslinked polycyclic hydrocarbon compound as a polymer component.
The weight ratio of resin to synthetic rubber at 30 ° C or higher is 3 to
Particularly preferred is 50 parts to 100 parts. As the cyclic olefin compound in the present invention, monocyclic olefin compounds or their alkyl derivatives and acrylate derivatives are particularly preferable. In addition, as the crosslinked polycyclic hydrocarbon compound in the present invention, a compound having one or more unsaturated bonds in the ring or a substituent thereof is particularly preferable. In the present invention, a resin containing the cyclic olefin compound or the crosslinked polycyclic hydrocarbon compound as a polymer component (hereinafter, also simply referred to as “cyclic resin”) is a lower olefin, an aromatic or a lower olefin, or It may contain an aromatic vinyl monomer as a copolymer component, or may be a mixture with an olefin resin and / or synthetic rubber. Further, the cyclic resin of the present invention particularly preferably has a bromine number of 20 or less.

[0005]

[Operation] Recently, C ₅ , C ₉ obtained by naphtha decomposition, etc.
Characteristic resin bodies are being developed by the technology for separating and purifying the monomers of each fraction and the new technology for the polymerization catalyst of each monomer. Among them, cyclic olefin-based monomers, especially cross-linked polycyclic hydrocarbon-based monomers, etc. Significant progress has been made with respect to these polymers. The present inventors have found that a resin containing such a cyclic olefin compound or a crosslinked polycyclic hydrocarbon compound as a polymer component is alkali resistant, acid resistant,
It has excellent resistance to water and chemicals, heat resistance, oxidation resistance, high melting point, is a transparent amorphous material, and is hygienic and conforms to the Japanese Pharmacopoeia test. We found that it has characteristics different from resins, and that it is a very excellent resin for use in pharmaceutical materials,
As a result of various studies, the inventors have found that a mixture of the resin and synthetic rubber, especially a cross-linked molded article, is extremely excellent as a stopper for pharmaceuticals, and arrived at the present invention.

The compound as the polymer component of the cyclic resin used as the stopper material for pharmaceuticals of the present invention will be described in more detail. First, as the cyclic olefin-based compounds, for example, cyclopentadiene (abbreviated as CPD),

[Chemical 1] Cyclopentene,

[Chemical 2] Methyl-cyclohexene,

[Chemical 3] Dimethyl-cyclohexene

[Chemical 4] Cyclooctene

[Chemical 5] And the like, and lower alkyl derivatives and acrylate derivatives obtained by substituting 1 to 3 lower alkyl groups such as a methyl group and an ethyl group.

The crosslinked polycyclic hydrocarbon compounds include
Bicyclic or more bridged cyclic hydrocarbon compounds, particularly bridged polycyclic olefin compounds and derivatives thereof, or bridged polycyclic saturated hydrocarbon compounds having unsaturated double bonds in their substituents Is particularly preferable. That is, crosslinked polycyclic cycloalkene compounds and lower alkyl derivatives thereof, arylyl derivatives, aralkyl derivatives, vinyl derivatives of crosslinked polycyclic cycloalkane compounds, allyloxycarboxy derivatives, (meth) acryloxy derivatives and the like can be mentioned. ..

More specifically, the following compounds can be mentioned. Bicyclo [2,2,1] -2-heptoene,

[Chemical 6] Bicyclo [2,2,1] 2,5-heptodiene,

[Chemical 7] Ethyl-bicyclo [2,2,1] -2-heptoene,

[Chemical 8] Ethylidene-bicyclo [2,2,1] -2-heptoene (also referred to as ethylidene-2-norbornene),

[Chemical 9] Phenyl-bicyclo [2,2,1] hept-2-ene,

[Chemical 10] Dicyclo [4,3,0] -3,8-nonadiene

[Chemical 11] Tricyclo [4,3,0,1 ^2,5 ] -3-decene,

[Chemical formula 12] Tricyclo [4,3,0,1 ^2,5 ] -3,8-decetene (also referred to as 3,8 dihydro-dicyclopentadiene),

[Chemical 13] Tricyclo [4,4,0,1 ^2,5 ] -3-undecene,

[Chemical 14] Tetracyclo [4,4,0,1 ^2,5, 1 ^7,10] -3-dodecene,

[Chemical 15] Dimethyl-tetracyclo [4,4,0,1 ^2,5 ,
^1,7,10 ] -3-dodecene,

[Chemical 16] Pentacyclo [7,4,0,1 ^2,5, 0,0 ^{8 and 13,} 1
^9,12 ] -3-Pentadecene,

[Chemical 17] Dimethyl - hexacyclo [6,6,1,1 ^3,6, 1
^10,13, O ^2,7, 0 ^9,14] -4-heptadecene,

[Chemical 18] Pentacyclo [6,5,1,1 ^3,6, O ^2,7, 0 ^9,13]
-4-pentadecene,

[Chemical 19] Ethylidene-ethyl-tetracyclo [4,4,0,1
^{2,5,1 7,10} ] -3-dodecene,

[Chemical 20] Bis (allyloxycarboxy) tricyclo [4,3,3
0,1 ^2,5 ] -decane,

[Chemical 21] Bis (methacryloxy) tricyclo [4,3,0,1
^2,5 ] -decane,

[Chemical formula 22] Bis (acryloxy) tricyclo [4,3,0,1
^2,5 ] -decane

[Chemical formula 23] Methyloxycarbonyltetracyclo [4,4,0,1
^{2,5,1 7,10} ] -3-dodecene,

[Chemical formula 24] Hexacyclo [6,6,1,1 ^3,6, 1 ^{10, 13,}
0 ^2,7, 0 ^9,14] -4-heptadecene,

[Chemical 25]

In the cyclic resin of the present invention, at least one selected from the above-mentioned cyclic olefin compound and crosslinked polycyclic hydrocarbon compound is used as the polymer component, but it is copolymerizable with these polymer components. Lower olefins, aromatics or lower olefins or aromatic vinyl monomers may be contained as a copolymer component. Specific examples of such other polymer components include ethylene,
Examples thereof include propylene, isoprene, butadiene, methylpentene, norbornene, butene, vinyltoluene and the like. Two or more kinds of such other copolymer components may be used in combination.

The cyclic resin of the present invention can be polymerized by a known technique, for example, Japanese Examined Patent Publications Nos. 47-11818 and 5-18.
8-43412, 61-1442, and 62-1976.
1, JP-A-50-75700, JP-A-55-129434,
58-127728, 60-168708, 61
-11516, 61-271308, 63-22
118, 63-221118, 63-24310
3, known techniques described in JP-A-2-180976 and the like can be mentioned.

More specifically, the following three methods can be used. (1) A cyclopentadiene and a corresponding olefin or cyclic olefin are subjected to an cycloaddition reaction (Diels-Alder reaction) to obtain a crosslinked cyclic hydrocarbon monomer, and the monomer is a solvent containing aluminum, tungsten, Polymerize using vanadium and boron compounds as catalysts,
A method of obtaining a crosslinked cyclic hydrocarbon resin by preparing a resinous material and purifying the resin. (2) a monomer as a polymer component of the cyclic resin of the present invention,
For example, a lower alkyl cycloalkene compound, a cycloalkadiene compound, a bridged polycyclic alkadiene compound, a bridged polycyclic alkene compound, etc. in a solvent using vanadium, aluminum, tungsten, boron compounds, etc. as a polymerization reaction To obtain a high molecular weight resinous material. Next, a method of hydrogenating the resinous material with a nickel, platinum catalyst or the like to obtain the cyclic resin of the present invention. (3) A method of polymerizing an acryloyl derivative of a crosslinked polycyclic compound with light and / or an organic peroxide to obtain a crosslinked cyclic resin and purifying it to obtain the cyclic resin of the present invention. In the above three types of polymerization reactions, a monomer such as an olefin compound or an aromatic compound may be further added to obtain a copolymer. According to any of the above-mentioned polymerization methods, in the cyclic resin body of the present invention, the presence of a monomer as a polymerization component, a low molecular weight oligomer, a metal catalyst, etc. is preferable in terms of generation of odor and deterioration of hygienic properties. Absent.

Further, the cyclic resin body has a bromine number (JIS K
2543) It is preferably 20 or less. When the cyclic resin body has a bromine number of more than 20, the molded plug body product is colored and discolored. As one of the countermeasures against this coloring and discoloration, an antioxidant is added. Examples of the antioxidant added to the cyclic resin body of the present invention include 2-6-di-t-
Butyl-4-methylphenol (BHT), octadecyl-3- (4'-hydroxy-3 ', 5'-di-t-butylphenyl) propionate (trade name: Irganox 1076, manufactured by Ciba Geigy), tetrakis [methylene (3,5-di-t-butyl-4-hydroxyphenyl) propionate] methane (trade name: Irganox 1010, manufactured by Ciba Geigy), tocophenol, 4,
4'-thiobis (6-t-butyl-3-methylphenol) (trade name: Antage RC, manufactured by Kawaguchi Kagaku), bis (2,2,6,6, -tetramethylpiperidyl) sebacate (trade name: Sanol LS) -770, Sankyo Co., Ltd.
Manufactured), 1,3,8-triaza-7,7,9,9-tetramethyl-n-octyl-spiro [4,5] decane-2,
4-dione (trade name: Sanol LS-772, manufactured by Sankyo Co., Ltd.), distearyl-thiodipropionate (trade name: Antigen TPS, manufactured by Sumitomo Chemical Co., Ltd.), pentaerythritol tetrakis (β-laurylthiopro). (Pionate) (Product name: Sumilizer TPD Sumitomo Chemical Co., Ltd.)
Manufactured), 1,3,5-trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl)
Examples thereof include benzene (trade name: Ionox 330, manufactured by ICI), tris (2,4-di-t-butylphenyl) phosphite (trade name: Irganox 168, manufactured by Ciba Geigy). The addition amount of these antioxidants is 0.005 to 100 parts by weight of the cyclic resin.
It is 1% by weight, and one or more kinds can be used in combination.

The content of the cyclic olefin monomer and / or the crosslinked polycyclic hydrocarbon compound monomer in the cyclic resin body of the present invention is preferably 30% by weight or more. Further, the molecular weight of the cyclic resin body is 5,000 to 100,000,000, and the low molecular weight resin body is a highly viscous body, but when it becomes a polymer resin, it becomes a powder resin.

The characteristics of the cyclic resin of the present invention are as follows. [Items of Properties] Specific Gravity: 0.98 to 1.4 (ASTM D792) Tensile Strength: 200 to 1000 kg / cm ² (ASTM D638) Tensile Elongation: 3 to 300% (ASTM D638) Flexural Modulus: 1 to 50 × 10 ⁴ kg / cm ² (ASTM D790) Softening point: 130 ° C or higher (ASTM D1525) Transparency: 90 to 100% (ASTM D1003) Water absorption rate: 0.01 to 0.1% (ASTM D570) Bromine number: 0 -20 (JIS K2543) 12th revision Japanese Pharmacopoeia 48 Rubber stopper test method for infusion: Conformity 49 Plastic container test method for infusion: Conformity The cyclic resin of the present invention has the softening point, physical properties (tensile strength, etc.) as described above. ), High toughness, inert to acids and alkalis, impervious to moisture absorption, oxygen and air, cold and heat resistant A ultra high molecular resin having a transparency in a non-crystalline.

The cyclic resin or cyclic resin composition according to the present invention may be a composition further mixed with one or more olefin resins. Examples of the olefin resin include various polyethylene (abbreviated as PE) and polypropylene (P
(Abbreviated as P), nylon (including amorphous nylon), PET, PBT, polymethylpentene, ethylene-methacrylic acid copolymer, polybutene, and the like.

In the present invention, a mixture of the above-mentioned cyclic resin or cyclic resin composition and synthetic rubbers, an alloy, and a mixture of the cyclic resin and synthetic rubber are partially co-crosslinked to obtain the intended purpose. Was achieved. The reason for this is that the cyclic resin body used in the present invention is a heat-resistant resin having a softening point of 130 ° C. or higher (ASTM D1525 method), synthetic rubbers, especially solution-polymerized synthetic rubbers. One of the points is that a rubber elastic body that is extremely hygienic can be obtained by mixing the alloys in such a ratio to form an alloy of both. In addition, in the case of a plug that requires extremely high heat resistance, elastic resistance, compression strain resistance, etc., if a crosslinking agent is added to the cyclic resin body and synthetic rubber, they will be easily crosslinked. The physical properties are hygienic, the physical properties and the chemical properties are excellent, and it is most suitable for a plug.

As described above, the cyclic resin or the cyclic resin composition according to the present invention may be mixed with synthetic rubbers, in particular, both of the alloys may be alloyed or partially crosslinked with a crosslinking agent.
It is possible to improve desirable characteristics as a drug stopper. The quality assurance period of pharmaceuticals is generally as long as 3 to 5 years, and in order to formulate an unstable and easily degradable drug for long-term storage, it is required to maintain appropriate conditions from the time of formulation. As a formulation method that can satisfy such requirements, use of a rubber stopper as shown in FIGS. 2 and 3 can be mentioned. The rubber stopper 8 is a stopper that fits perfectly into the mouth 10 of the container 9 and does not absorb or permeate oxygen, air, or moisture. A mixture of the cyclic resin of the present invention and synthetic rubber, an alloy body is preferable. Are suitable for this, and more preferable are partially crosslinked products.

Examples of synthetic rubbers used in the present invention include IR (including liquid isoprene rubber) and BR (liquid 1,
2-including polybutadiene), ethylene-propylene rubber, ethylene-propylene-diene terpolymer copolymer, butadiene-isoprene copolymer, styrene-isoprene copolymer, acrylonitrile-butadiene copolymer or hydrogenated product thereof, styrene. -Butadiene copolymer, IIR, BIIR, CIIR, isoprene-isobutylene-divinylbenzene copolymer (abbreviated as IIRD)
And so on. These synthetic rubbers may be used alone or in combination.

The presence ratio of each component in the plug material of the present invention is preferably 3 to 50 parts by weight of the cyclic resin body with respect to 100 parts by weight of synthetic rubber. When the amount is 3 parts by weight or less, the hygienic property, which is a feature of the present invention, decreases, and when 50 parts by weight or more, the rubber elasticity is lost, the production efficiency of the plug body in a general-purpose rubber processing machine is slightly decreased, and the cost is increased. ..

The cross-linking agent for partially cross-linking the mixture or alloy of the cyclic resin body and synthetic rubber of the present invention with the cross-linking agent is, for example, 1,1,3,3-tetramethylbutyl hydroperoxide, 2,5. -Dimethyl-hexane-2,5-dihydroperoxide, di-t-butylperoxide, 1,1-di (t-butylperoxy) -3,
3,5-trimethylcyclohexane, 2,5-dimethyl-2,5-di (t-butylperoxy) hexane, 2,
5-dimethyl-2,5-di (t-butylperoxy) hexyne-3,1,3-di (t-butylperoxyisopropyl) benzene, 2,5-dimethyl-2,5-dibenzoylperoxyhexane, 2, 5-dimethyl-2,5
-It is preferable to add 0 to 3 parts by weight of di (peroxybenzoyl) hexyne-3, n-butyl-4,4-bis (t-butylperoxy) valerate, etc. to 100 parts by weight of synthetic rubbers for crosslinking. .. Examples of the crosslinking aid include 1,2-polybutadiene, trimethylolethane trimethacrylate, trimethylolpropane trimethacrylate, zinc white, N, N'-m-phenylene bismaleimide, trimethylolpropane-N, N'-m-. Phenylene dimaleimide or the like is used in an amount of 0 to 10 parts by weight based on 100 parts by weight of synthetic rubber. In the case of a composition comprising such an olefin resin or synthetic rubber and a cyclic resin,
By varying the combination of the constituents in various ways, a pharmaceutical stopper having each characteristic can be obtained. However, the cyclic resin of the present invention is preferably 30% by weight or more in the entire composition.

In addition, to prepare the material of the present invention,
Processing aids can be added to facilitate the mixing of the cyclic resin with the synthetic rubbers or the molding operation into products.
Examples of processing aids include silicon oil, fatty acids, fatty acid esters and the like. The pharmaceutical plug according to the present invention may be a plug formed by directly molding a material comprising the above-described cyclic resin, synthetic rubbers, and further a crosslinking agent, and further, a plug of the present invention. It may be a laminate of resin films.

An ultraviolet absorber, an ultraviolet light shielding agent and the like can be added to the cyclic resin of the present invention, the cyclic resin composition or the resin to be laminated as described above. Examples of ultraviolet absorbers and light-shielding agents include p-t-butylphenyl salicylate, 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2 (2'-hydroxy-5'-methylphenyl) benzotriazole, Two
(2'-Hydroxy-3'-t-butyl-5'-methylphenyl) -5-chlorobenzotriazole, 2 (2 '
-Hydroxy-3 ', 5'-di-t-butylphenyl)
-5-chlorobenzotriazole, bis (2,2,6,
6-Dimethyl-4-piperidine) Sebacet (Sanol L
S770, manufactured by Ciba Geigy), polymer-type hindered amine (Sanol LS9444, manufactured by Ciba Geigy), fine particle titanium oxide, zinc oxide, and the like. One or more of them may be added in a total amount of 0 to 2% by weight. Is preferred.

In the present invention, cyclic resins, synthetic rubbers,
As a mixing or polymer alloying means such as an anti-aging agent, a known mixing roll, indense mixer,
For example, a Banbury mixer, a kneader, a single-screw or twin-screw extruder is used, but a non-open type is preferable. In particular, since the cyclic resin according to the present invention has a high softening point, it is preferable to mix it with a non-open type mixer at 100 ° C. to 300 ° C. under a nitrogen atmosphere. The subsequent processing and molding method of the rubber plug is performed by the same steps and operations as those for general-purpose rubbers. Further, means for laminating a resin film on the molded rubber plug can also be based on a known technique.

[0024]

EXAMPLES The method for synthesizing a cyclic resin according to the present invention and the production of a stopper for a pharmaceutical product of the present invention using the resin or resin composition will be specifically described below, but the present invention is not limited to these specific examples. It is not limited. Cyclic Resin Synthesis Example 1 (DCP Resin Polymer) 10 liters of a reactor equipped with a stirrer, 3.6 liters of purified and dehydrated toluene, and purified tricyclo [4,3,3]
0,1 ^2,5 ] 3,8-decene (abbreviated as DCP) 1.2k
g, and add triethylaluminum in a nitrogen atmosphere 7
2 g, triethylamine 236 g and titanium tetrachloride
62 g is added at a temperature of 5 ° C. or lower, the temperature is raised to 25 ° C., and the mixture is stirred and polymerized for 24 hours. After that, methanol 500m
The reaction was stopped with 1 and the resin was precipitated with methanol, washed with acetone-isopropyl alcohol (1: 1), and vacuum dried at low temperature. 800 g of polymer was obtained. Next, the polymer obtained above was put into a 5 liter autoclave reactor equipped with a stirrer as a 10 wt% cyclohexane solution, 25 g of palladium carbon was added under a hydrogen atmosphere, hydrogen substitution was carried out, and the temperature was raised to 120 ° C. , Hydrogen pressure 7
Hydrogen is replenished at 0 atm for 12 hours.
After hydrogenation, the catalyst is centrifuged and precipitated with a large amount of acetone-isopropyl alcohol (1: 1) mixed solvent. BHT 0.
Add 4 parts by weight and 0.1 parts by weight of Antigen TPS,
560 g of a purified resin body (a) was obtained. This resin body (a) had a softening point of 153 ° C. or higher and a bromine number of 0.2.

Synthesis Example 2 of Cyclic Resin (with DCP and ethylene
Copolymer of 10 liter, equipped with a dropping funnel in a reactor equipped with a stirrer, charged with 5 liters of purified and dehydrated toluene, and then charged with 350 g of purified and dehydrated DCP, and kept at a temperature of 3 ° C. or lower,
Ethylene aluminum sesquichloride 10 as a catalyst
5 g, dichloroethoxyoxovanadium 110 g
Is dropped while passing a dry mixed gas of ethylene gas and nitrogen gas 1: 2, the temperature is raised to 20 ° C. after completion of the dropping, and the above mixed gas is passed under stirring for 2 hours for polymerization. Then, the copolymerization is stopped with 30 ml of methanol, the copolymer is precipitated in methanol, washed with acetone, and vacuum low temperature drying is performed. 312 g of a copolymer was obtained. Then 5
The copolymer obtained above was added to a liter autoclave equipped with a stirrer as a 10 wt% cyclohexane solution, 25 g of palladium carbon was put therein, and the inside of the reactor was replaced with hydrogen gas, and the temperature was raised to 120 ° C. with stirring. Hydrogen pressure 7 at the same temperature
The pressure is raised to 0 atm, and while supplementing hydrogen gas at the same pressure, 10
Hydrogenation is carried out for an hour. Then remove the catalyst by centrifugation,
A large amount of acetone-isopropyl alcohol (1: 1) mixed solvent is precipitated and filtered to obtain a resin body. 0.6 parts by weight of BHT was added to 100 parts by weight of the resin body and vacuum dried to obtain 300 g of the resin body (b). The resin body (b) had a softening temperature of 146 ° C. or higher and a bromine number of 0.1.

[0026]Synthesis Example 3 of Cyclic Resin (Crosslinked Polycyclic Hydrocarbon
And a monocyclic olefin copolymer) Purification and dehydration in a 10-liter three-neck reaction vessel equipped with a stirrer
Toluene (4.5 liters) and purified hexacyclo
[6, 6, 1, 1^3,6, 1^10,13, 0^2,7, 0 ^9,14] −
A mixture of 4-heptadecene and cyclopentene (1: 1)
Nomar 300g, ethyl aluminum sesquichlori
De 90 g, dichloroethoxyoxovanadium 15
g under a nitrogen atmosphere at a temperature of 5 ° C or lower, and a temperature of 10 ° C.
The temperature is raised to 0, the mixture is stirred for 24 hours, and a copolymerization reaction is performed. Next
Polymerization was stopped with 150 ml of tanol and methanol was added.
The copolymer is precipitated with, washed and filtered. Obtained co-weight
Irganox 1076 (product)
Name) Add 0.3 parts by weight, mix evenly, vacuum dry,
160 g of a copolymer resin (c) was obtained. Softening of the resin (c)
It had a chemical conversion point of 136 to 156 ° C. and a bromine number of 6.3.

Synthesis Example 4 of Cyclic Resin 4 5 liters of cyclohexane purified and dehydrated in a 10 liter reactor equipped with a stirrer and dimethyl-tetracyclo [4,4,0,1 ^2,5 1 ^7,10 ] -3 purified and dehydrated -Dodecene (300 g) was charged, and then dichloroethoxyoxovanadium (20 g) and ethylaluminum sesquichloride (110 g) were added dropwise under a nitrogen atmosphere at a temperature of 5 ° C or lower.
Mixed gas of nitrogen gas: hydrogen gas = 150: 1 with temperature 1
The polymerization reaction is carried out at 0 ° C. for 15 hours. Then add 1 liter of isopropyl alcohol to stop the polymerization,
Further, the polymer is precipitated with isopropyl alcohol and washed. 100 parts by weight of this polymer, 0.2 parts by weight of Ionox (trade name) and Irganox 168 (trade name)
0.1 part by weight is added and vacuum drying is performed. The softening temperature of the obtained resin was 137 to 143 ° C., and the amount of resin was 182 g. This resin is called resin (d).

[0028] equipped with a stirrer reactor Synthesis Example 5 5-liter cyclic resin, purified bis (methacryloxy) tricyclo [4,3,0,1 ^2,5] - charged decane 500g cyclohexane 500g,
10 g of benzoyl peroxide was added to a nitrogen gas atmosphere, mixed uniformly, gradually heated, and a polymerization reaction was carried out at 120 ° C. for 5 hours. The solvent is removed to form a viscous resin body, and t
-Butyl peroxybenzoate 20 g and 4,4'-
Thiobis (6-t-butyl-3-methylphenol)
Add 3g and mix evenly, and mold temperature 170 ℃ 1
It is heated for 0 minutes to form a resin and then powdered. Wash thoroughly with warm water. The softening point of the obtained resin (e) is 148 ° C.
As described above, the bromine value was 4.5.

Synthesis Example 6 of Cyclic Resin (Crosslinked Polycyclic Hydrocarbon
Compound resin body) Methyloxycarbonyltetracyclo [4,4,0,1]
^2,5, 1 ^7,10] -3-dodecene 250g and 1,2-dichloroethane 1000 ml, 1-hexene 1.9g
In addition, the concentration of tungsten hexachloride as a catalyst is 0.05mo
l / l chlorobenzene solution 46 ml, paraaldehyde concentration 0.1 mol / l 1,2-dichloroethane solution 35 ml, triisobutylaluminum concentration 0.5 mol / l toluene solution 19
Under a nitrogen gas atmosphere, 3 ml of the reactor equipped with a stirrer is added, and a polymerization reaction is carried out at 60 ° C. for 10 hours. The polymerization reaction is stopped with 50 ml of methanol, the polymer is further precipitated with methanol, washed with acetone-methanol (1: 1), and then vacuum dried. Next, the polymer is dissolved in 4500 ml of tetrahydrofuran, 23 g of a palladium-alumina catalyst containing 5% by weight of palladium is added, and hydrogenation reaction is carried out for 5 hours while hydrogenating at a hydrogen gas pressure of 100 kg / cm ² and a temperature of 170 ° C. Thereafter, post-treatment of the cyclic resin is performed in the same manner as in Synthesis Example 1 to obtain a polymerized resin. The resin 1
0.5 parts by weight of BHT was added to 00 parts by weight of resin (f)
And Resin (f) has a softening point of 147 ° C. or higher and a bromine value of 0.
It was 1.

[0030] equipped with a stirrer reactor Synthesis Example 7 10 l annular resin, purified toluene were charged 5 L dehydrated, tetracyclo [4,4,0,1 ^2,5 purified under a nitrogen gas atmosphere, 1 ^{7 , 10} ] -3-
152 g of dodecene and 19 g of methylcyclohexene were added, and then ethylaluminum sesquichloride 18
g, vanadium oxytrichloride 11g at a temperature of 5 ° C
Mix below. Next, ethylene: nitrogen gas = 1: 2, the mixed gas is dried and the temperature is raised while flowing from the gas injection pipe to 10
The temperature is adjusted to 0 ° C., and 15 liters of the same mixed gas is allowed to flow for 1 hour to carry out a polymerization reaction. Next, 50 ml of methanol was added to stop the reaction, and the resin was precipitated with a larger amount of methanol and washed with a mixed solvent of acetone-isopropyl alcohol (1: 1) to make 100 parts by weight of Irganox 1070 resin.
(Product name) 0.3 part by weight is added and vacuum drying is performed. The obtained resin (g) has a softening point of 152 ° C or higher and a bromine number of 0.5.
Met.

[0031]Examples 1 to 5 and Comparative Examples 1 and 2 BR as synthetic rubber [JSR BR01 (trade name),
Made of Japanese synthetic rubber, ML _{1 + 4}100 ° C 44] 100 weight
The cyclic resin (c) of the present invention obtained as described above to
(G) 30 parts by weight of Labo Plastomill (manufactured by Toyo Seiki)
Mixing) at a temperature of 130-180 ° C.
Then, inject the slide stopper 3 having the shape shown in FIG. 1 into the mold and cool it.
To form an elastic slip stopper for a syringe. The molded slip
The stopper is described in the Ministry of Health and Welfare Notification No. 422 and No. 42.
Disposable syringe conforms to the test method specified in the standard.
The test was carried out (Examples 1 to 5). Also shown in Table 1.
Using a commercially available resin, molding and sliding in the same manner as in Examples 1 to 5
A stopper was obtained, and this was also tested in the same manner (Comparative Example 1,
2). The results are shown in Table 1.

[0032]

[Table 1]

As shown in Table 1, the products of the present invention of Examples 1 to 5 meet the standard value as a slip stopper for a syringe. on the other hand,
The sliding stoppers using the commercially available resins of Comparative Examples 1 and 2 are inferior in hygiene.

Examples 6 to 12 Amount (parts by weight) of the cyclic resin (a), (b) according to the present invention obtained in the above-mentioned synthesis example, relative to 100 parts by weight of synthetic rubber (IIR, IIRD or EPDM). The rubber stopper material was prepared by changing the crosslinking agent, the crosslinking aid and the crosslinking conditions as shown in Table 2. Using these materials, the rubber plugs shown in FIGS. 2 and 3 were molded by the same means as in Example 1 (Examples 6 to 1).
0). Further, a stopper body in which an annular resin film is further laminated on the molded rubber stopper by the laminating method described later (Examples 1 and 1).
2) was also manufactured.

The method for molding a rubber plug having a laminated annular resin film is based on the method proposed by the present inventors in JP-A-62-176450, JP-A-61-272134 and JP-A-63-296756. did. That is, the leg portion 1 of the rubber plug
On the surface of the lower mold having an annular depression corresponding to 1, the annular resin of the present invention as a film having a thickness of 0.3 to 0.5 mm is placed, and the compounded rubber fabric sheet of Table 2 is placed thereon. The upper mold having a convex portion corresponding to the space 15 of the rubber stopper is placed, and the compounded rubber is heated and pressed by the upper and lower molds to form the rubber stopper leg 11 in which the resin film 18 is laminated on the rubber stopper leg. To do. Next, the laminated rubber stopper legs are put in a mold having a leg shape deeper than the rubber stopper leg portion 11, and on the lower mold surface thereof,
The compounded rubber dough sheet and the annular resin film are further placed, an upper mold having a recess corresponding to the head 12 of the rubber stopper is placed on the upper mold, and the compounded dough sheet is heated by both upper and lower molds. By pressing, the rubber stopper for freeze-dried preparation shown in FIG. 3 is obtained. FIG. 3 shows a state in which the rubber stoppers are cut off one by one, and after cleaning, a chemical solution is put into the vial container 9, the rubber stopper is stoppered in the container mouth 10, and the aluminum cap 14 is wound and tightened.

[0036]

[Table 2]

(1) to (10) in Table 2 mean the following:
It (1) EXXON Butyl 365: Esso c
chemical Ltd., Unsaturation degree 20 mol%,
ML_{1 + 8}100 41 to 49 (2) polysar Butyl XL20: po
lysar Elastomere (3) JSR EP35: Japan synthetic rubber, polypropylene
Content 43 mol%, ML _{1 + 4}100 83 (4) 1,1-di (t-butylperoxy) -3,3,5
-Trimethylcyclohexane: manufactured by NOF CORPORATION (5) 2,5-dimethyl-2,5-di (t-butylpero)
X) Hexane: manufactured by NOF CORPORATION (6) N, N'-m-phenylene bismaleimide: Kawa
Kuchi Kagaku Co., Ltd. (7) 1,2-polybutadiene: molecular weight about 2000,
Made by Nippon Soda Co., Ltd. (8) Block Copolymer: Product name Modeler A4
200 (EGMA: PMMA), manufactured by NOF CORPORATION (9) Ultra-high molecular weight polyethylene powder: trade name Heisei
X-Million 240M, manufactured by Mitsui Petrochemical Co., Ltd. (10) γ-mercaptotrimethoxysilane: Nippon Uni
Mosquitoes

For each rubber plug molded as described above,
"48. Rubber stopper test method for infusion" of the 12th revised Japanese Pharmacopoeia
The hygiene test based on the above was performed. We also conducted a special hygiene test based on other medical findings. The above results are shown in Table 3 and Table 4.
Shown in.

The details of the special hygiene test are as follows. Number of fine particles (test of number of particles generated from rubber stopper) : Put 10 rubber stoppers in a hard glass bottle, add 300 ml of non-dust water, wrap the container mouth with a film, and rotate by hand 2 revolutions / second to 20 It vibrates for a second. Then, after allowing to stand for 1 hour, the number of fine particles in water is measured by a light shielding type automatic fine particle measuring instrument (manufactured by HIAC). The presence of fine particles of 5 μm or more in the injection solution is a most important item because it causes problems such as occluding blood vessels.

Peeling off rubber fragments (Fragmentati)
on) ; 5 ml of water is put into a bottle (10 ml capacity), a rubber stopper is capped, and then an aluminum cap 14 is wound and tightened.
2 ml of water is put into an injection cylinder equipped with a test needle 22G (0.70 × 32 mm), and this is penetrated through the needle insertion part 13 of the rubber stopper 20 times. At the time of the 20th penetration, the water in the syringe is injected into the bottle, and then the injection needle is pulled out. After vibrating the inside of the bottle, remove the rubber stopper, filter the content liquid, and count the number of rubber pieces on the filter paper. This test method is an improvement of the BS method.
The BS standard is 3 rubber pieces or less, but at present, 2 pieces or less are required in the industry.

Gas component test in head space ; 8 ml of 2 wt% saline solution was put in a bottle, and a rubber stopper was stoppered,
Further, the aluminum cap 14 is tightened. This glass bottle is steam-heated in a pressure vessel at a temperature of 121 ± 1 ° C. for 60 minutes and then left to stand for about 10 hours. Next, 5 ml of gas in the head space 16 in the bottle is sampled with a gas syringe and measured by gas chromatography. Column: 10%
OV-101 (180-200 mesh WHP), carrier gas He 50 ml / min, column temperature 100-2
00 ° C (4 ° C / minute temperature rise), presence / absence of peak, and size.
This test is a test for examining the generation of an extremely small amount of gas due to rubber and compounding agents, which has been a problem in recent years.

Alkali resistance test : 10 rubber stoppers were put in an alkali resistance container, 0.5% by weight solution of sodium carbonate was added 10 times the weight of the rubber stoppers, and then the rubber stoppers were stoppered to cap aluminum. Tighten 14 Next, temperature 1 in pressure vessel
Steam heat at 21 ° C. for 30 minutes. After standing to room temperature and cooling, the rubber stopper was removed, and the transmittance of the test solution in the visible part at wavelengths of 430 nm and 650 nm was measured using a quartz cell. Pass 95% or more. This test is a basic test for testing the relationship between rubber and chemicals, and rubber products with low transmittance are not suitable for use.

Water absorption test ; vulcanized and molded rubber product at a temperature of 1
It is dried at 05 ° C and normal pressure for 3 hours. Next, after leaving it in a desiccator containing a desiccant for about 1 hour, its weight (A) is precisely weighed. Next, it is immersed in purified water in an amount 10 times that of the rubber stopper, and steam-heated in the pressure vessel at 121 ± 1 ° C. for 30 minutes.
After cooling, leave only the rubber stopper in the desiccator for 30 minutes to remove the surface water, and weigh the weight (B) at that time accurately ((B)
-(A) / (A) × 100) (%) was calculated and the increase in weight was 2
The weight% or less is passed.

Lubricity test : A rubber plug is placed on a fluororesin plate, one end of the plate is fixed, and the other end moves at a constant speed when the rubber plug moves. The angle at the beginning of this movement is measured.

[0045]

[Table 3]

[0046]

[Table 4]

As shown in Table 3, synthetic rubbers IIR and II
A rubber plug obtained by blending RD and EPDM with a cyclic resin and further cross-linked (Examples 6 to 9), a rubber plug obtained by blending EPDM with a cyclic resin (Example 10), and a rubber plug made of a cross-linked rubber and a resin Each of the freeze-dried rubber stoppers (Examples 11 and 12) on which a film was laminated passed and conformed to the standard value of the 12th revised Japanese Pharmacopoeia. Also, as shown in Table 4,
It can be clearly seen that the product of the present invention is also suitable for a special hygiene test based on a medicinal point of view and is excellent in hygiene.

Examples 13 and 14 Synthetic rubber BR [NIPOL BR1220 (trade name),
cis 96-98%, manufactured by Nippon Zeon Co., Ltd.] 30 parts by weight, IR (NIPOL IR2200 (trade name), c
is98%, ML _{1 + 4} 100 82, Nippon Zeon Co., Ltd.
Manufacture] 25 parts by weight or 35 parts by weight of the cyclic resin (a) according to the present invention obtained in Synthesis Example 1 was mixed with 70 parts by weight (Examples 13 and 14), and 2,5- Dimethyl-2,5-di (t-butylperoxy) hexane
0.7 parts by weight were blended with a roll. For molding, a mold having the shape of the rubber stopper shown in FIG. 4 is used, a film of the cyclic resin (a) is placed on the mold surface, and the compounded rubber material is placed on the film as a sheet. Using mold
The upper and lower molds are heated and pressed (temperature 170 ° C. × 10 minutes) to form a laminated rubber stopper. Next, the fixed butyl 24, the inner stopper 21, and the pull ring 23 are placed in the chemical container plastic container 22 blow-molded with the annular resin film of the present invention, and the rubber stopper 8 is placed between the outer stoppers and heated and pressurized by ultrasonic vibration. And welded to complete the stopper of the plastic container. Further details of the method of manufacturing the stopper are according to the methods disclosed in JP-A Nos. 2-1275 and 3-205141 proposed by the present inventors. The stopper of the obtained plastic container is easy to manufacture the stopper, does not contaminate the drug solution, maintains its hermeticity for a very long time, and has a high quality assurance of the drug solution.

[0049]

EFFECT OF THE INVENTION A material obtained by mixing the synthetic resin with the cyclic resin according to the present invention, or a polymer alloy material, or a rubber plug obtained by crosslinking the cyclic resin and the synthetic Zam with a cross-linking agent is highly hygienic, and has acid and alkali properties. The elastic rubber stopper is inert to chemicals and can pass the test method standards of the 12th revised Japanese Pharmacopoeia. Therefore, the stopper of the present invention is very excellent and suitable as a rubber stopper for pharmaceuticals and medical instruments. Further, a mixture of a cyclic resin and synthetic rubber or a polymer alloy is advantageous in that its preparation and processing are easy, and a highly hygienic container body can be manufactured by using an ordinary rubber processing machine.

[Brief description of drawings]

FIG. 1 is a schematic cross-sectional view showing a state in which a slip stopper according to an embodiment of the present invention is attached to a syringe.

FIG. 2 is a schematic cross-sectional view showing a state in which a freeze-dried preparation rubber stopper according to another embodiment of the present invention is capped in a vial bottle and an aluminum cap is wound and tightened.

FIG. 3 is a schematic cross-sectional view showing a rubber stopper for a freeze-dried preparation, which is a further embodiment of the present invention and further laminated with a cyclic resin film.

FIG. 4 is a schematic cross-sectional view showing a stopper of a plastic container for infusion according to still another embodiment of the present invention.

[Explanation of sign]

 1 Syringe 2 Outer cylinder 3 Slip stopper 4 Annular protrusion 5 Slip stopper push rod 6 Needle attachment part 7 Chemical solution 8 Rubber stopper 9 Container 10 Container mouth 11 Bifurcated leg 12 Rubber stopper head 13 Injection needle stick 14 Aluminum cap 15 Space 16 Hit space in container 17 Annular engagement part 18 Laminated resin film 19 Protrusion 20 Outer plug 21 Inner plug 22 Plastic container 23 Tearable member (pull ring) 24 Fixed part

Claims (8)

[Claims] 1. A medical plug comprising a material containing a cyclic olefin compound and / or a crosslinked polycyclic hydrocarbon compound as a polymer component, and a resin having a softening point of 130 ° C. or higher and synthetic rubbers. .. 2. A pharmaceutical product comprising a cyclic olefin compound and / or a crosslinked polycyclic hydrocarbon compound as a polymer component and a resin having a softening point of 130 ° C. or higher, synthetic rubbers and a crosslinking agent. Stopper. 3. The weight ratio of the resin containing the cyclic olefin compound and / or the crosslinked polycyclic hydrocarbon compound as a polymer component and having a softening point of 130 ° C. or higher to the synthetic rubber is 3.
It is 50 parts to 100 parts, The stopper body for pharmaceuticals of Claim 1 or Claim 2 characterized by the above-mentioned. 4. The cyclic olefin compound is one or more selected from monocyclic olefin compounds and their alkyl derivatives and acrylate derivatives, according to any one of claims 1 to 3. The described stopper for pharmaceuticals. 5. The drug according to any one of claims 1 to 4, wherein the crosslinked polycyclic hydrocarbon compound has one or more unsaturated bonds in a ring or a substituent. Stopper. 6. A resin containing the cyclic olefin compound or the cross-linked polycyclic hydrocarbon compound as a polymer component is a lower olefin, an aromatic compound, or a lower olefin compound or an aromatic vinyl monomer is a copolymer component. 6. The pharmaceutical stopper according to any one of claims 1 to 5, wherein the stopper is for use as a drug. 7. The resin containing the cyclic olefin compound or the crosslinked polycyclic hydrocarbon compound as a polymer component is a mixture with an olefin resin and / or a synthetic rubber. The stopper for medicine according to claim 6. 8. The resin containing a cyclic olefin compound or a crosslinked polycyclic hydrocarbon compound as a polymer component has a bromine number of 20 or less.
A stopper for a drug according to any one of 1.