JP3105407B2 - Medical and pharmaceutical rubber compounds and products, and medical and pharmaceutical equipment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to rubber compounds and products for medical and pharmaceutical use, and to medical and pharmaceutical devices made of the rubber. Medical and pharmaceutical equipment materials for storing or administering medicines to humans, for example, advanced sanitary products such as infusion equipment, syringes, dialysis machines, medicine containers, and rubber stoppers for containers, "12th Revised Japanese Pharmacopoeia" Rubber compounds, rubber products,
Equipment related.

[0002]

2. Description of the Related Art The use of rubbers in the fields of medical and pharmaceutical instruments and containers has long begun with natural rubber.
Increasingly, synthetic rubbers are increasingly used, and even now, mixtures with thermoplastic elastomers, synthetic resins, and the like are widely used. As a test method for this type of rubber compound product (hereinafter abbreviated as rubber product), “Japanese Pharmacopoeia”, 12th revision (abbreviated as JP12), 48 rubber stopper test method for infusion, 49
There is a test method for plastic containers for infusions, and the standard pass value is determined. Further, in the field of medical supplies and pharmaceutical tools, which are constantly evolving, higher quality materials and products are being demanded.

From around 1950, isobutylene / isoprene copolymer rubber (hereinafter sometimes abbreviated as “IIR”) has been recommended as a suitable material for sanitary rubber products.
Since crosslinking of R is extremely difficult, a combination of a strong crosslinking agent and a crosslinking aid is required. Such a combination is
For example, RTVanderbilt, "RUBBER HANDBOOK", theVa
nderbilt (Issued in 1968), Synthetic Rubber Processing Technology Book 8
Vol., "Butyl Rubber", Taiseisha Co., Ltd. (published in 1973).

Recently, a method of producing an adhesive for vulcanizing IIR at a low temperature (Japanese Patent Application Laid-Open No. Sho 60-130665), a method of crosslinking an IIR in the presence of a quinoid, an organic peroxide and an acryloyl monomer (Japanese Patent Application Laid-Open No. 62-74934), IIR crosslinking by coexistence of an organic peroxide and a polyfunctional monomer having an electron-withdrawing group (Japanese Patent Application Laid-Open No. 6-172547).
No. Gazette). In particular, for rubber products in fields requiring high hygiene, rubber products obtained by blending ultra-high molecular weight polyethylene fine powder with IIR (Japanese Patent Application Laid-Open No.
Japanese Patent Application Laid-Open No. 4-213346), IIR crosslinking using a combination of a special organic peroxide and a maleimide.
No. 347) is known.

On the other hand, various uses of acryloyl monomers for crosslinking of synthetic rubbers have been reported, and a co-crosslinking agent (Co Agents) for crosslinking an ethylene-propylene copolymer rubber (EPR) with an organic peroxide has been reported. [Reference: LP LENAS, "Rubber chemistry and Techn"
ology ", vol. 37 (1964) p. 229], using various rubbers as crosslinking aids in organic peroxide crosslinking [Literature: Takuma Matsumoto," Synthetic Rubber "vol.12 No.3 p.4 (197
0)], an ethylene propylene non-conjugated diene copolymer (EP
D-meth) to produce a graft copolymer (Japanese Patent Publication No. 57-13568), a method of crosslinking rubber with an acryloyl monomer having two unsaturated functional groups and a platinum catalyst (see Kaisho 57-190011
JP-A-3-97749), a method of cross-linking IIR with an organic peroxide, a polyfunctional monomer, and sulfur (JP-A-3-97749). 192940) and halogenated butyl rubber (CIIR or BII).
Crosslinking by the combined use of an organic peroxide of R) and an acryloyl monomer (Japanese Patent Publication No. 55-46420) has also been reported.

[0006]

As described above, although there have already been many proposals for cross-linking of IIR, they sufficiently satisfy hygiene and physical properties which are particularly important as properties for use in the medical and pharmaceutical fields. There are difficulties in obtaining a product that can. For example, a crosslinked rubber with an organic peroxide,
It emits a bad odor, also depending on the type of crosslinking agent that the pH of the crosslinked rubber pieces may exhibit acidity decreases, in the crosslinked product _{H 2 O, CO, CO 2} , acetone (CH ₃ -O-
CH ₃ ) and the like are present as decomposition residues.
There is a problem that it is considered to be a rubber having a large compression strain. In view of such circumstances, the present invention is a novel isoprene / isobutylene copolymer rubber compound and a crosslinked rubber compound having improved hygiene and physical properties. For example, International Standards Organization (abbreviated ISO), European Pharmacopoeia (abbreviated EP),
Rubber products that can pass the test items and quality standards stipulated in official regulations such as US Pharmacopoeia XXII (abbreviated USP), West German Industrial Standard DIN 58, 366-368 (abbreviated as DIN), British Standard 3263 (abbreviated as BS) The purpose is to provide. Further, in the present invention, a rubber compound that can pass a test item corresponding to a high standard which has recently been regarded as a problem in this kind of field and has become required and a special standard uniquely set by the applicant. And rubber products.

[0007]

As a means for solving the above-mentioned problems, the present invention relates to a method for producing a copolymer having 100 or more parts by weight of an isobutylene / isoprene copolymer rubber and having two or more acryloyl, methacryloyl or itaconoyl groups in one molecule. The present invention provides a rubber compound for medical and pharmaceutical use wherein the compound is compounded in an amount of 0.2 to 30 parts by weight and can be crosslinked without compounding an organic peroxide and without using a platinum catalyst . In the present invention, the above-mentioned isobutylene / isoprene copolymer rubber is 50 to 50% of the total amount of the rubber compound for medical and pharmaceutical use.
A particularly preferred embodiment is 93% by weight.
Further, in the present invention, an inorganic reinforcing agent and / or a filler is further added in an amount of 0.5 to 30 parts by weight based on 100 parts by weight of the above-mentioned isobutylene / isoprene copolymer rubber, and other than that a heavy metal compound is not added. Is a particularly preferred embodiment. The present invention further provides a rubber product for medical or pharmaceutical use wherein the rubber compound of the present invention is crosslinked, wherein the crosslinking is natural crosslinking, heating, light irradiation and / or electron beam. It is particularly preferable to perform crosslinking one or more times statically and / or dynamically using one or more crosslinking means selected from irradiation. Furthermore, the present invention provides a syringe, a transfusion device, an infusion set, a blood collection device, an artificial kidney, a catheter, a tube, a blood pack, a two-chamber syringe with a needle, and a vial device, all or a part of which is made of the above rubber product. Alternatively, a medical or pharmaceutical device characterized by being a rubber stopper is provided.

[0008]

The present inventors have found that as a crosslinking agent for isobutylene / isoprene copolymer rubber, an acryloyl group
A group selected from a methacryloyl group and an itaconoyl group
By mixing a compound having two or more, preferably two or more identical groups in a specific ratio, it can be sufficiently crosslinked without using an organic peroxide crosslinking agent or a heavy metal-containing compound, and the crosslinked rubber product is very It has been found that the present invention has high hygiene properties and has physical properties particularly required in the technical field of the present invention, and has reached the present invention. The present invention also provides a method for cross-linking the rubber compound of the present invention and medical and pharmaceutical devices obtained by cross-linking and molding the rubber compound of the present invention.

The isobutylene / isoprene copolymer rubber referred to in the present invention refers to 95 to 99.5% by weight of isobutylene group.
And 0.5 to 5% by weight of an isoprene group, and is usually abbreviated as butyl rubber (IIR). U.S. Pat. No. 2,356,128, U.S. Pat.
No. 371 proposes an IIR in which the content of isoprene group is increased to 30% by weight, and there was a time when such a product was commercially available, but the price and use of the polymer were not suitable and the current market was not suitable. Is gone. Therefore, in the present invention, IIR
Is generally commercially available.
The characteristics of IIR are largely derived from its isobutylene group, the degree of unsaturation is 0, the gas permeability is very low, strong acids such as concentrated sulfuric acid and concentrated hydrochloric acid, strong alkalis such as concentrated NaOH, H
It is an excellent rubber that is chemically stable without being attacked by peroxides such as ₂ O ₂ , has heat resistance, and has strong adhesiveness. In the IIRs according to the present invention, the isobutylene group is represented by a repeating unit represented by the following general formula:

Embedded image In the general formula, the number of n is 500 to 150,000. Since IIR is extremely difficult to crosslink, to make it easy to crosslink, after dissolving IIR in a solvent, chlorine gas,
Or a chlorinated isobutylene-isoprene copolymer chlorinated or brominated by passing bromine gas (CI
IR), a brominated isobutylene / isoprene copolymer (BIIR), or an isobutylene / isoprene / divinylbenzene copolymer (DVIIR) obtained by partially crosslinking IIR with divinylbenzene. Accordingly, the isobutylene / isoprene copolymer rubbers referred to in the present invention specifically include the above IIR, B
IIR, CIIR and DVIIR, which are hereinafter collectively referred to as "IIRs". Incidentally, it is known that polyisobutylene rubber causes a molecular cleavage reaction with respect to an organic peroxide [Reference: (Rubber chemistry)
and Technology vol42 (1969) p1147, vol.41 (1968) p1004] in the Journal of the Rubber Society of Japan
IIR containing 9.5% by weight also causes this reaction, so that the crosslink density of the rubber product does not increase. Therefore, the present inventors have studied the use of cross-linking co-crosslinking agents (Co agents) such as organic peroxides in order to improve the cross-linking density of IIR, particularly the cross-linking density, and as a result, a compound having a specific molecular structure, That is, a compound containing two or more acryloyl groups, two or more methacryloyl groups, or two or more itaconoyl groups in one molecule, preferably one kind of an acryloyl group, a methacryloyl group, or an itaconoyl group in one molecule. A new processing technology that can be crosslinked without losing the characteristics of IIRs by mixing a compound containing two or more groups with the IIRs as the co-crosslinking agent and heating, irradiating with light and / or irradiating an electron beam. It has been found that sanitary rubber products can be manufactured by applying the method. In the present invention, H ₂ O, C0, CO ₂ , (CH ₃ ) ₂ O are contained in the crosslinked product.
It is considered that unlike the case of an organic peroxide that leaves a residue such as the above, the co-crosslinking agent forms a cyclic condensate, which increases the crosslink density. The case of a compound having two or more acryloyl groups will be described as a typical example, as shown in Chemical formula 2.

Embedded image

The co-crosslinking agent according to the present invention will be described more specifically. First, compounds containing two or more acryloyl groups in one molecule include alkyl-modified dipentaerythritol tri (or penta) acrylate, ε-caprolactone-modified dipentaerythritol tri (or tetra) acrylate, and caprolactone-modified neopentyl hydroxypivalate Glycol ester diacrylate, diglycidyl bisphenol A diacrylate, dipentaerythritol penta (or hexa) acrylate, trimethylolpropane triacrylate, neopentyl glycol hydroxypivalate diacrylate, 1,4-butanediol diacrylate, 2-propenoic The acid [2- [1,1-dimethyl-2-[(1-
Oxo-2-propenyl) oxy] ethyl] -5-ethyl-1,3-dioxan-5-yl] methyl ester,
1,6-hexanediol diacrylate, pentaerythritol triacrylate, dimethylol propane diacrylate, triallyl (or iso) tricyanurate, triallyl triacrylate, tetramethylol methane tetraacrylate, neopentyl glycol diacrylate, di (or tetra) Examples include ethylene diacrylate, bis (4-acryloxypolyethoxyphenyl) propane, 1,5-pentanediol diacrylate, and tetramethylolmethane triacrylate.

The compound according to the present invention containing two or more methacryloyl groups in one molecule includes, for example, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, 1,3-butylene glycol dimethacrylate, Trimethylolpropane trimethacrylate allyl methacrylate, 1,6-hexanediol dimethacrylate, trimethylolethane trimethacrylate, dipropylene glycol dimethacrylate, 2,2-bis (4-methacryloxydiethoxyphenol) propane,
Neopentyl glycol dimethacrylate, diethylene glycol dimethacrylate, ethylene dimethacrylate, 1,3-butylene methacrylate, 1,4-butylene methacrylate, and the like.

The compound according to the present invention containing two or more itaconoyl groups in one molecule includes, for example, pentaerythritol ditriitacolate (itaconoyl group 2
Or a mixture of three), dipentaerythritol itacolate (having 3, 4, 5, itaconoyl groups)
A mixture of six). The itaconoyl group referred to in the present invention is represented by the following general formula.

Embedded image

Since the above-mentioned co-crosslinking agent according to the present invention belongs to Article 2, Dangerous goods, Class 4, Class 3, Petroleum non-water-soluble liquid of the Fire Services Act, wear protective gloves, protective glasses, etc. Prevents adhesion to skin. Acute oral toxicity LD ₅₀ is 2,000～15,0
Caution is required because some are 00 mg / kg.

In the case of a monofunctional compound having only one of an acryloyl group, a methacryloyl group or an itaconoyl group in one molecular formula, the compound becomes a graft bond state in a molecule of IIRs and has a tensile strength of IIRs. In terms of physical properties such as the amount of compressive strain and the like, it is not suitable for the use of the elastic body for medical or pharmaceutical use of the present invention.

[0015] The proportion of said IIRs in the rubber compound according to the invention is 50 to 93% by weight. If it is less than 50% by weight, I
Properties of IRs, namely gas impermeability of polyisobutylene,
This is because characteristics such as heat resistance, high viscosity, and chemical stability are lost, and if the content exceeds 93% by weight, the product is deformed and the amount of compressive strain is increased, which is not preferable as a medical or pharmaceutical device material. .

The proportion of the co-crosslinking agent compound in the rubber compound according to the present invention is 0.2% to 100 parts by weight of IIRs.
-30 parts by weight. If the amount is less than 0.2 parts by weight, the amount of strain such as the amount of compressive strain becomes large, and it is unsuitable for use in the present invention. On the other hand, if it exceeds 30 parts by weight, the amount of the expensive additive increases, which is economically unsuitable.

The rubber compound according to the present invention may further contain, as other compounding agents, an inorganic reinforcing agent and / or a filler,
One or more selected from organic reinforcing agents and / or fillers, antioxidants, stabilizers and the like can be added in a total amount of 0.5 to 30 parts by weight per 100 parts by weight of IIRs.
Examples of the inorganic reinforcing agent include silica-based fillers, clays, titanium oxide, and the like. Since the thermal conductivity at the time of crosslinking of rubbers is improved, crosslinking is uniformly performed, and deformation of products is prevented. Show the effect. The amount of the inorganic reinforcing agent is preferably 0.5 to 30 parts by weight based on 100 parts by weight of IIRs.
If the amount exceeds 30 parts by weight, fine particles may be generated from the rubber product surface, which is not preferable.

In the present invention, heavy metal compounds having a specific gravity of 6.0 or more, such as heavy metal compounds such as lead, cadmium, and platinum, are not added. Lead compounds such as lead peroxide, lead oxide and the like, chloroplatinic acid, colloidal platinum, tin chloride and the like are known to act as a crosslinking aid for shortening the crosslinking time of IIRs or improving the crosslinking density. However, in the present invention,
Since the presence of heavy metals should be avoided in the field of use as final rubber products, they are not used even if they have a crosslinking effect. In addition, hygiene is high by this non-use,
It becomes rubber that passes the standards of various official books.

The rubber compound of the present invention may further contain an organic reinforcing agent, an antioxidant, a stabilizer and the like. Particularly preferred organic reinforcing agents include ultra-high molecular weight polyethylene powder (for example, Hi-Zex Million Meta-240), polyethylene (PE), polypropylene (PP), polycarbonate (PC), polybutadiene (BR), 1,2 bond Styrene butadiene rubber (SB
R), polysulfone resin (for example, trade name VDEL)
And at least one kind thereof can be used in an amount of 20 to 90 parts by weight based on 100 parts by weight of IIRs.

Further, as processing aids, for example, paraffin, silicone oil, and as crosslinking aids, silane coupling agents (for example, vinyltrimethoxysilane, r-methacryloxypropyltrimethoxysilane, r-glycidoxypropyltrimethoxysilane) Silane, r-mercaptopropyltrimethoxysilane, β- (3.4-epoxycyclohexyl) ethyltrimethoxysilane, tetrakis (2
Ethylhexy) titanate. 3. Dipropoxy-bis (acetylacetonato) titanium [titanium acetylacenate], magnesium oxide, titanium oxide, zinc oxide, co (dibutylamino) -4.6-dipt-S-triazine, bis (2-diethylamino) -4. 6-dimercapto-S-triazine) and the like.
0 to 5 parts by weight can be added to 100 parts by weight of Rs.

Further, as an anti-aging agent, for example, 2,6
C-tert-butyl-P. Cresol n-octadecyl-β
-(4'-hydroxy-3 ', 5'-di-tert-butylphenyl) propionate, tetrakis [methylene,
(3 ', 5'-di-tert-butyl-4-hydroxyphenyl) propionate] methane, dilauryl, 3,3',
And at least one selected from benzophenone-based compounds or benzotriazole-based light stabilizers as light stabilizers, particularly reactive light stabilizers,
0.05 to 1 part by weight can be added to 0 part by weight.

The reason for this is that the type and amount of the compounding agent fluctuate depending on many factors such as the type of medical device and medical device, desired properties and effects, molding machines, tools, productivity, and unit price. Since IIRs are one of the most difficult to mold and crosslink, it is important to design a product by combining many factors into a rubber product having optimal properties for medical and pharmaceutical applications.

The rubber compound according to the invention can be crosslinked without an organic peroxide, as described above. As a crosslinking method, any of a method of static crosslinking by crosslinking and molding using a mold or a method of molding after dynamic crosslinking by an extruder, an internal mixer, a curl or the like may be used. Heating, light irradiation, and electron beam irradiation can be used as the crosslinking means. In the case of thermal crosslinking, there is a method of performing crosslinking by heating at a temperature of 140 to 300 ° C. in a mold, or a method of performing dynamic crosslinking by heating at 140 to 300 ° C. in an internal mixer or an extruder. . Photo-crosslinking and electron beam cross-linking are performed at temperatures
Light (ultraviolet) irradiation or electron beam irradiation is performed at 100 ° C. The crosslinking reaction may be completed by repeating photo-crosslinking or electron beam crosslinking two or more times. Also, if necessary, 30 to 80
Spontaneous cross-linking, which is allowed to stand at ℃, can also be performed. Further, each crosslinking means can be appropriately combined with static crosslinking and dynamic crosslinking. The rubber product of the present invention obtained by crosslinking and molding is then subjected to washing and, if necessary, sterilization and other processes for known medical products and pharmaceutical products. Specific crosslinking conditions, post-treatments and the like will be specifically described in Examples of the present invention described later.

Further, a crosslinked product of the rubber compound of the present invention itself or a composition obtained by mixing another resin with the compound is crosslinked according to the present invention. A film or container material can be obtained by laminating two or more layers of alcohol, ethylene-vinyl acetate copolymer or a saponified product of the copolymer, nylon, amorphous nylon, aluminum, or a resin on which silicon oxide is deposited. Since the material has high hygiene and physical properties, it can be used for plugging syringes and cylinders, infusion set, infusion set components, blood collection components, artificial kidney components, catheters, tubes, needles, etc. It is very suitable to be molded into each part of a two-chamber syringe, a rubber stopper for a vial, a container for various chemicals and a drug solution.

[0025]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. [Examples 1-3 and Comparative Examples 1-5] 100 parts by weight of DVIIR (trade name XL-10,000, manufactured by Policer International), polyethylene powder (trade name: FLO-
THENE UF, manufactured by Iron and Steel Chemical Industry Co., Ltd., melting point 103
℃ 5) 5 parts by weight, finely divided silica (trade name Nipsil L)
P, 5 parts by weight of Nippon Silica Co., Ltd.) and 0.5 parts by weight of di-t-butyl-P-cresol were blended with the crosslinking agents of 1) to 6) in the proportions (parts by weight) shown in Table 1 ( Examples 1 to 3).
The compounding operation is SRIS [Japan Rubber Association Standard Standard 3604
(1980)], and operated at a roll temperature of 60 to 90 ° C. Further, as shown in Table 1, the ratios outside the range of the present invention or those of known blends and similar blends were compared with those of Comparative Examples 1 to 3.
5 and operated similarly. The compounding dough is oscillating, disc, rheometer (abbreviated as ODR)
Using a testing machine, Japan Rubber Association Journal vol40 (1967) P
874, ASTM D-2705, SR1S 3102
Vibration vulcanization test [Small angular vibration (torsional vibration) of rotary reciprocating motion is given, and the stress corresponding to it is measured as a torque value, the highest torque value (C) is obtained, and this and the lowest torque value (b) Is determined, and the results are also shown in Table 1.

[0026]

[Table 1]

In Table 1, 1) to 6) are as follows. 1) Ethylene glycol dimethacrylate: manufactured by Mitsubishi Rayon Co., Ltd., MW 198.2 2) Trimethylolpropane trimethacrylate: manufactured by Mitsubishi Rayon Co., Ltd., MW 238.4 3) 2-hydroxypropyl methacrylate: Mitsubishi MW 144.2, manufactured by Rayon Co., Ltd. 4) Organic peroxide: dicumyl peroxide (abbreviated as DCP). 5) Stearic acid 6) γ-mercaptopropylmethoxysilane

The co-crosslinking agent of Example 1 shown in Table 1 has two methacryloyl groups, the co-crosslinking agent of Example 2 has three methacryloyl, and the cross-linking agent of Comparative Example 1 has one methacryloyl in one molecule. Contained in Thermal crosslink density is ODR ｛(c)
− (B) torque value (kg / cm)}. Examples 1 and 2 show high torque values, but Comparative Example 1 is small. Further, even if the amount of one acryloyl crosslinking agent is increased from the composition of Comparative Example 1 as in Comparative Example 2, the rate of increase in the torque value is small.
This is because the compounds of Examples 1 and 2 are cross-linked between the molecules of DVIIR to form a network, whereas the compounds of Comparative Examples 1 and 2 have a network in which an acryloyl group is grafted (branched) to DVIIR. This is because they cannot be formed. Comparative Example 3,
No. 4 is an example in which an organic peroxide (DCP) was used as a co-crosslinking agent according to a known technique, but it was not excellent in crosslinkability, and furthermore, produced an unpleasant odor as a rubber requiring hygiene. Comparative Example 5 also produced an offensive odor.

[Examples 4 to 8, Comparative Examples 6 to 8] Table 2 below
As shown in BIIR (trade name, POLYSAR BR
OMO BUTYL X-2, manufactured by Policer International Co., Ltd., bromine content 2.1% by weight, ML _{1 + 8} (1
25 ° C.) 41 to 49) 100 parts by weight of ultra-high molecular weight polyethylene powder (trade name “HIZEX MILLION 240”)
M, manufactured by Mitsui Petrochemical Co., Ltd.) 5 parts by weight, di-t-butyl-p-cresol 0.5 part by weight, and a crosslinking agent shown in Table 2 below were blended in the same manner as in Examples 1 to 3 above. O.S. D. An R test was performed to measure the crosslink density. The results are also shown in Table 2. In addition, BIIR
The result of compounding treatment using the known rubber cross-linking compound as a comparative example is shown.

[0030]

[Table 2]

In Table 2, 7) to 16) are as follows. 7) Organic peroxide: dicumyl peroxide (abbreviated as DCP) 8) Pentaerythritol triacrylate: MW 298.1 manufactured by Osaka Organic Chemical Co., Ltd. 9) 1,4-butanediol diacrylate: Osaka Organic Chemical Co., Ltd. ), MW 198.2 10) Acrylate of ε-caprolactone-modified dipentaerythritol: Nippon Kayaku Co., Ltd., trade name, DCPA2
0 11) Vinyl trimethoxysilane: manufactured by Nippon Unicar Co., Ltd. 12) Polybutadiene rubber (BR): NEOCI
S60, manufactured by Zeon Corporation, 98% cis body, ML
_{1 + 4} (100 ° C) 65 13) Zinc ratio: No. 1, manufactured by Mitsui Kinzoku Kogyo Co., Ltd. 14) Tetramethylthiuram disulfide: trade name TM
T, manufactured by Kawaguchi Chemical Co., Ltd. 15) Dibenzothiazyl sulfide: trade name DM, manufactured by Kawaguchi Chemical Co., Ltd. 16) Sulfur: manufactured by Hosoi Chemical Industry Co., Ltd.

The co-crosslinking agent of Example 4 shown in Table 2 has three acryloyl groups, and the co-crosslinking agent of Example 5 has two acryloyl groups.
The number of acryloyl groups in the co-crosslinking agent (acrylate of ε-caprolactone-modified pentadierythritol) of Example 6 was unknown, but the equivalent ratio = ｛(molecular weight of one molecular formula).
/ (Number of methacryloyl groups)}.
As for the crosslink density {(C)-(b)} of BIIR, Comparative Example 6 and Examples 4, 5, and 6 show the same level of crosslink density. Preferably, the crosslinking time is slightly longer in the examples of the present invention. Examples 7 and 8 are examples in which a crosslinking accelerator is used in combination with the crosslinking agent of the present invention, and it can be seen that the crosslinking density is increased. In Comparative Example 6, an organic peroxide (DCP) was used in combination with the co-crosslinking agent according to the present invention. The crosslink density in this example is slightly worse than in Example 4. Comparative Examples 7 and 8 are based on a conventional technique having the highest crosslinking density in which sulfur, zinc white, TMT, and DM are blended in accordance with known techniques described in Seiya Orabe, “Polymer Digest (1981)” No. 7, p. Although this is a formulation example, its use in sanitary rubber products has been regarded as a problem in view of the toxicity of the crosslinking agent. In the examples of the present invention, although the crosslink density is slightly lower than these, sufficient physical properties can be obtained as a sanitary rubber product, and there is no problem in terms of toxicity.

Example 9: Example of dynamic crosslinking according to the present invention
IIR [Product name Butyl 365 (unsaturation degree 2.0
Mol%, 100 parts by weight of Exxon Chemical Co., Ltd.), 15 parts by weight of clay (trade name: Hydrite10, diojia kaolin), ethylene glycol dimethacrylate (trade name: NK ester 1G, Shin-Nakamura Chemical Co., Ltd.)
5.0 parts by weight in advance with a two-roll mill, and then uniformly mixed with a plunger extruder (screw rotation speed 120 rpm).
m, thermal cross-linking was performed for 7 minutes in a nitrogen gas atmosphere using a cylinder rear temperature of 190 ± 1 ° C., a cylinder front and die temperature of 200 ± 5 ° C., and a die diameter of 3 mm). Then, the cross-linked product was immersed in cyclohexane. And microgel particles were present in a large amount, and it was confirmed that IIR was a crosslinked product. Next, a resin using a crosslinked polycyclic hydrocarbon as a polymer (trade name: DAIKYO RESIN CZ, Daikyo Seiko Co., Ltd.)
75 parts by weight and 1,2 polybutadiene (trade name RB)
840, manufactured by Nippon Synthetic Rubber Co., Ltd.) was uniformly mixed in a kneader with a kneader, and a calendered resin film was obtained.
When the tensile strength at break of the film was measured in accordance with ASTM638, it was 205 kg / cm ² and the elongation was 50%. As a result of a test based on the syringe test method of the Ministry of Health and Welfare Notification No. 442 syringe, PH 0.1, heavy metals 0.1 p
pm or less, KMnO ₄ consumption 0.1 ml or less, evaporation residue 0.1 mg or less, which was much lower than the standard value, and was good.

[Examples 10 to 14 and Comparative Examples 9-1]
9] CIIR [Product name ESSO CHROROBUT
YL1066, EXXONCHEMICAL Co., Ltd.]
100 parts by weight, finely divided silica [Pushur L
P, manufactured by Nippon Silica Co., Ltd.], 8 parts by weight, zinc white (manufactured by Mitsui Kinzoku Co., Ltd.), 1 part by weight and other compounding agents shown in Table 3 were added. D. An R test was performed. The results are also shown in Table 3.

[0035]

[Table 3]

In Table 3, 17) to 22) mean the following. 12) and 13) mean the same as in Table 2. 17) Dipentaerythritol hexaacrylate: MW547, manufactured by Nippon Kayaku Co., Ltd. 18) Polybutadiene (BR): NIPOL 1
242S, manufactured by Nippon Zeon Co., Ltd., cis 37%, ML
_{1 + 4} 53 19) 2-dibutylamino-4,6-dimercapto-S-
Triazine: trade name Desnet DB, manufactured by Sankyo Chemical Co., Ltd. 20) Magnesium oxide: trade name Kyowa Mag 150 =
Kyowa Chemical Industry 21) Ethylenethiourea: Trade name Accel 22, Kawaguchi Chemical Co., Ltd. 22) Zinc diethyldithiocarbamate: Trade name Accel EZ, Kawaguchi Chemical Co., Ltd.

In Table 3, Comparative Examples 9 and 10 are based on the superior compounding among the examples of cross-linking agents of "Halogenated butyl rubber" of "Special Synthetic Rubber" published by Japan Rubber Association, Showa 48-11, and published by Showa 48-11. , This and the composition of the present invention (Examples 10 to 1)
By comparing 4), it can be seen that the present invention shows the same degree of crosslinking density {(c)-(b)} as that of the comparative example in CIIR crosslinking. The crosslinking agents of Comparative Examples 9 and 10 are toxic and cannot be used in the field of medical and pharmaceutical devices of the present invention.

Examples 15 to 20: Examples of reheat treatment Each of the crosslinked rubbers obtained in Examples 1, 3, 8, and 10 was used as a test sample and subjected to heat treatment (crosslinking) again under the conditions shown in Table 4. . Each piece of rubber after re-heat treatment is JIS K6301 (75)
Test measurements were made according to the vulcanized rubber physical method. Table 4 shows the results
The hardness (Hs) of the rubber piece was increased, and it can be seen from this result that the rubber piece was completely crosslinked by the second crosslinking treatment.

[0039]

[Table 4]

In Table 4, 23) to 25) and each test method are as follows. 23) Electron beam irradiation device: Nisshin High Voltage Co., Ltd. EP
5M at S-300 type, voltage 100kW, current 100mA
rad irradiation. 24) Air aging test: hot air is replaced at a rate of 1 hour or more according to JIS K6300 (74). 25) Medium-pressure mercury lamp: pressure 1-2 bar, lamp 150W,
Irradiation was performed with ultraviolet light having a light source of 300 to 35 nm.

JP12 [twelfth revised Japanese Pharmacopoeia] test;
Next, the third, eighth, tenth, and first embodiments are described.
4, The crosslinked rubber pieces obtained in Comparative Examples 1 and 6 were tested according to the 12th revised Japanese Pharmacopoeia. A 10-fold amount of water is added to each sample, and the extraction is performed by heating with high-pressure steam at 121 ° C. for 60 minutes. The test conditions of foreign official standards such as DIN and BS are milder at a temperature of 121 ° C. for 30 minutes. Table 5 shows the results.

Test by DIN: In a test for detecting metal elements (Pb, Ca, Mg), 30% HNO ₃ was added to 100 ml of a test solution obtained in the same manner as in the test for elution of JP12.
The volume was set to 0 ml and measured by atomic absorption spectroscopy. In each case, the gas used was acetylene, and Pb was a hollow vacuum tube lamp 283.3μ.
m and Ca were measured with a hollow vacuum tube lamp 422.7 μm, and Mg was measured with a hollow vacuum lamp 285.2 μm.

Sulfide test: A 100 ml Erlenmeyer flask was charged with a rubber stopper having a surface area equivalent to 20 cm ² ,
Add 2% by weight citric acid to make up to 5 ml. Colorimetrically measure the discoloration (black) of the lead acetate paper in the flask. When organic peroxide is used as a cross-linking agent, sulfur can be used as a cross-linking aid, but when sulfur is used as an auxiliary, blackening occurs in this test.

Amount of fine particles (test of the amount of particles generated from a rubber stopper): 10 rubber stoppers were placed in a hard glass bottle, and dust-free water 3
Add 00 ml, cover the container opening with a film, and vibrate by hand at about 2 revolutions / second for 20 seconds. Then, after standing still for one hour, the number of fine particles in water is measured by a light shielding type automatic fine particle measuring device (manufactured by HIAC). In addition, 5μ in injection solution
The presence of fine particles of m or more is an important item because it causes problems such as blockage of blood vessels.

Separation of rubber fragments (Fragmentat
Ion); 5 ml of water is put into a bottle (10 ml capacity) shown as 2 in FIG. 1, a rubber stopper 1 is plugged, and then an aluminum cap 4 is tightened. Test needle [22G (0.7 × 3
2 mm)] is filled with 2 ml of water, and this is made to penetrate through the needle insertion portion 5 of the rubber stopper 20 times. At the time of the 20th penetration, the water in the syringe is poured into the bottle, and then the injection needle is pulled out. After the inside of the bottle is vibrated, the rubber stopper is removed, the liquid content is filtered, and the number of rubber pieces on the filter paper is counted. The test method is B
It is an improvement of the method of S, and the standard of BS is 3 rubber pieces or less, but currently less than 2 rubber pieces are required in the industry.

Chemical leakage: 500 ml of water is put into the bottle 2 of FIG. 1, the rubber stopper 1 is stoppered, and the aluminum cap 4 is tightly wound. After heating this to 121 ° C. for 30 minutes in a container,
Rocket needle 7 (J Meta-S 200
No., rocket needle with infusion set), leave for 1 hour while keeping the bottle upside down, then pierce with an air needle, drain 400 ml of water in the bottle, and at this point pull out the rocket needle from the rubber stopper Observe the liquid leak (ml) at this time,
Measure.

Water repellency (Water repellenc)
y); Put 500 ml of distilled water into bottle 2 of FIG.
And tighten the aluminum cap 4 tightly. Next, it is placed in a pressure-resistant heating vessel and steam-treated at a temperature of 121 ° C. for 30 minutes.
After standing at room temperature for 4 hours, the inner wall of the bottle is observed. At this time, those that do not recognize water droplets are accepted.

Injection needle puncture resistance test (Determin
Injection needle 7 (21, S, W, G, outer diameter 0.81 mm, length 3)
8mm) was measured at a speed of 20 cm / min through the rubber stopper with a measuring device (tension type rubber tensile tester).
The test is accepted at 0.5 kg. This test is a modification of the corresponding test of BS. BS standard value is 1000g or less.

Test of gas components in headspace: A glass bottle 2 shown in FIG. 1 is charged with 8 ml of a 2% by weight saline solution, a rubber stopper 1 is closed, and an aluminum cap 4 is further tightened. The glass bottle is steam-heated in a pressure vessel at a temperature of 121 ± 1 ° C. for 60 minutes and then left for about 10 hours. Next, 5 ml of the gas in the head space 6 in the bottle is sampled with a gas syringe, and this is measured by gas chromatography. Column: 10% OV-101 (180-200 mesh WH
P), carrier gas He 50 ml / min, column temperature 1
The presence or absence of the peak at 00 to 200 ° C. (4 ° C./min. Temperature rise) and the magnitude are observed. This test is a test for examining the generation of trace amounts of gas by rubber and compounding agents, which has become a problem in recent years.

Alkali-resistant solution test: Ten rubber stoppers were placed in an alkali-resistant container, and a 0.5% by weight solution of sodium carbonate, which was 10 times the weight of the rubber stopper, was added. And tighten. Next, in a high-pressure vessel, temperature 121
Heat at 30 ° C. for 30 minutes. After allowing to cool to room temperature and removing the rubber stopper after cooling, the test solution was applied to a quartz cell at a wavelength of 430 nm.
The transmittance of the visible part at 50 nm is measured. Pass 95% or more. This test is a basic test for examining the relationship between rubber and a chemical solution, and rubber products with low transmittance are unsuitable.

Water vapor permeability test; 2 in the glass bottle of FIG.
A 8% by weight saline solution is put in, the rubber stopper 1 is stoppered, and the aluminum cap 4 is further tightened. After storing this glass bottle in a desiccator containing silica gel for 6 months at room temperature, a change in weight is measured, and a water vapor transmission amount (g) is measured with a rubber stopper. The average value of five samples is taken, and 1 g or less is regarded as a pass. It is a voluntary standard test of the present inventors.

Water absorption test: Crosslinked rubber product was treated at a temperature of 1
Dry at 05 ° C under normal pressure for 3 hours. Next, after being left in a desiccator containing a desiccant for about 1 hour, the weight (A) is precisely weighed.
Next, the rubber stopper is immersed in purified water 10 times as much as the rubber stopper, and steam-heated as it is in a pressure vessel at a temperature of 121 ± 1 ° C. for 30 minutes.
After cooling, only the rubber stopper was left in a desiccator for 30 minutes to remove water on the surface, and the weight (B) at that time was accurately weighed.
([(B)-(A) / (A)] × 100) (%) is determined, and 2% by weight or less is regarded as acceptable.

Adsorption test of drug solution: Isosorbite nitrate (drug for ischemic heart disease, melting point: 72 ° C., manufactured by Nippon Pharmaceutical Co., Ltd.) was diluted to 0.040% by weight with physiological saline, and 3 ml of this solution was exactly 10 ml vial. , A rubber stopper was capped, an aluminum cap was fastened and left standing for 24 hours in an inverted state. This is subjected to a high performance liquid chromatograph (manufactured by HLPC), and the amount of isosorbite nitrate is measured to obtain the adsorbed weight loss.
Column: FINEPAK SILC18 (manufactured by JASCO), mobile phase methanol: water = 7: 3, flow rate 1 ml /
Minute, detector UVIDEC100-IV (220 nm, manufactured by JASCO Corporation)

[0054]

[Table 5]

As shown in Table 5, DVIIR (Example 3), BIIR (Example 8) or CIIR (Example 1)
0), a crosslinking agent is blended by a normal two-roll operation,
Crosslinked. Using each of the obtained rubbers as a test sample, JISK
When the physical properties of 6301 were tested, all of them had sufficiently good properties as medical and pharmaceutical products. In addition, as a result of tests based on the Japanese Pharmacopoeia, the twelfth revision, it was confirmed that all the test items were good at the standard value or less, and that they could be used for rubber parts in contact with drug solutions, for example, rubber stoppers for containers, stoppers for syringes, etc. Was. Furthermore, it has passed the DIN test and the special hygiene test. In other words, it is understood that the product is an extremely hygienic product that passes the new standards required for recent rubber parts and resin products for pharmaceuticals, and stricter standards than conventional products. The same test was conducted on rubbers obtained by using a compound having only one acryloyl group as a cross-linking agent (Comparative Example 1) and by cross-linking using a compound having two methacryloyl groups and an organic peroxide (Comparative Example 6). Is also shown in Table 5, but there are some items which are unsuitable in the cross-linking properties, JP12 and special hygiene test items.

[0056]

As described above, the present invention co-crosslinks IIRs (IIR, BIIR, CIIR, DVIIR) with compounds containing two or more acryloyl, methacryloyl or itaconoyl groups in one molecule. By crosslinking as an agent, (1) it has better physical properties and hygiene than using an organic peroxide as a co-crosslinking agent, and exhibits excellent properties as a sanitary rubber product. (2) JP12, US
It can pass various official standards such as P, ISO, EP, BS, DIN, etc., and can also pass strict standards which are recently regarded as important. (1), (2) It has great potential for being widely used in industry as a rubber compound and a rubber product for pharmaceuticals.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view showing a specific example in which a rubber product name of the present invention is applied to a glass bottle, showing a state in which a rubber stopper is plugged and wound with an aluminum cap.

[Explanation of symbols]

1 rubber stopper, 2 glass bottle, 3 drug solution,
4 Aluminum cap, 5 Rubber stopper 1 Injection needle piercing position mark 6 Headspace, 7 Injection needle.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-57-190011 (JP, A) JP-A-4-213347 (JP, A) JP-A-7-157610 (JP, A) JP-A-4-199 202581 (JP, A) JP-A-4-140138 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61L 29/00-31/18

Claims (7)

(57) [Claims] A compound having two or more acryloyl groups, methacryloyl groups or itaconoyl groups in one molecule is compounded in an amount of 0.2 to 30 parts by weight with respect to 100 parts by weight of an isobutylene / isoprene copolymer rubber. A rubber compound for medical or pharmaceutical use, which can be crosslinked without compounding and without using a platinum catalyst . 2. The rubber composition of claim 1, wherein said isobutylene / isoprene copolymer rubber is contained in an amount of 50 to 9 in the total amount of said rubber composition for medical and pharmaceutical use.
The rubber compound for medical and pharmaceutical use according to claim 1, which is 3% by weight. 3. An inorganic reinforcing agent and / or filler is further added in an amount of 0.5 to 30 parts by weight based on 100 parts by weight of the isobutylene / isoprene copolymer rubber, and no heavy metal compound is added. Claim 1 characterized by the following:
Or a rubber compound for medical or pharmaceutical use according to any one of claims 3 to 7. 4. The isobutylene / isoprene copolymer rubber is isobutylene / isoprene copolymer rubber, isobutylene / isoprene / divinylbenzene copolymer rubber, chlorinated isobutylene / isoprene copolymer and bromide of isobutylene / isoprene copolymer. 1 selected from
The rubber compound for medical or pharmaceutical use according to any one of claims 1 to 3, characterized in that: 5. A rubber product for medical or pharmaceutical use, wherein the rubber compound according to claim 1 is cross-linked. 6. The method according to claim 1, wherein the crosslinking is carried out one or more times statically and / or dynamically using at least one crosslinking means selected from natural crosslinking, heating, light irradiation and / or electron beam irradiation. The rubber product for medical and pharmaceutical use according to claim 5, characterized in that: 7. A syringe, a transfusion device, an infusion set, a blood collection device, an artificial kidney, a catheter, a tube, a blood pack, and a needle, all or a part of which are made of the rubber product according to claim 5 or 6. A medical or pharmaceutical device which is a two-chamber syringe, a vial or a rubber stopper.