JPH0622584B2 - Radiation resistant medical rubber parts - Google Patents

Description

TECHNICAL FIELD The present invention relates to a radiation resistant medical rubber part, particularly ethylene-propylene or ethylene-propylene-
The present invention relates to a radiation-resistant medical rubber part which is mainly composed of a diene compound copolymer elastomer and to which a radiation sterilization method can be applied.

[Conventional technology]

Manufacture and sale of medical device equipment requires approval and permission from the Minister of Health and Welfare or the prefectural governor under the Pharmaceutical Affairs Law, and medical rubber parts have performance as rubber's original elastic body, aging, other physical, In addition to the chemical properties, the hygiene properties naturally required in the field of use thereof require that high properties be maintained even after sterilization.

At present, polyethylene (PE), polypropylene (P) is used for resin or rubber as a material for medical instruments and instruments.
P), polyvinyl chloride (PVC), polystyrene (P
S), polymethylmethacrylate (PMMA), nylon, polyurethane (PU) and other resins, styrene-butadiene rubber (SBR), butadiene rubber (BR), isoprene rubber (IR), natural rubber (NR), silicone rubber (Si) ), Chloroprene rubber (CR), isobutylene
A rubber such as isoprene rubber (IIR) is used as it is or after adding a compounding agent, and it is usually sterilized after attaching a molded part by heating and pressurizing to a medical part.

As the sterilization method, a chemical solution sterilization method, a boiling method, a high-pressure steam sterilization method, a dry heat method, an aseptic excess method, a gas sterilization method, a radiation sterilization method and the like are carried out.

The outline of the above-mentioned sterilization method and problems when applied to the currently used component materials will be described below.

(B) The chemical solution sterilization method is a sterilization method using a disinfecting chemical solution such as alcohol, oxidol, marquiurochrome, cresol, etc., but the toxicity of the chemical solution, the handling method of the chemical solution,
Furthermore, there is a problem in drying after sterilization, so it is used in small-scale areas.

(B) The boiling method is a method of immersing in boiling water for 15 minutes or more and boiling, and is applied to materials such as rubbers, glass, metals and fibers having a softening point of 110 ° C. or higher. However, this condition is not suitable for medical devices that place importance on hygiene and safety, because viable bacteria remain.

(C) In the high-pressure steam sterilization method, the temperature is 121 ° C in a pressure resistant container.
This is a method of applying high pressure heat and aseptic with the above steam. Therefore, it has a drawback that it cannot be applied to materials having a low softening point such as PE, PVC and PS.

(D) The dry heat method is a method of dry heat at a temperature of 140 ° C. to 200 ° C., but the sterilization efficiency is lower than that of the high pressure steam method and it takes a long time. Also, it cannot be applied to materials having a low softening point.

(E) Aseptic filtration is a method of passing through materials such as membranes and porcelain filters, and the improvement of materials has progressed, and it has come to be widely used as a sterilization method for purified water and drug solutions. However, there is a problem of drug adsorption to the filter or conversely elution from the filter, and even if it is used on a small scale,
It is not suitable for mechanical instruments because of cost.

(F) The gas sterilization method is ethylene oxide gas (EO
G), a method using a gas such as propylene oxide gas (POG), the gas can be transported in a small cylinder, the container and the operation are relatively easy, and the sterilization and the gas at a low temperature of 40 to 60 ° C. It has been widely adopted because it is cheap in addition to the reason that it is easily obtained. However, there are problems that EOG may be adsorbed and left on a sterilized product, or may cause a chemical reaction to produce a harmful substance, and that the EOG itself is toxic and requires careful exhaust and operation.

As a method for solving the problems in each of the methods (a) to (f) described above, the (g) radiation sterilization method has been closed up. This method is a sterilization method by irradiation of radiation, and electromagnetic radiation (γ rays, X rays) is used depending on the radiation source used.
Method and particle radiation (high energy electron beam, β ray,
(α rays) can be roughly divided into methods, but the practical radiation source is γ
Ray, X-ray and electron beam. In particular, for sterilizing medical instruments and instruments, a method of using γ-rays with cobalt 60 has become the mainstream, and in recent years, electron beams have also been used.

As for the sterilization dose, in the UK, West Germany, Switzerland and Australia, it is customary to use γ-rays of 2.5 Mrad, 2.5 to 4.5 Mrad in France and 2.5 M in the USA.
It is less than or equal to rad. In any case, the probability of being aseptic is 9
9.9999%, or ^10-6 .

However, the above-mentioned conventional medical resin / rubber materials cannot be used because they cannot maintain the physicochemical properties necessary and sufficient for use as medical materials after sterilization by radiation.

By the way, as a method for producing a radiation resistant organic polymer material used for electric wires, cables, etc. of a nuclear reactor, an ethylene-propylene copolymer (hereinafter abbreviated as EPM) or an ethylene-propylene-diene compound copolymer (hereinafter There is a known technique in which a large amount of a filler, a reinforcing agent, a flame retardant, etc. are blended with EPDM) and cross-linked [Journal of the Atomic Energy Society of Japan Vo
125, No. 4, P258 (1983), JP-A-56-1
No. 16729, No. 116730, No. 116731] Furthermore, a technique for radiation-crosslinking EPM or EPDM (Japanese Patent Publication Nos. 47-44277, 54-17355, 56-56).
3364, the same 56-14169, the same 56-40445,
Nos. 56-8863 and 56-8863) or a method of crosslinking a resin using an electron beam (Japanese Patent Publication No. 52-52).
-31257, JP-A-57-177002).
There is also a report on electron beam sterilization ["Antibacterial and Antifungal" Vol.
12, P611-618 (1984) Vol13, P29
9-305 (1985)].

[Problems to be solved by the invention]

When the above EPM and EPDM molded products are irradiated with radiation in the air, low molecular weight products of aldehydes, peroxides and hydroperoxides are produced, and an offensive odor is generated, depending on conditions, ozone is produced, rubber is crosslinked and molecular chains are generated. It is known to cause complicated reactions such as cleavage and coloring of the.
Therefore, even if EPM or EPDM is cross-linked by the above-mentioned known technique, it cannot be used as a material for medical rubber parts to which radiation sterilization can be applied.

In view of the above situation, the present invention is intended to provide a novel radiation resistant medical rubber part which is composed of a crosslinked elastomer containing EPM or EPDM as a main component and which can be subjected to radiation sterilization.

[Means for Solving the Problems] The present invention comprises a copolymer elastomer of ethylene and propylene and / or a copolymer elastomer of ethylene, propylene and a diene compound as a main component, and further adds a compounding agent to form a cross-linked product. Radiation resistant medical rubber parts. As used herein, the term “radiation” is a general term for particle beams or electromagnetic waves that move at high speed, as in the general definition. For example, α rays, β rays, γ rays,
Includes X-rays, electron beams, neutron rays, etc.

As a particularly preferred embodiment of the present invention, the propylene content of the copolymer elastomer is 10 to 60 mol% in the above description, and titanium oxide, white carbon and clay as an inorganic compounding agent are added to 100 parts by weight of the copolymer elastomer. 3 to 60 parts by weight of at least one of the above, and 0.001 to 5 parts by weight of other compounding agents are included.

The present inventors examined the content and composition of the propylene or diene compound of EPM and / or EPDM as a material for radiation sterilization when manufacturing a rubber part for medical use.

The EPM referred to in the present invention is an elastomer obtained by solution polymerization of ethylene and propylene with a vanadium compound-alkylaluminum catalyst, and EPDM is an elastomer obtained by similarly polymerizing ethylene-propylene and a diene compound. The sterilization temperature required for an elastomer has a propylene content of 10 to 60 mol% in a preferable range, and 20 to 30 mol% shows a minimum temperature. A random copolymer of ethylene and propylene is preferable. PE or P
The embrittlement temperature of only P is as high as −18 ° C. and it does not show a rubbery state. Further, if the content of PP exceeds 60 mol% and becomes high, crosslinking molding becomes difficult. Generally, rubber molecular weight is 10,000-
1 million out of which 10 are commercially available EPM or EPDM
10,000 to 500,000. The higher the molecular weight, the higher the crosslinking efficiency and the sanitary rubber part suitable for the rubber part of the present invention. In addition, EPM
EPDM is a rubber in which a diene-based compound is introduced into the rubber to facilitate cross-linking, and sulfur and a donor sulfur-based compound can be cross-linked to improve physical properties. This diene compound includes ethylidene norbornene, dicyclopentadiene,
EPDM having 1,4-hexadiene and the like and having an iodine value of 3 to 30 in the elastomer is preferable for the purpose of the present invention.
In the present invention, EPM and EPDM may be mixed and used. Next, a catalyst and an antiaging agent are important when manufacturing the EPM or EPDM.

As the antiaging agent added when copolymerizing EPM or EPDM, hindered phenol (mono, di, tri and multiphenol) compounds are preferable, and in addition, phosphite compounds, propionate compounds and the like can be mentioned. It is preferable to add two or more kinds in a proportion of 0.001 to 3% by weight.

Phenylamine (mono, di, tri) type anti-aging agents have strong resistance to radiation and are widely used for preventing rubber aging, but are not applicable because they are colored and do not show hygiene when used as medical rubber parts of the present invention. .

Elastomers containing ethylene groups, propylene groups and both groups undergo a turbulent reaction as the main reaction when an antiaging agent is added and they are irradiated with γ-rays in a vacuum, but when irradiated in the presence of oxygen in the air, radical reactions occur. The rubber is decomposed and causes physical and chemical changes. That is, the main reaction caused by γ-ray irradiation is considered to be an oxidation reaction, and it is considered that EPM or EPDM causes an oxidation reaction even with a small amount of γ-ray irradiation.

Therefore, various compounding agents are selected in order to minimize such an oxidation reaction, and EPM and / or EPDM is compounded with the rubber in the preceding step of molding as a radiation resistant medical rubber component.

Such compounding agents include cross-linking agents, anti-aging agents,
Radiation resistant agents, fillers and reinforcing agents, crosslinking aids, rubber processing agents, pigments and the like can be roughly classified.

The present invention mixes at least one of these compounding agents and crosslinks them. Generally, when a highly reactive substance is blended with EPM and EPDM, it becomes difficult to maintain hygiene, and the product fails the standard of "Japanese Pharmacopoeia" and cannot be used as a medical rubber part. Therefore, it is preferable to mix many kinds of the above-mentioned compounding agents. Substances that have a tentative effect are shown below.
The numbers described in parentheses () indicate the above properties (1) to (3), and a plurality of numbers indicate a plurality of properties.

Zinc white (), calcium stearate (),
Polystyrene (), anthracel (), acenaphthylene and acenaphthene or derivatives thereof (), phenyl ether and phenyl ketone compounds (), hindered phenols and amines (), silane coupling agents (), organic sulfur donating vulcanizing agents (), Vulcanization accelerator (), crosslinking activator () (), processing aid (), organic peroxide (), polyphenyl sulphate (), polyethylene-2,6 naphthalene dicarboxylate (), bis ( 2,2,6,6 tetramethylpiperidyl) adipate salur (), polyester resin (), N-dichlorohexyl-2-benzothiazyl sulfenamide (), tetraethyl thiuram disulfide (), tetrabutyl thiuram disulfate Id (), dipentamethylene thiuram disulfide (), di-n-butyl-dithiocarba Phosphate zinc (
), Γ-mercaptobropyrtrimethoxysilane (
), Trimethylolpropane trimethacrylate (), tris- (3,5-di-t-butyl-4-hydroxybenzyl) isocyanurate (), β- (3,
4-epoxycyclohexyl) ethyltrimethoxysilane (), ultra high molecular weight polyethylene (), thermoplastic elastomer (), hexadecylphenyl phenyl ether (), silicic acid fine powder (), vinyltris (β-methoxyethoxy) silane , (), 1,1-
Di (t-butylperoxy) -3,3,5-trimethylcyclohexane ().

0.001 to 5 parts by weight of at least one substance selected from the above antioxidants, radiation resistant agents, processing aids, crosslinking aids, and pigments per 100 parts by weight of copolymer elastomer, and further as an inorganic compounding agent. Titanium oxide (), white carbon (), clays (), barite ()
It is preferable to mix at least one of them in an amount of 3 to 60 parts with respect to 100 parts by weight of rubber. And EP
M or EPDM is 50 to 85% by weight in medical rubber parts
Was found to be the most preferable.

The compounding method of the compounding agent to EPM and / or EPDM is not particularly limited, but in the following examples, a two-roll rubber or the like is used and “Rubber test method” P108 to 118.
It was compounded in accordance with the method described in (Japan Rubber Association), dispensed, heated and pressed in a mold, and molded and crosslinked.

In the sterilization method of the medical rubber part obtained as described above, irradiation with a radiation dose of 0.3 to 7 Mrad was performed with γ rays or electron beams. It was found that the medical rubber parts at this time were colorless and odorless and passed the hygiene test standards of "Japanese Pharmacopoeia" and "Ministry of Health and Welfare Notification" and became medical rubber parts that comply with the Pharmaceutical Affairs Law. The composition of the medical rubber component which can be sterilized by radiation and passes the standards of the Pharmaceutical Affairs Law and the Pharmacopoeia has been obtained for the first time by the present invention.

〔Example〕

Experiment 1 Comparison of Rubber and Resin (Example 1, Comparative Examples 1 to 9) Table 1 shows the types of rubber and resin. Calcium carbonate 30 for 100 parts of rubber / resin shown in the table (parts by weight below)
Parts, 0.5 parts of stearic acid, and 1.7 parts of 1,3- (t-butylperoxyisopropyl) benzene were compounded with a two-roll rubber compounding roll. The crosslinking was performed at a temperature of 160 ° C. for 30 minutes. The obtained rubber plate was cut into a dumbbell No. 3 type described in JIS K 6301, and a test piece was given 20% strain.
Slat Covegor type, Co ⁶⁰ source, γ-ray 2Mra
d irradiation treatment was performed. Based on JIS K 6301, tensile strength (abbreviated as TB) kg / cm ² and elongation (abbreviated E)
The results of measuring B))% are also summarized in Table 1.
The overall evaluation of both is shown by symbols as follows.

Excellent ◎, good 〇, acceptable △, not acceptable × As shown in Table 1, EPM has high physical properties even after γ-ray irradiation. On the other hand, NR, SBR, IR, BR, and CR cracked from the test piece and the surface and were cut during the test. Although not included in the sample, 11R softens from the surface. Si, PV
C, EVA and Nylon are γ-ray resistant resins, but EB
Is low and is not suitable for the purpose of the present invention.

Experiment 2 Effect of radiation resistant additive on EPDM (Examples 2 to 10, Comparative Examples 10 and 11) Table 2 shows EPDM and its additives, EPM, PP and PE. Compounding amount is 100 parts of rubber / resin, 1 part of zinc flower
Part, white carbon 20 parts, 1,1-di (t-butylperoxy) -3,3,5-trimethylcyclohexane 1.3 parts, and other radiation resistant additives are listed in Table 2.
As shown in. The test conditions are the same as in Experiment 1,
The gamma dose is 5 M rad, and the aging rate (%) after irradiation and the comprehensive evaluation are also summarized in Table 2.

Propylene 66 mol%, ethylidene norbornene, iodine value 24: Sumitomo Chemical's trade name NASA's bis (2,2,6,6 tetramethylpiperidine) adipate, Sanol 770: Sankyo's trade name propylene, 40 mol%: Product name made by Japan Synthetic Rubber Propylene, 58 mol%, ML _{1 + 4} (100 ° C)
38: Trade name of Mitsui Petrochemicals Tris (3,5-di-t-butyl-4-hydroxybenzyl) isocyanurate: Low density PE (MI410) manufactured by Guttori Tsch: Showa Denko product name Sumitomo Chemical product name “Japan Pharmacy KMnO ₄ consumption test in accordance with "Rubber test method for infusion": Distilled water of 10 times the weight of a rubber test piece was added, and the test solution was heated at 121 ° C. for 1 hour in a high-pressure steam sterilizer. 01N KMnO ₄ consumption (ml) As shown in Table 2, EPDM has high TB and EB numbers. However, γ-ray irradiation causes some aging. Therefore, by incorporating the radiation resistant additive shown in Examples 4, 5 and 6, the aging rate is also reduced. The EPMs of Examples 8, 9, and 10 have a small TB value and poor crosslinking efficiency or good aging rate. In Example 11, the γ-ray resistance is slightly improved. Comparative Example 1
0 and 11 have a high aging rate. KM that conforms to the “rubber test method for infusion” of “Tenth Revised Japanese Pharmacopoeia”
It can be seen that the consumption amount of the nO ₄ liquid increases as the test piece having a larger aging rate.

Experiment 3 Influence of rubber compounding agent amount (Examples 12 to 14, Comparative Examples 12 and 13) EPDM (Mitsui EPT4045, propylene amount 44 mol%, iodine value 25 ML _{1 + 4} (100 ° C.) 42, manufactured by Mitsui Petrochemical) was added to 100 parts. Zinc white 3 parts, AC polyethylene (made by Allied) 2 parts, stearic acid 0.5 part, white carbon (Tokushiru UR: made by Tokuyama soda) 20 parts,
1 part of 2,6-di-t-butyl-4-methylphenol,
Other cross-linking compounding agents and fillers were added as shown in Table 3. The crosslinking conditions and γ-ray irradiation conditions were the same as in Experiment 2. The results of various tests performed on the obtained rubber material are also summarized in Table 3.

As is clear from the results in Table 3, Example 12 is a donor organic sulfur cross-link, but the test was performed according to the rubber gland test method for infusion of the hygiene test even after irradiation with γ-ray of about twice the sterilization radiation dose. As a result, the standard can be passed.

In addition, Example 13 is a sulfur cross-linking agent. Compared to the clay amount of 20.0 parts in this example, the example is 60.0 parts, and the comparative examples 12 and 13 are 100 parts. You can see that it fails the rubber parts. (In addition, it has been reported that the radiation resistance of a general rubber radiation resistant electric cable is better as the amount of the filler is larger.) Experiment 4 Rubber parts of dialysis type artificial kidney device (Example 15) Molding of the product was performed at a temperature of 165 ° C. for 30 minutes, and the γ-ray irradiation of the molded product was performed at 3M rad or 6 as in Experiment 1.
M rad. Next, Yakuhin No. 494 (6, 1983)
The test was carried out by the elution test method for the support and the circuit connecting pipe, which is the approval standard of the 20th month. The results are shown in Table 5.

In addition, about the thing which used the sample for 24 hours by heating a physiological saline solution (70 ± 5 ° C), acute toxicity test (male mouse), intradermal reaction test (male rabbit), pyrogenic substance test (rabbit),
A hemolytic test (rabbit defibrosis), a sterility test (thioglycolic acid medium 31 ± 1 ° C. for 7 days) and a fungal test (dextrose, peptone medium 23 ± 2 ° C. for 5 days) were performed. No abnormalities were observed.

As a result of the above test, the product of the present invention was able to pass all of the physical test, hygiene test and biological test as a rubber component of the dialysis type artificial kidney device.

Experiment 5 Small rubber parts (Examples 16, 17, 18, 1)
9 and 20) Table 6 shows the types of rubber and poetry. HMWPE, YSBR, special silicon oxide, and the like were mixed in advance with a premixer, and a certain amount of the mixture was placed in an extruder together with EPDM. Screwing ratio 3 to 4, L / D20, metering type, cylinder temperature 150 to 190 ° C, hopper side temperature 200
Knead at ~ 220 ℃ for about 20-60 seconds, the shape of the plug is a cone (diameter φ13.5 mm, height 9 mm), the center is hollow and the part with which the sucker engages, the temperature is 50-70 ℃ Vacuum molding was performed in the mold at an injection pressure of 70 to 100 kg / cm ² .
Cutting, followed by boiling and washing for about 10 minutes, drying and packaging. After assembling and packaging in a syringe, high energy electron beam sterilization with an electron accelerator was performed at 5 MeV-30 kW, a treatable amount of 75%, and a penetration thickness of about 30 cm. Current 65-1
It was 40 mA and the absorbed dose was 2 to 6.5 Mrad. The viable cell count was <10 ⁻⁵ aseptic when measured by the standard inoculum plate culture method.

Table 7 shows the results of irradiated objects in accordance with the "10th Amended Japanese Pharmacopoeia""Rubber Stick Test Method for Infusion": ML _{1 + 4} (100 ° C) 65, ethylene amount 69W
%, The third component was added with 0.05% by weight of a hindered phenol anti-aging agent during the production of dicyclopentadiene synthetic rubber Polyethylene powder having an average molecular weight of 5,000,000, melting point 13
6 ° C., Bizex million (trade name, manufactured by Mitsui Petrochemical Co., Ltd.) thermoplastic elastomer: styrene-ethylene-butylene-styrene block copolymer, molecular weight: about 80,000, Kraton G: (trade name, manufactured by Shell Chemical Co., Ltd.), polyether ether ketone Powder, melting point 334 ° C
Victorex PEEK450G (ICI product name) Hexadecylphenyl ether molecular weight about 4
00, viscosity 21 (cst) (manufactured by Matsumura Petroleum Industry Co., Ltd.) AEROSIL200: (trade name, manufactured by Nippon Aerosil Co., Ltd.), surface area 200 ± 5 m ² / g, particle size about 12 mμ Vinyltris (β-methoxyethoxy) silane K
BC1003: (Shin-Etsu Chemical trade name) 1,1-di- (t-butylperoxy) -3,3
5-Trimethylcyclohexane, Perhexa 3M: (trade name of NOF CORPORATION) From the results shown in Table 7, there is a sterilizing effect even though the electron beam irradiation amount is small. It was found that the physical properties of the molded product obtained by crosslinking the rubber and the resin with the silane coupling agent with the electron beam were suitable as the plug although the antioxidant was not mixed.
Even after 6 months of irradiation, the pH, the consumption of KMnO ₄ solution, and the value of ultraviolet absorption show excellent hygienic properties.

From the above test results, it can be said that the rubber parts similar to the above can be used for rubber parts such as plasma separators, blood filters, blood circuits, and infusion set syringes.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The present invention is mainly composed of EPM and / or EPDM, and can be sufficiently resistant to radiation sterilization and sterilization treatment by being mixed with an inorganic and organic compounding agent of a radiation resistant agent and cross-linked, and is described in the Pharmaceutical Affairs Law. It can be widely used because it can be used for rubber parts of equipment and medical instruments described in "Japanese Pharmacopoeia".

Claims (3)

[Claims] 1. A radiation-resistant medical rubber part comprising a copolymer elastomer of ethylene and propylene and / or a copolymer elastomer of ethylene, propylene and a diene compound as a main component, and further adding a compounding agent and crosslinking and molding. . 2. The radiation resistance according to claim 1, wherein the propylene content of the copolymer elastomer of ethylene and propylene or the copolymer elastomer of ethylene, propylene and diene compound is 10 to 60 mol%. Medical rubber parts. 3. 100 parts by weight of a copolymer elastomer, 3 to 60 parts by weight of at least one or more of titanium oxide, white carbon and clay as an inorganic compounding agent, and an antioxidant and a radiation resistant agent as a compounding agent. A processing aid, a pigment, and at least one or more of the group consisting of a crosslinking aid in an amount of 0.001 to 5 parts by weight.
The radiation resistant medical rubber component as described in (1) or (2).