JPS6138705B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to medical containers, and more particularly to medical containers suitable for use in closed medical systems. Prior Art and Problems In recent years, closed systems have been used in medical treatments such as blood donations, blood transfusions, and infusions to prevent liquids to be processed (eg, blood, medical solutions) from coming into contact with the outside world. Medical containers to be incorporated into such systems require transport of the liquid to be treated by the difference in gravity and the flexibility of the container material, and are made of flexible plastic. In addition, in order to keep the liquid to be treated sterile, this type of medical container must be subjected to high-pressure steam sterilization, and must have heat resistance to withstand such treatment. Furthermore, this medical container may contain blood, for example, and the blood may be frozen and stored, so it is necessary to have enough cold resistance to withstand even such freezing temperatures. Plastic materials with excellent flexibility include soft polyvinyl chloride and ethylene-vinyl acetate copolymer, but soft polyvinyl chloride is superior in that it can withstand high-pressure steam sterilization (ethylene-vinyl acetate copolymer coalescence does not withstand autoclaving). However, soft polyvinyl chloride is inferior to ethylene-vinyl acetate in cold resistance and contains a large amount of plasticizer. As described above, conventional medical containers are not excellent in both heat resistance and cold resistance, and are also fraught with problems such as additives or compounding agents leaching out. Therefore, there is currently a strong desire to provide an excellent medical container that has both of these properties and is acceptable from the standpoint of safety. Purpose of the Invention Therefore, the purpose of the present invention is to provide a medical container that has both heat resistance that can withstand high-pressure steam sterilization and excellent cold resistance, and is satisfactory in terms of safety. Another object of the invention is to provide a medical container with excellent flexibility. A further object of the invention is to provide a medical container with excellent water vapor barrier properties. Furthermore, an object of the present invention is to provide a medical container with excellent transparency. Another object of the present invention is to provide a medical container that does not cause problems with the elution part. According to the present invention, there is provided a collapsible medical container having improved cold resistance and heat resistance capable of withstanding high-pressure steam sterilization, the container being formed from an ethylene-vinyl acetate copolymer cross-linked by electron beam irradiation. The container body is completely sealed except for a non-sealed portion at a predetermined portion of the periphery, and the non-sealed portion includes an end portion of an accessory necessary to achieve the function of the medical container. is inserted, and the accessory is sealed to the main body at the insertion end via an intervening layer made of uncrosslinked ethylene-vinyl acetate copolymer. Generally, the ethylene-vinyl acetate copolymer forming the body has a vinyl acetate content of 10 to 35% by weight and is crosslinked to have a gel fraction of 50 to 85% by weight. This body also typically has a wall thickness of 0.1 to 0.6 mm. Preferably, the ethylene-vinyl acetate copolymer forming the intervening layer has a vinyl acetate content of 15 to 40% by weight. The accessory is preferably made of a polymeric material that is heat resistant to withstand autoclaving and exhibits blocking properties against ethylene-vinyl acetate copolymer at elevated temperatures. Such polymeric materials typically include high density polyethylene and a first mixture thereof with an ethylene-vinyl acetate copolymer;
and polypropylene, and this and ethylene-
a second mixture with a vinyl acetate copolymer. The ethylene-vinyl acetate copolymer in the first and second mixtures typically has a vinyl acetate content of 15 to 40% by weight. Also, the first mixture may contain up to 80% by weight, and the second mixture may contain up to 80% by weight.
The mixture contains up to 85% by weight of ethylene-vinyl acetate copolymer. Accessories attached to the main body include a drainage port, etc. DETAILED DESCRIPTION OF THE INVENTION In order to provide a flexible container to be used in a closed medical system, the present inventors investigated various materials and found that they are free of leachable materials and have excellent cold resistance. Ethylene-vinyl acetate copolymer was chosen as the material for the container body. The ethylene-vinyl acetate copolymer (hereinafter referred to as EVA copolymer) that forms this container body is
Preferably it has a vinyl acetate content of 35% by weight. If this content is less than 10% by weight,
EVA copolymer is transparent (high transparency means that the liquid inside the container can be easily observed visually).
(This is one of the important properties that containers used in closed medical systems should have) and flexibility (as mentioned above, containers used in closed medical systems have problems due to the weight of the liquid inside and the flexibility of the container). Therefore, flexibility is an important property as it transports the liquid content, and it must be easily flattened by atmospheric pressure as the liquid content is drained or reduced, that is, it must be easily crushed. ) also decreases, and furthermore, the fusion bonding properties due to high frequency, which can provide strong fusion bonding, also decrease. On the other hand, when the vinyl acetate content exceeds 35% by weight, the transparency
Although the flexibility and high-frequency weldability are improved, the water vapor permeability increases (the water vapor barrier property decreases). If the water vapor permeability increases, the amount of transpiration of the liquid contained in the container increases, which is undesirable because it tends to cause a change in the concentration of the liquid contained in the container, such as blood or drug solution, during long-term storage. Additionally, the wall thickness of the container body, which is made of EVA copolymer, has a significant effect on transparency, flexibility, and water vapor permeability. If the wall thickness is too thin, water vapor permeability increases and there is a risk of damage depending on the handling method. For this reason, the medical container of the present invention preferably has a wall thickness of 0.1 to 0.6 mm, preferably 0.3 to 0.5 mm. Although EVA copolymer has excellent cold resistance,
Even if the above conditions are met, the heat resistance (i.e., no peeling, deformation, melting, etc. during high-pressure steam sterilization) that can withstand high-pressure steam sterilization (usually 115-121℃ for 15-45 minutes) is required. Not enough. Therefore, in the present invention, the EVA copolymer described above is irradiated with a certain type of ionizing radiation to crosslink the EVA copolymer, thereby imparting desired heat resistance. We have also found that the best heat resistance can be obtained by crosslinking the EVA copolymer so that the gel fraction is approximately 50% or more. (Gel fraction is the percentage of the weight of the hot xylene insoluble content to the weight of the crosslinked EVA copolymer). Possible ionizing radiation species include gamma rays and high-speed electron beams. However, gamma rays have a low dose rate, and irradiation in air cannot provide a sufficient gel fraction. Therefore, in this invention, a high-speed electron beam was selected as the radiation species. High-speed electron beams are obtained using Van de Graaff type accelerators or linear accelerators, and the dose rate is high (generally several Mrad/
(seconds) is variable, and the desired gel fraction can be obtained with irradiation for several seconds even in air. Therefore, sheets etc. can be continuously irradiated, making it suitable for mass production. However, high-speed electron beams have limited penetrating power;
It is not suitable for large wall thicknesses or complex shapes. For this reason, it is preferable to irradiate a flat and relatively thin sheet-like object as in the present invention. Further, it is preferable to make the container flat in an empty state from the viewpoint of ease of crushing as described above. Such electron beam irradiation also improves the cold resistance of the EVA copolymer. In other words, cryopreservation of blood components that will be profitable in the future (for example, according to WHO standards, plasma should be cryopreserved in a freezer at -40°C or lower, or with dry ice and an organic solvent such as alcohol). For cryoprecipitate, plasma is frozen at -20°C or lower, thawed at 5°C, centrifuged, and the supernatant is collected. The plasma is removed leaving about 20ml, mixed and dissolved, frozen at below -20°C and stored in the freezer), and can withstand use in cold regions ( In other words, it will not be damaged even when handled at these low temperatures). As mentioned above, in this invention, the EVA copolymer is crosslinked with electron beams so that the gel fraction is about 50% or more. It is difficult to fuse EVA copolymers with such a degree of crosslinking to each other. In other words, when cross-linked EVA copolymers with a gel fraction of 50% or more are stacked and fused together using high frequency, they appear to be completely adhered at first glance, but if they are reheated in boiling water, etc. It tries to return to its shape and easily peels off. To deal with this, in the present invention, a pair of sheets or flat tubes made of the desired EVA copolymer are first sealed to provide the desired container shape, and then the whole is irradiated with an electron beam to form the container body. It has gained. Although the main body of the medical container of the present invention is thus provided, this alone does not function as a medical container. It is necessary to attach to this main body the accessories necessary to achieve the function of a medical container, such as drainage ports and other tubes.
The material forming this accessory must have some flexibility and be able to withstand autoclaving. By the way, if you use the above-mentioned accessories with the cross-linking
It is extremely difficult to attach to a container body made of EVA copolymer. In fact, a drainage port made of high-density polyethylene is inserted into one end of the container body made of cross-linked EVA copolymer, welded with high frequency, physiological saline is injected into this port as an infusion solution, the stopper is closed, and high pressure is applied. After steam sterilization, the drain port was completely separated from the container body. After installing such a drain port, it is possible to irradiate the main body with an electron beam to crosslink it, but as mentioned above, the electron beam has a limited ability to penetrate, and the wall thickness is relatively thick. The sheet on the opposite side is not sufficiently crosslinked because it is blocked by the accessories. The present inventors conducted various studies to attach accessories to a container body made of crosslinked EVA copolymer, and found that when sealing an EVA copolymer sheet or tube to the shape of the container body, the end of the accessory Leave an unsealed part where the parts can be inserted, and keep the crosslinking by electron beam so that the gel fraction is 85% or less. Then, attach the accessories to uncrosslinked EVA.
It has been found that accessories can be attached with heat resistance that can withstand high-pressure steam sterilization by sealing with high frequency waves or the like through an intervening layer made of a copolymer. In order to install the above accessories more completely, the gel fraction of the cross-linked EVA copolymer that forms the container body must be (50% or more) and 85% or less, and the following conditions must be met: I found this to be highly desirable. (1) The vinyl acetate content of the uncrosslinked EVA copolymer forming the intervening layer should be 15 to 40% by weight. If the content is less than 15% by weight, the adhesive strength will be insufficient, while if it exceeds 40% by weight, the adhesive layer will tend to flow during high-pressure steam sterilization, making it easy for accessories to separate. The preferred vinyl acetate content is between 20 and
It is 30% by weight. (2) In addition to being heat resistant (not deformed) to withstand high-pressure steam sterilization, the accessories must also be heat resistant at high temperatures.
It must be made of a material that exhibits blocking properties against EVA copolymer. As such materials,
Furthermore, taking safety (hygiene), price, etc. into account,
High density polyethylene and polypropylene are suitable. Vinyl acetate content in these polymer materials
Blending 15-40% by weight of uncrosslinked EVA copolymer further improves adhesive strength. The blend ratio of high density polyethylene and EVA copolymer is preferably 100/0 to 20/80 by weight, while the blend ratio of polypropylene and EVA copolymer is preferably 100/0 to 15/85 by weight. The medical container of the present invention described above, including its manufacturing method, will be explained in more detail with reference to the drawings. First, as shown in FIG. 1A, an EVA copolymer tube 11 obtained by inflation molding.
for example by high frequency induction heating to provide the shape of the container body. This seal is only required at the bottom end 12 and top end 13 of the container. At this time, the non-sealed portion 14 is provided to the extent that accessories described below can be inserted therein. Alternatively, a pair of EVA copolymer sheets 11' obtained by extrusion molding or the like may be stacked on top of each other, leaving the non-sealed portion 14 and the bottom and top edges 12, 1 as shown in FIG. 1B.
3 and side edges 15 are sealed by high frequency induction heating. These methods were used to form the desired container shape.
The EVA copolymer container body is irradiated with an electron beam, generally at a dose of 5 to 20 Mrad, to crosslink the EVA copolymer to obtain the desired gel fraction. Next, as shown in FIG. 2, which shows a partially cut away part, an accessory to be attached to the container body 20, for example, one end of the drain port 21 is covered with a small tube 22 as an intervening layer made of uncrosslinked EVA copolymer. cap and insert it into the container body so that the small tube contacts the unsealed portion of the container body. Then, by fusion-bonding, for example, by high-frequency induction heating, and accessories are attached, a medical container as shown in FIG. 3 is obtained. Incidentally, the drain port 21 may be covered with a suitable cap 23.
Further, it is convenient to provide a through hole 24 in the bottom seal portion of the container for suspending the container. Examples of this invention will be described below. Example 1 An EVA copolymer with a vinyl acetate content of 15% by weight was inflation-molded to a folded diameter of 130 mm and a wall thickness of 0.4 mm, and as shown in Figure 1A, the non-sealed part (folded diameter of 17 mm, After sealing the desired container shape leaving a length of 10 mm, electron beam irradiation (absorbed dose: 15 Mrad) was performed to crosslink the gel fraction to 80%.
In this way, a 500 ml infusion container body was obtained. On the other hand, a small tube (outer diameter 15 mm, inner diameter 13 mm) made of uncrosslinked EVA copolymer was attached to one end of a drainage port (outer diameter 13 mm, inner diameter 10 mm, length 25 mm) made of the polymer material shown in Table 1 below. , length 10 mm), and insert it into the unsealed part of the container body as shown in Fig. 2, which is partially cut away, and fuse it by high-frequency induction heating to form the desired shape. A container for infusion was obtained. 500 ml of physiological saline was dispensed into this container from the drainage port, and a high-density polyethylene film (thickness 0.1 mm) was heat-fused to the outer end of the drainage port to seal it, and a rubber stopper was then capped. . The container containing the drug solution thus obtained was subjected to high-pressure steam sterilization (121°C, 30 minutes), and the condition of the drain port was observed.

[Table] As a result, the material used for the drain port
In the case of No. 1 and No. 2, the drain port was not deformed, but the adhesive part moved by about 2 mm (the drain port shifted toward the outer end of the opening). However, there was no fluid leakage, and there was no problem with the infusion procedure. No.3
In the case of No. 4, the adhesion was good, and there was no deformation of the drain port or leakage. No.5 and No.6
In this case, although the adhesion was good, the drainage port was found to be collapsed, which interfered with the infusion procedure. Example 2 A crosslinked ethylene-vinyl acetate copolymer with a gel fraction of 80% was prepared using the same materials and methods as in Example 1.
A 500ml infusion container body was obtained. A drainage port was fused within this non-sealed portion (folded diameter: 17 mm, length: 10 mm) using the same method as in Example 1. At this time, the material for the drainage port is No. 3 and 4 in Table 1, and the material for the small tube has a vinyl acetate content of 15% by weight.
An ethylene-vinyl acetate copolymer was used. After dispensing 500 ml of physiological saline in the same manner as in Example 1, the tube was tightly stoppered and sterilized with high pressure steam. As a result, there was no deformation or leakage of any of the liquid drainage ports, but peeling occurred at a portion of the adhesive part approximately 3 mm from the inside of the container. However, there was no problem with the infusion procedure. Reference Example 1 Using the same materials and methods as in Example 1, a crosslinked ethylene-vinyl acetate copolymer with a gel fraction of 80% was produced.
A 500ml infusion container body was obtained. A drain port (length 25 mm) made of materials No. 3 and No. 4 in Table 1 was inserted into this non-sealed part (folded diameter 17 mm, length 10 mm) and fused by high frequency induction heating. After dispensing 500 ml of physiological saline in the same manner as in 1, the tube was sealed and sealed with a rubber stopper. Although the infusion container main body was crushed here, no liquid leakage from the drainage port adhesive portion or peeling of the adhesive portion was observed. When this was sterilized using high-pressure steam (121°C, 30 minutes), the drainage port completely popped out and most of the saline flowed out from the adhesive part of the drainage port. Example 3 A container of the present invention was manufactured using an EVA copolymer with a vinyl acetate content of 20% by weight. On the other hand, a container was made from the same material, uncrosslinked EVA copolymer, and polyvinyl chloride. 600 water in each of these containers
After dispensing ml and sealing it, place it in a polyethylene bag or directly place it on dry ice-ethanol (-
72°C) and left for 1 hour to freeze the water content. Each container was dropped onto a linoleum floor from each height shown in Table 2, and cold resistance was tested by observing the state of damage to each container. The results are also listed in Table 2.

[Table] As can be seen from the above results, the medical container of the present invention has significantly improved cold resistance. Specific Effects of the Invention The medical container of the present invention described above has heat resistance that can withstand high-pressure steam sterilization, improved cold resistance, and has excellent flexibility and flexibility, which is required for containers for closed medical systems. easy to use. Therefore, it is suitable for performing medical operations such as infusion, blood collection, separation, and blood transfusion in a closed system. In addition, it has excellent transparency, making it easy to confirm foreign substances in the liquid and to prepare blood components (separation operations). Furthermore, since the material forming the medical container of the present invention does not contain additives such as plasticizers and stabilizers, they do not migrate to the content liquid. Furthermore, since the medical container of the present invention has a high water vapor barrier property, there is little change in the component concentration of the liquid content (medicinal solution, blood, etc.), and the liquid content can be stably stored for a long period of time. Furthermore, all the sealing can be done by heat fusion of high-frequency seals without using solvents, so it is hygienic.

[Brief explanation of the drawing]

FIGS. 1A, 1B, and 2 are diagrams showing the method of manufacturing the medical container of the present invention in the order of steps, and FIG.
The figure is a perspective view of the medical container of the present invention. 11...EVA copolymer tube, 11'...
EVA copolymer sheet, 12, 13, 15... Sealed part, 14... Non-sealed part, 20... Container body, 21... Accessories, 22... EVA copolymer intervening layer.

Claims (1)

[Scope of Claims] 1. A collapsible medical container having improved cold resistance and heat resistance capable of withstanding steam sterilization, the container being formed from an ethylene-vinyl acetate copolymer crosslinked by electron beam irradiation. The container body is completely sealed except for a non-sealed portion at a predetermined portion of the periphery, and the non-sealed portion includes an end portion of an accessory necessary to achieve the function of the medical container. is inserted, and the accessory is sealed to the main body at the insertion end via an intervening layer made of uncrosslinked ethylene-vinyl acetate copolymer. 2. The medical container according to claim 1, wherein the ethylene-vinyl acetate copolymer forming the main body has a vinyl acetate content of 10 to 35% by weight. 3. The medical container according to claim 1 or 2, wherein the ethylene-vinyl acetate copolymer forming the main body is crosslinked to have a gel fraction of 50 to 85% by weight. 4. A medical container according to any one of claims 1 to 3, wherein the main body has a wall thickness of 0.1 to 0.6 mm. 5. The medical container according to any one of claims 1 to 4, wherein the ethylene-vinyl acetate copolymer forming the intervening layer has a vinyl acetate content of 15 to 40% by weight. 6. Claims 1 to 5, wherein the accessory is made of a polymer material that has heat resistance that can withstand high-pressure steam sterilization and shows blocking properties against ethylene-vinyl acetate copolymer at high temperatures. Medical containers described in any of paragraphs. 7 In the group in which the polymeric materials consist of high-density polyethylene and a first mixture thereof with an ethylene-vinyl acetate copolymer, and polypropylene and a second mixture thereof with an ethylene-vinyl acetate copolymer. The medical container according to claim 6, which is selected from the following. 8. Claim 7, wherein the first mixture contains up to 80% by weight of ethylene-vinyl acetate copolymer.
Medical containers listed in Section 1. 9. A medical container according to claim 7 or 8, wherein the ethylene-vinyl acetate copolymer in the first mixture has a vinyl acetate content of 15 to 40% by weight. 10 The second mixture contains up to 85% ethylene-
The medical container according to claim 7, which contains a vinyl acetate copolymer. 11. A medical container according to claim 7 or claim 10, wherein the ethylene-vinyl acetate copolymer in the second mixture has a vinyl acetate content of 15 to 40% by weight.