JPS61259671A - Medical tool - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to medical devices such as blood bags for preserving, storing, and transporting blood, and in particular,
The present invention relates to a blood-compatible medical device that causes less change in shape and destruction of platelets contained in the blood bag, and that can significantly preserve the shelf life of platelets.

[Prior Art] In recent years, blood component therapy has been actively carried out, and blood component therapy is one of the most important methods. For example, in the case of bleeding due to thrombocytopenia, platelet plasma
concentrate (PC) is often used to create a dramatic frontal effect.

With the development of such blood component therapy, in recent years, conventional silicone resins have been replaced with glass bottles for blood collection, fraction 1, storage, and blood transfusion. In order to enter the line <' in the system, and furthermore, the N
Due to its superior properties such as volume and impact resistance, blood bags made by Plasdec have rapidly become popular.

In general, platelet components only contain a small amount of M in the blood collected from healthy people, and their function deteriorates over time once they are taken out of the body, so a large amount of platelets is required at once. In order to carry out the platelet component transfusion method, it was necessary to obtain bare faces from a large number of healthy individuals. Furthermore, when blood is collected, sorted, and stored using Plusbook blood bags such as L, the number of floating platelets and aggregation ability decrease significantly over time, making the above problems even more pronounced. was. This is because platelets stick to the inner surface of the plastic blood bag with pseudopodia, and a large number of platelets aggregate, causing a release reaction and destroying the platelets. It has been found that this is happening because the
There is a desire to develop a blood bag that does not stimulate platelets, a so-called bag with high blood compatibility.

There are various methods to improve the blood compatibility of blood bags. Broadly speaking, there are two methods: changing the material of the blood bag itself, coating the inner surface with a substance with high biocompatibility 1, and graph 1- Although there is modification of the inner surface of the blood bag by polymerization or plasma polymerization, it impairs the mechanical strength, heat resistance, etc. performance of the bag itself5.
Fearless contact is common. Known methods include, for example, treating a vinyl chloride sheet with a low-humidity plasma treatment to form a surface layer, and applying a silicone resin, a hydrophilic hydrogel, or the like, which is considered to be a material with high biocompatibility.

[Problems to be Solved by the Invention] However, even if the inner surface is modified by the method described above, uniform coating is impossible because the surface of the vinyl chloride sheet is hydrophobic. Although the blood compatibility of the blood bag was improved to some extent, sufficient effects were not produced. In other words, even if the surface of the soft vinyl chloride resin is cross-linked by low-temperature plasma treatment, the elution of plasticizers, etc. can be prevented and the shelf life of platelets will be improved to some extent, but the surface will change over time and the inner surface of the blood bag will be damaged. The number of sticky platelets increased, and the sticky platelets became deformed with protruding pseudopodia. Furthermore, although coating the inner surface with silicone resin, hydrophilic hydrogel, etc. had the effect of reducing the number of platelets adhering to the inner surface, almost no effect was observed on reducing the aggregation ability of platelets after storage in the bag. .

Therefore, in the previous patent application, the present inventor proposed that in order to prevent the loss of platelets due to the destruction of platelets in the blood bag,
In addition, in order to enable long-term preservation of platelets, at least a portion of the inner surface of the blood bag is made of a resin containing vitamin E. In other words, vitamin E is contained in the resin/layer that makes up the main body sheet of the blood bag, and the periphery of the main body sheet is fused using means such as high-frequency heating to form a bag shape. It is made by connecting tubes with an opening.

Vitamin E has the effect of suppressing the peroxidation of biological membrane lipids, and on the other hand, oxidative lipids promote the platelet release reaction, leading to platelet aggregation. The function becomes as if stopped.In this way, vitamins have excellent platelet aggregation.
Although it has a +1 effect, vitamin [is water-soluble]
1, it is difficult to directly introduce it into the blood, and it is also possible to include it in the preservation solution using a surfactant, etc. If platelet aggregation is inhibited, a considerable amount of vitamin F will be included in the blood or concentrated platelet plasma, so when blood transfusion is performed, platelet aggregation due to B vitamins 11J1 + t- effect. However, even in patients who received blood transfusions, there was a risk that platelet function would be stopped, reducing the effectiveness of the treatment. However, as in the blood bag of the invention, simply by adding vitamin 3 to the resin forming the blood bag, the amount of platelets adhering to the inner surface of the blood bag is small (4T). No destruction occurred, and the aggregation of platelets in the blood bag was prevented, improving the shelf life.Moreover, when blood transfusion was performed, the aggregation function of platelets was extremely active.

On the other hand, after dissolving vitamin F in a solvent and applying this to the white liquor circulation path of the artificial organ, the solvent is evaporated and the
Preventing side effects in patients using artificial organs by forming a coating of vitamins on the inner wall of the JA ring pathway, that is, the surface that comes into direct contact with blood.
The technique to use it is Japanese Patent Publication No. 59-64056 bow, No. 59-6
Although it is already known from Japanese Patent No. 4057 and No. 59-64058, the conditions for applying or coating vitamin E are complicated, and in some cases, safety to the cow body cannot be guaranteed.

On the other hand, compared to the inventions disclosed in the above-mentioned patent publications, the previous patent application proposed by the present inventor has been improved in terms of how vitamin F is supported, etc., but is still insufficient in terms of practical application. I understand that. Firstly, since vitamins are contained throughout the resin layer sheet, the effect cannot be fully demonstrated unless large amounts of expensive materials are used, resulting in extremely high manufacturing costs. In order to contain vitamin F in the entire resin layer, vitamin F is present only on the inner surface of the blood bag, and vitamin F is also present on the outer surface, resulting in the problem that mold is likely to grow on the outer surface of the bag. there were.

In view of the above circumstances, the present invention aims to prevent the loss of platelets due to platelet destruction in medical devices such as blood bags as described above, and also to prevent the growth of mold on the outer surface. It is an object of the present invention to provide a medical device with a small number of materials, and a further object of the present invention is to provide a medical device that is easy to manufacture, has low raw material costs, and has no practical disadvantages.

Means for Solving the Problems 1 In order to achieve the objects described in 1 and 2, the present invention makes the main body of the medical device multi-layered with two or more layers, and only the parts that come into direct contact with blood (to the main body seam 1) contain vitamin E. It is characterized by containing. In other words, the main body sheet material of a medical device such as a blood bag is a multilayer sheet made of the same or different resins, and the innermost layer is a multilayer sheet that is in direct contact with blood.
The resin layer is made as thin as possible to contain a high concentration of vitamins, and the material that makes up the outer surface (resin layer) does not absorb the vitamins and mold can grow. The second practical obstacle is removed. In addition, since the above J: sea urchin has the innermost layer made as thin as possible to contain vitamins at a high concentration, and a non-vitamin-containing layer is laminated on the outside, the cost of raw materials is low and manufacturing is easy.

Next, the present invention will be explained in more detail with reference to the drawings. The following example shows the case where the medical device of the present invention is applied to a blood bag.

Figure 1 is a front view of the blood bag, and Figure 2 is a cross-sectional view.The peripheral edge 2 of the blood bag is fused by heating means such as high-frequency heating, and the upper part has a plurality of openings. 3a,
3b and a tube 3c. Thus, the resin layer 4 constituting the main body 1 of the blood bag 1 contains vitamin F, and the resin layer 5 outside thereof does not contain vitamin E at all.

The platelets are prevented from adhering to the resin layer 4 containing vitamin E and from aggregating, and are stored in the bag 1 while retaining their activity. In addition, the vitamins that migrate within the resin layer 4 and attempt to migrate to the outer surface of the bag are
Since there is no vitamin F on the surface blocked by
Mildew is less likely to grow.

Although the present invention has been described using a blood bag as an example in order to more clearly explain its effects, it is not necessary to limit it to blood storage bags because of the mechanism by which its effects are expressed.
It is clear that the same effect can be expected from devices used to take blood out of the body and perform some processing, such as containers for filling blood or circuits for transporting blood. According to the prior art, JP-A-59-6
No. 4054, No. 59-64056, No. 59-64057
It is easy to imagine that it can be used for the purpose of No. J: and No. 5.9-64058, that is, as a member for artificial organs.

The multilayer sheets 1~ constituting the main body of the blood bag of the present invention are:
There are no particular restrictions as long as there are two or more layers. In addition, among the constituent resins, the base resin (resin before containing vitamins) of the innermost layer, that is, the layer that makes surface contact with blood, is a soft vinyl chloride resin.
Urethane resins, single-component poly-[dylene, dylene vinyl acetate-hinyl chloride graft copolymer resins, etc.], polymers containing these as main components, and blends of these can be used, preferably soft chloride resins. It is vinyl resin. Vinyl chloride resins include vinyl chloride resin small mobolymers and polymers whose main component is vinyl chloride resin, such as concentrated vinylidene, vinyl acetate, and -dylene. 400
~3000, θf or preferably 700 to 2500, but if limited to extrusion molded products, such as main body seams 1~ and blood collection tubes, 700 to 3000, preferably 1000 to 2
It is 500.

In addition, as a plasticizer, dihe 4-silphthale 1~(Kano P
), di-2-ethylhexyl phthalate (D(IP)
, di-n-octyl phthalate (DnOP), diisooctyl phthalate (DTOP), didecyl phthalate (DDP), diisodecyl phthalate (DIDP)
, phthalic acids such as butylbenzyl phthalate (BBP)■
Steles, dioctyl azelate (DO8), dioctyl azelate (DOZ), dioctyl sebacate (DO
3), aliphatic polybasic acid esters such as tributyl tormelite-1 to trimerite-1 to trioctyl-1-limerite-1 to acid nisderates, 1-libdelacedercitre-1 to . 1~Ryokujiruarechirushi 1~Lee 1~. Citric acid esters such as 1 helibutyl citrate 1, etc., and di-2-ethylhexyl phthalate 1-(BPBG) are preferable.
It is. These plasticizers are used in the above vinyl chloride resin 100
Weight: 5 to 100 parts, tR parts, preferably 10 to 100 parts
80 parts, especially 40 to 80 parts, preferably 50 parts if limited to the main body and tubes for blood collection.
~70 parts by weight is blended.

In addition, in the soft vinyl chloride resin composition, if necessary, metal soaps containing calcium, zinc, etc. and stearic acid, lauric acid, ricinoleic acid, naphthenic acid, etc. may be used as stabilizers, and epoxidized soybean oil, J-poxy Epoxidized vegetable oil such as linseed oil is used as a stabilizing agent, and other lubricants,
It can contain antioxidants and the like. However, such soft vinyl chloride resin is not suitable for use in accordance with the Ministry of Health and Welfare Notification No. 448 of 1965 (Ministry of Health and Welfare Standards) or Japanese Pharmacopoeia 10th Revised General Test Method 42 [Test Method for Plastic Containers for Infusions]. There is no particular limitation as long as it passes the Japanese Pharmacopoeial Standards).

In addition, the physical properties of resins other than the vinyl chloride resin satisfy the physical properties required by the blood bag member in the same way as in the case of the vinyl chloride resin, and the safety of the resin meets the above-mentioned vinyl chloride resin blood set standards. It is acceptable as long as it passes the Infusion Type Plastic Container Test Method.

Further, in order to form the resin containing vitamin E,
The base resin may be kneaded with a Henshil mixer or the like and pelletized at the pre-processing stage of the base resin, for example, when blending with a vinyl chloride resin. Thus, the resin to which vitamin F is added can be formed into blood bag members such as sheets or tubes by the same method as the base resin.

At this time, the amount of vitamin [, for example, α-1 ~] fluor in the range of 0.5 to 100 parts, preferably 2 to 50 parts.The reason is that the amount of vitamin F added to the base material is 0.5 to 100 parts by weight. If it is less than M parts, the purpose of the present invention will hardly be achieved, and if it exceeds 100 parts by weight, the other physical properties required for blood bags, that is, the strength, will be greatly affected, and the blood bag will not be suitable. If it lacks practicality, it will also lack practicality in terms of space.Furthermore, if it is less than double-layered, its effectiveness can be seen, but it is still not practical at present. The purpose of this defense cannot be fully achieved, and if it exceeds 50 parts by weight, it may be possible to put it into practical use as a blood bag, but it cannot be said to be a blood bag with a high quality level in terms of physical properties. .

Regarding the resins constituting the other layers, vitamin E is dispersed in the resin. It's fine if it doesn't exist. However, if you want to maximize the benefits of multilayer sheets 1 through 1, such as improving the strength of the sheet, use soft nylon, polyester, or different grades of the same resin. You can also do it. Furthermore, if the member is limited to the main body seam 1- of the blood bag, the total wall thickness is 0.1~
It may be 1.0 mm, preferably in the range of 0.2 to 0.8 nv. The reason for this is that if the wall thickness is outside this range, the operability of the bag will be extremely poor. Furthermore, the wall thickness of the sear 1 constituting the innermost layer of the main body sear 1 is 0.0
It is preferably 1 to 0.5 nv, preferably 0.05 to 0.4 mm, and less than half of the total thickness of the main body sheet. The reason is that when the sheet thickness becomes 0.05 nv or less,
This is because the range of molding conditions becomes narrower, and if it becomes 0.01 mm or less, the range of molding conditions becomes extremely narrow, which significantly impairs productivity. Furthermore, if the thickness of the sheet exceeds the total thickness of the main body seams 1 to 1, the object of the present invention cannot be fully achieved, especially in the surfaces 1 to 1.

The blood bag of the present invention obtained as described above is used by connecting three blood bags as a sealed system by a duplex 5, as shown in FIG. 3, for example. A bare-faced nail 6 attached to the tip of a tube 5 is punctured into a healthy person's vein, and 200 ml of the vein is collected into a first blood bag 1a containing a CPD solution. The collected venous blood is immediately centrifuged 1111 (for example, at 1.50 rpm for 10 minutes), and the upper plasma portion is expressed into a second blood bag 1b to obtain multifaceted platelet plasma (PRP).

This was further centrifuged for 1 lIlt (for example, 3000rrll)
11) Attach the second blood bag 1b containing 50 ml of platelet-poor plasma (ppp) from the upper layer to the platelet sedimentation platelet agitator for 10 minutes and stir it (for example, at 15 rpm for 15 minutes). The platelets are resuspended to form concentrated platelet plasma (PC), and the PC is stored in the second blood bag 1b until it reaches the component axis.

[Example 1 The sample used in the example was prepared as follows. For vinyl chloride resin, mix the compound shown in Table 1 using a Henschel mixer (2 (l f )).
00 rpm x 30 minutes at a maximum temperature of 90"C (7), and pelletized using a pelletizer at a molding temperature of -17 = 140°C.For resins other than vinyl chloride resin, extrusion Select a grade of resin,
Vitamin E was added in the ratio shown in Table 1 and stirred in a tumbler for 20 minutes to uniformly disperse vitamin E on the outer surface of the resin pellet.

However, as for the resin used as the outer layer, a non-vitamin F-containing resin was used as is.

The resins shown in Tables (1) and (2) were selected for the beret l-nisu produced by the above method, and molding was carried out using a two-layer inflation extruder to the thickness shown at the same time in Table (3).

Resin Evaluation 1 (Moldability) In Table 1, a two-layer inflation sheet with resin example 1 as the inner layer and resin example 2 as the outer layer with a fold diameter of 15 mm and a total wall thickness of o and 4 mm was molded at a molding temperature of 170 to 190°C. When molding was carried out at a speed of 10 nl/III in and the ratio of the inner and outer layers was changed, the thickness of the inner layer was 0.0.
If it is less than 5 mm, it will be very difficult to mold, and 0.01
If the thickness was less than 'mm, it could not be formed.

Table■ Vinyl chloride resin composition (pellets 1~) Table■ Resin composition other than vinyl chloride (pellets) table■ Example of a sheet for strength confirmation' *Base resin: Vinyl chloride resin (average degree of polymerization 1300)
100, plasticizer (DOPI 50, epoxidized soybean oil 10, Ca-Zn stabilizer 3 (each PKr) Table ■v Evaluation of constituent resins of Examples 2 Regarding Examples 1 to 10 in Table ■, 2-layer inflation sheet I~ at a molding temperature of 170~19o
6. Molding was performed at a molding speed of 10 m/min.

After punching out the sheet with a JIS No. No. dumbbell, it was punched at a tensile speed of 200 m1 at room temperature using a Strograph (manufactured by Shimadzu).
The tensile strength was measured under the conditions of 1/min. The results are shown in FIG. The number of specimens was 1 o inspection, and the average value was taken. In addition, the cutting condition was observed during the tensile test. On the other hand, based on the same test data regarding commercially available medical devices and previous prototypes, we investigated the required strength of sheets and tubes or injection molded products. As a result, Example 7
Although the tensile strength of Examples 1 to 8 met the required strength, the vitamin E-containing resin layer broke first, and in particular, Example 8 was difficult to laminate as a medical material. Ta.

Blood Compatibility Test 1 For each of Examples 11 to 14 and Comparative Example 1.2 shown in Table IV, a two-layer inflation sheet with a folded diameter of 150 mm was formed, and this was autoclaved at 120°C for 1.
It was applied for 20 minutes at 5 ko/cm2 [gauge pressure], and platelet diastolic ability was evaluated.

The platelet diastolic ability test was conducted by the following method. In other words, 4.5 m (l) of venous blood from a healthy individual was collected using a polypropylene syringe containing 05 ml of 3.8% sodium citrate, transferred to a polypropylene test tube, and 800 r, p, m A dilution solution (saline = 38% sodium citrate - 0:1) was added to the obtained PRP to make a platelet suspension □.This solution was dropped onto the sample and kept constant. After a while, the platelets were expanded and fixed with 2% glitaraldehyde, dehydrated stepwise with ethanol series, and after drying, observed under a microscope. 0.11mm
2.1.The platelet count and its morphological changes were investigated. Morphological changes were classified into 31=I' below.

Type 1: (The shape of the platelet that landed is spherical or (2 of 6 with 1 to 2 high fixed numbers. Type 3: Platelets are collapsed and a membrane protrudes between them. Type 3: Platelets are expanded and become plate-like. As a result, as shown in Figures 5A and 5B, Comparative example 1.
2, Examples 11 to 14 clearly showed that the number of platelets deposited on the sheet was small, but the morphological change of platelets deposited on the sheet was also small. Inspection-2 For Example 11.12a3 and Comparative Example 1 as well as Example 13.14 and Comparative Example 2 shown in Table ■, two-fold inflation seams 1- with a folding diameter of 150 mm were molded (note this).
When the inlet or outlet member is fixed, the periphery of the sheet is simultaneously heat-sealed using high-frequency heating to form a blood bag (empty bag). The blood bag thus obtained and the blood bag into which 28 mfi of CPU liquid was injected were sterilized using high-pressure steam (120°C, 1.5kg/c).
[gauge pressure] for 20 minutes) to examine blood compatibility.

Collect 200 mρ of blood from a healthy person into the blood bag prepared above and containing 1 CPU fluid, and centrifuge it. 1
ll (1500 rDm, 10 min) to obtain PRP;
Furthermore, pnp was centrifuged (300 rpm, 10 minutes) to obtain PC. The PC was prepared in Example 11.12 and Comparative Example 1, and the PC prepared in the same manner was prepared in Example 13.1.
4 and Comparative Example 20 blood bags were each 10 m'
Each sample was injected and stored under aseptic conditions. 24 hours, 48 hours,
After storage for 72 hours, a portion of the PC from each bag was taken out and evaluated as follows. First, the number of floating platelets was measured using a Coulter Coulter 2BI. The percentage of the platelet count after each storage time to the platelet count at the time of PC bag injection (before storage) was used as an index. The result is the 6th Δ
6B. The number of specimens was 5, and the average value of A was taken.

Next, in order to determine platelet aggregation ability, DP aggregation was measured using an ablebometer. The ratio of the maximum aggregation rate after each storage time to the maximum aggregation rate before storage was used as an index. The results are shown in FIGS. 7A and 7B.

External mold growth test] ~ Breaking diameter 150 for Example 2 and Comparative Example 1 in Table IV
A two-layer inflation sheet 1 to 1 mm in diameter was molded, and a blood bag was formed by attaching an injection port and a tJI outlet member to the sheet, and heat-sealing the sheet periphery using high-frequency heating. Into the blood bag obtained in this way, 50 Mβ TSB medium (I~Lypto-soy broth medium) was injected,
After heat-sealing the injection port using high-frequency heating, leave it indoors for 1 hour, then place it in a sterile petri dish and incubate at 25℃ for 1 hour.
51" and then stopped. (A small amount of sterile distilled water was added to the petri dish to prevent it from drying out.The evaluation was performed by measuring and comparing the area of the mold that had developed.The number of specimens was 5. The average area was measured. No difference was observed between the raw chestnuts of Example 11 and Comparative Example 1, but the area of Comparative Example 2 was about 13 times that of Comparative Example 1.

[Effects of the Invention] As described above, the medical part according to the present invention has the effect of preventing aggregation of the member plate, and in a blood bag assembled using this member plate, platelet components are Platelets are stored without exerting an aggregation function and without causing any change in shape or destruction even if they adhere to the inner surface of the blood bag, so there is little loss of platelets when stored in the blood bag, and they can be stored for a long period of time. The survival activity of platelets is not affected,
1" In other words, when reinjected into the body, the platelet's ability is fully utilized and effective treatment can be performed during blood transfusion. It is a blood bag with extremely high blood compatibility and is inexpensive. It is a blood bag that can be easily commercialized because it can be manufactured in several minutes. Furthermore, the tendency for mold to grow on the outer surface is suppressed, making it easier to commercialize.

−26=

[Brief explanation of drawings]

Fig. 1 is a front view when the medical device of the present invention is applied to a blood bag, Fig. 2 is a sectional view, Fig. 3 is a schematic diagram showing an example of how the blood bag is used, and Fig. 4 is a diagram showing the present invention. Figure 5A is a diagram showing the relationship between the tensile strength of Sea 1~ and vitamin 1-containing oil, Figure 5A is a diagram showing the relationship between the number of platelets attached and vitamin 1-containing fabric, and Figure 5B is the morphology of platelets. Diagrams showing changes, Figures 6A and 6B are diagrams showing platelet reduction rate, and Figures 7A and 7B are J-diagrams showing 〇P aggregation rate before and after storage. . 1.1a, 1b, 1c...Blood bag, 2...Edge, 4...Vitamin E-containing resin (inner layer), 5...Outer layer. Applicant Takashi Koma 271 I N grl Shaft ω size M W Xuandon PE 1:: Published by 10 years old

Claims (1)

[Scope of Claims] 1. A blood-compatible medical device for the purpose of storing, preserving, and transporting blood, comprising a molded article formed in multiple layers from two or more of the same or different resins, 1. A medical device characterized in that at least a portion of the layer forming a surface in direct contact with a member is made of a resin containing vitamin E group or a derivative thereof. 2. The medical device according to claim 1, wherein the blood compatible medical device is a blood bag. 3. The medical device according to claim 1, wherein the member is a tube used in a blood transport circuit. 4. The medical device according to claim 2, wherein the member is a blood bag body sheet. 5. The medical device according to claim 1, wherein the member is a tube that connects to another medical device. 6. According to any one of claims 3 to 4, the base resin of the resin containing the vitamin E group or a derivative is a vinyl chloride resin, a urethane resin, or an ethylene vinyl acetate-vinyl chloride graft copolymer. medical tools. 7. Either claim 4 or 6, which is a two-layer sheet in which the base resin of the member that comes into direct contact with blood is vinyl chloride resin, and a layer of vinyl chloride resin is formed on the outside of the base resin. Medical equipment listed in section. 8 The resin forming the sheet has an average degree of polymerization of 700 to 25
00 vinyl chloride resin 40 to 100 parts by weight of plasticizer
The medical device according to claim 4 or 7, containing 80 parts by weight. 9 The thickness of the layer forming the surface in direct contact with blood is the same as or thinner than the thickness of the layer forming the surface not in direct contact with blood, and the former thickness ranges from 0.01 to 0.5m
m, preferably 0.05 to 0.4 mm, and the total thickness range of the former and latter is 0.1 to 1.0 mm, according to any one of claims 4, 7, and 8. Medical equipment listed in section. 10 The vitamin E content of the resin forming the layer that forms the surface that comes into direct contact with blood is, based on 100 parts by weight of the base resin,
Claims 4, 7, which are 0.5 to 100 parts by weight.
Medical devices listed in either section 8 or 9.