JPS61257658A - 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 medical device in which platelets in the blood bag undergo little change in shape or destruction, and can maintain a high shelf life of platelets.

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

With the development of blood component therapy, the conventional silicone resin coating has recently been replaced with Laspin, which allows all processes from blood collection, separation, storage, and transfusion to be performed in a closed system, and also because of its light weight and durability. Plastic blood bags have rapidly become popular due to their impact resistance and other properties.

In general, platelet components are only contained in trace amounts in the blood collected from healthy people, and their function declines over time once they are taken out of the body, so a large number of platelets are required at one time. In order to perform the platelet component transfusion method, it was necessary to collect blood from a large number of healthy individuals immediately before transfusion. Furthermore, when blood is collected, separated, and stored using a plastic blood bag such as the one described above, the number of floating platelet cells and aggregation ability decrease significantly over time, making the above problems even more pronounced. This is because platelets stick to the inner surface of the PlusDeck blood bag with pseudopodia, and then a large number of platelets aggregate, causing a release reaction and destroying the platelets. It has been found that this occurs due to the presence of blood cells, and there is a desire to develop a blood bag that does not stimulate platelets, a so-called high blood bag.

There have been various methods to increase the performance of blood bags, and they can be broadly divided into changing the material of the blood bag itself, coating the inner surface with a substance that is highly biocompatible, or using methods such as graft polymerization or plasma polymerization. Although there is a modification of the inner surface of the blood bag, the latter method is common since it does not impair the mechanical strength, heat resistance, and other performance of the bag itself. As such methods, for example, surface crosslinking of vinyl chloride sheets by low-temperature plasma treatment, application of silicone resins, hydrophilic hydrogels, etc., which are considered to be highly biocompatible substances, and the like are known.

[Problems to be Solved by the Invention] However, even if the inner surface is modified by the method described above (because the surface of the vinyl chloride sheet is hydrophobic, uniform coating is impossible), the blood bag Although this 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 adherent platelets increased, and the adhered platelets became deformed with protruding pseudopodia. Furthermore, although applying silicone resin, hydrophilic hydrogel, etc. to the inner surface 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.

On the other hand, JP-A-59-64056, JP-A-59-640
No. 57 and Japanese Unexamined Patent Publication No. 59-64058 disclose that vitamin E is dissolved in a solvent and applied to the blood circulation path of an artificial organ, and then the solvent is evaporated and the solution is applied to the inner wall of the circulation path, that is, to the blood circulation path. A technique has been disclosed to prevent side effects in patients using artificial devices by forming a coating of vitamin E on surfaces that come in direct contact with the surface, but the conditions for applying or coating vitamin E are complicated, and in some cases, it may be harmful to living organisms. Safety may not be guaranteed.

The present invention is not directed to artificial instruments, but rather aims to prevent the loss of platelets due to platelet destruction in medical devices such as the blood bags mentioned above, and also to enable long-term storage of platelets. It is intended to be a Noh play. That is, an object of the present invention is to provide a compatible medical device, particularly a blood bag, which causes less change in shape and destruction of platelets.

A further object of the present invention is to provide a blood bag in which the loss of platelets due to storage within the blood bag is reduced and the survival activity of blood platelets can be prolonged.

[Means for Solving the Problems] In order to achieve these objectives, the inventor of the present invention conducted intensive studies and found that blood was collected using a blood bag made of a main sheet material mixed with vitamin E, and the blood was collected by centrifugation. When platelet concentrate plasma was obtained, it contained more platelet components in a healthy state compared to conventional methods, and even when stored for a long time, there was very little decline in platelet function during component transfusion. This discovery led to the present invention.

That is, the present invention relates to a medical device for storing, preserving, and transporting blood, wherein at least a portion of the members that directly contact blood among the members constituting the main body of the device contain vitamin E. It is.

[Function] Vitamin E has the effect of suppressing peroxidation of biological membrane lipids, and on the other hand, oxidative lipids promote the platelet release reaction and cause platelet aggregation. Therefore, when vitamin E is present, the aggregation function of platelets appears to have stopped. Although vitamin E has an excellent anti-platelet aggregation effect, vitamin E is poorly water-soluble and cannot be introduced directly into the bloodstream. Although it is possible to include it in the liquid, this J
: If platelet aggregation is prevented in a medical device such as a blood bag, a considerable amount of vitamin E will be contained in the blood or platelet concentrate plasma. Because of the platelet aggregation inhibiting effect, even in patients who received blood transfusions, platelet function was stopped, which could reduce the therapeutic effect.

Surprisingly, as in the blood bag of the present invention, simply by incorporating vitamin E into the members constituting the inner surface of the blood bag, the adhesion of platelets to the inner surface of the blood bag is reduced; There is no deformation or destruction of the face platelets,
In addition, aggregation of platelets in the blood bag was inhibited and storage stability was improved, and it was observed that the aggregation function of platelets was extremely active when blood transfusion was performed. Note that vitamin E does not necessarily need to be contained in all components. For example, it may be only the main body sheet of the blood bag, or it may be made up of multiple layers, with only the layer forming the surface that comes into direct contact with blood. Furthermore, in order to form the member for a blood bag of the present invention, it is only necessary to add it in advance to the resin forming the member. Therefore, the manufacturing process of the blood bag is extremely simple.

In addition, the above-mentioned Japanese Patent Application Laid-open Nos. 59-64056 and 1983-
No. 64057 and Japanese Unexamined Patent Publication No. 57-64058 use vitamin E like the present invention, but their purpose is to prevent transient leukopenia that occurs as a side effect in patients using artificial devices. Therefore, the objective itself is different from the present invention, and naturally the expected effects of the present invention are different. In other words, each of the inventions disclosed in the above-mentioned Japanese Patent Application Publications is used for artificial devices, and involves the accumulation of white blood cells in a part of the body (for example, the lungs) due to the influence of blood that has circulated outside the body in a short period of time. However, the present invention is used for blood storage containers, etc., and platelets in blood stored outside the body for a long time may stick to the inner wall of the container during storage. This prevents the platelets from adhering to or coming into contact with each other, thereby preventing a loss in the number of platelets and the loss of the functions originally possessed by platelets.

Furthermore, each of the inventions disclosed in the above-mentioned Japanese Patent Laid-Open Publication No. 2003-12000 requires complex coating formation conditions for vitamin E, and in some cases,
Safety for living organisms may not be guaranteed. For example, regarding the former, it is difficult to maintain coating uniformity, and if this is attempted, the range of manufacturing conditions will be narrowed, resulting in the need for highly accurate and expensive coating equipment. A new installation will be required. However, even if uniformity of application is not required, for example, as introduced in the embodiments of the invention, after passing a solution of vitamin E dissolved in a solvent through the blood circulation path, Even if there is a coating method that eliminates this problem, it is a complicated process from a production standpoint and requires a certain amount of equipment. Secondly, it is difficult to volatilize the solvent sufficiently, and if this is attempted, the process will become complicated and expensive drying equipment will need to be installed.

Regarding the latter, that is, safety, as explained above, due to the process, solvent residue tends to occur due to uneven coating and insufficient drying. Since it is only attached to the inner wall surface, the vitamin E coating may peel off and dissolve into the blood.
There was a risk that it would disperse in the form of oil droplets, and there was also a risk that residual solvent would dissolve into the blood. Needless to say, if the residual solvent enters the patient's body, it will have an adverse effect on the patient.

The more severe the symptoms, the greater the impact.
In some cases, it can even threaten the patient's life.

Furthermore, although vitamin E entering the body generally has a good effect on the living body, for patients with various symptoms in particular, the excess substance may be placed in unnecessary places and may be harmful to the living body. On the other hand, if vitamin E is injected into blood vessels in a problematic form, for example in the form of oil droplets, it may have an adverse effect on the living body and impair the therapeutic effect. In contrast, the present invention adds a simple process of kneading vitamin E into the resin forming the layer constituting the surface that comes into contact with blood in advance, that is, before molding, or adds a simple process to the resin. When a resin has a compounding process or other resin kneading process, such as vinyl chloride resin, vitamin E can be uniformly dispersed in the resin by simply adding it at the same time as other additives. The process will be very simple.

In addition, since the present invention does not use a solvent, there is no need to worry about residual solvent, and since vitamin E is kneaded into the resin, it is harmful to living organisms if it dissolves in the blood. The level is negligible, and a highly safe medical device for living organisms can be obtained.

(Specific Description of Configuration) Next, the present invention will be described in further 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.

As shown in FIG. 1, the blood bag 1 of the present invention has a peripheral portion 2 fused by heating means such as high-frequency heating, and has a plurality of openings 3a, 3b and a tube 3C in the upper part. have. Thus, the resin layer 4 constituting the main body sheet of the blood bag 1 contains vitamin E.

Vitamin E used in the present invention includes tropherols such as α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, α-tocotrienol, β-tocotrienol, and γ-tocopherol.
There are tocotrienols such as tocotrienol and δ-tocotrienol, but α-tocopherol is the most preferred. These tocopherols or tocotrienols may also be used in the form of esters, such as acetate esters.

On the other hand, as the base resin constituting the blood bag of the present invention, in addition to soft vinyl chloride resin, urethane resin, chlorinated polyethylene resin, ethylene vinyl acetate/vinyl chloride dalat copolymer resin, etc., and resins containing these as main components Copolymers and blends of these can be used.
Preferably it is a soft vinyl chloride resin. Vinyl chloride resins include vinyl chloride resin homopolymers and other monomers whose main component is vinyl chloride resin, such as copolymers such as vinylidene chloride, vinyl acetate, and ethylene. For products and injection molded products, it is 400 to 3000, preferably 100 to 2500, but if limited to extrusion molded products, such as main body sheets and blood collection tubes, it is 700 to 300.
0, preferably 1000-2500.

In addition, as a plasticizer, didecyl phthalate (DHP),
Di-2-ethylhexyl phthalate (DOP), di-
n-octyl phthalate (DnOP), diisooctyl phthalate (DIOP), didecyl phthalate (DD
P), phthalate esters such as diisodecyl phthalate (DIDP), butylbenzyl phthalate (BBP),
Aliphatic polybasic acid esters such as dioctyl adipate (ooA, >, dioctyl azelate (DO7) and dioctyl sebacate (Dos), trimellitic acid esters such as tributyl trimellitate and trioctyl trimellitate, tributylacetyl Citric acid esters such as citrate, trioctyl acetyl citrate, tributyl citrate, and butylphthalyl butyl glycolate (
BPBG), and di-2-ethylhexyl phthalate is preferred. These plasticizers are used in general molded products, such as extrusion molded products and injection molded products, in an amount of 5 to 100 parts by weight per 100 parts by weight of the vinyl chloride resin.
Preferably, the amount is 10 to 80 parts by weight, particularly 40 to 80 parts by weight, preferably 50 to 70 parts by weight if limited to the main body sheet and blood collection tube.

In addition, in the soft vinyl chloride resin composition, if necessary, metal soaps such as calcium, zinc, etc. and stearic acid, lauric acid, ricinoleic acid, naphthene M, etc. may be used as stabilizers, and epoxidized soybean oil, epoxidized Using epoxidized vegetable oil such as linseed oil as a stabilizing agent, its land lubricant,
It can contain antioxidants and the like. Therefore, such soft vinyl chloride resins are not compatible with the standards for vinyl chloride resin blood sets (Ministry of Health and Welfare Notification No. 448 of the Ministry of Health and Welfare of 1965) or the 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, resins other than the vinyl chloride resin have physical properties that satisfy the physical properties required by blood bag members in the same way as the vinyl chloride resin, and whose safety meets the above-mentioned vinyl chloride resin blood set standards or for infusion use. Any material that passes the plastic container test method is fine.

Moreover, if the above-mentioned member is limited to the main body sheet of the blood bag,
Its wall thickness is 0.1-1 mm, preferably 0.2-0
．． It is sufficient if it is within the range of 811101. The reason is that outside this range, the bag's operability deteriorates significantly.

In addition, in order to form the resin containing vitamin E, in the base resin or at the pre-processing stage of the base resin, for example, in the case of vinyl chloride resin, at the time of blending.
It may be added at the same time as other additives and kneaded using a tumbler or Henshil mixer to form pellets. Thus, the resin to which vitamin E 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 E added to the base resin varies depending on the use of the member, but 0% of vitamin E1, such as α-tocopherol, is added to 100% of the base resin.
．． 5 to 50 parts by weight, especially when the member is limited to the blood bag body sheet, 0.5 to 3091 parts, preferably the former is in the range of 2 to 30 parts by weight, and the latter is in the range of 2 to 20 parts by weight. . The reason for this is that if the amount of vitamin E added to the base material is 0.5 parts by weight or less, the purpose of the present invention will hardly be achieved, and if it is limited to 50 parts by weight or 9 parts to the main sheet, 2 parts by weight or less.
If the thickness exceeds 1 part, the other physical properties required for a blood bag, that is, the strength, will be greatly affected, and the bag will not be practical as a blood bag, and it will also be impractical from a commercial perspective. . Furthermore, if the amount is less than 2 parts by weight, although some effects can be seen, the object of the present invention cannot be fully achieved. Although there is a possibility that it could be put to practical use as a blood bag, it cannot be said to be a blood bag with a high quality level in terms of physical properties.

The thus obtained blood bag of the present invention is used, for example, by connecting three blood bags as a sealed system with a tube 5 as shown in FIG.

A blood collection needle 6 attached to the tip of a tube 5 is punctured into a healthy person's vein, and blood is collected from the vein 200mj2 into the first blood bag 1a containing the CPD solution. The collected venous blood is immediately centrifuged (for example, at 1500 rpm for 10 minutes), and the upper plasma portion is squeezed out into the second blood bag 1b to obtain platelet-rich plasma (PPP).

This is further connected to the centrifugal valve 1111 (for example, 3000 rpm
) for 110 minutes), leaving 50 mf of platelet-poor plasma (PPP) in the upper layer in the platelet sink, and extruding the excess PPP into the third blood bag 1C. Platelet sinking and PPP50II
The second blood bag 1b containing Il is subsequently attached to an agitator and resuspended while stirring (for example, 15 rpl for 15 minutes) to form platelet plasma concentrate (PC), which is then stored in the second blood bag 1b until component transfusion. Insert your PC and save.

[Example] The samples used in the examples were prepared as follows.

For vinyl chloride resin, a compound not shown in Table 1 was mixed at 1 soorpm using Henschel (20R).
It was produced for 30 minutes at a maximum temperature of 90°C, and pelletized using a pelletizer at a molding temperature of 140°C. In addition, for resins other than vinyl chloride resin, select extrusion grade resin and add vitamin E at the ratio shown in Table ■.
was added and stirred in a tumbler for 20 minutes to uniformly disperse vitamin E on the outer surface of the resin pellet. (
Blank space below) Resin Evaluation 1 (Moldability) From Table 1, using the resins of Example 4.9.10.12 and Comparative Example 1, the test pieces shown in Figure 4 were molded using an injection molding machine at a temperature of 170 to 190°C. Molding was performed at a mold temperature of 50°C. As a result, in Examples 9 and 10 and Comparative Example 1, good molded products were easily obtained, whereas in Example 12, it was necessary to raise the molding temperature to prevent insufficient filling of the resin. , the occurrence of burns was observed in a short period of time. Further, in Example 9, although insufficient resin filling and occurrence of burning were not observed, dimensional stability was poor and the test piece had a distorted shape.

In addition, the resins of Example 4.9.10.11.12.13.14 and Comparative Example 1 were molded using an extrusion molding machine to a width of 400 nua.
, a sheet with a wall thickness of 0.4 mm was molded at a temperature of 170°C to 20°C.
0℃, molding speed 8 m/win, o-ru temperature 4
It was molded at 0°C. As a result, Example 4.11.1
2 and Comparative Example 1 had relatively narrow molding conditions, but good sheets were obtained, whereas Example 9
．． 10, drawdown occurred, especially in Example 9.
Regarding this, the desired sheet could not be obtained. Further, in Examples 13 and 14, it was necessary to increase the molding temperature in order to improve the flow of the resin, and as a result, burns were likely to occur, and in particular, in Example 14, the desired sheet could not be obtained. Regarding No. 13, although the desired sheet 1- could be obtained, it was a sheet with large heat shrinkage.

Resin evaluation 2 (strong rf1) From Table ■, the resins of Examples 4 to 8 and Comparative Example 1 had a wall thickness of 0.
A 4 mm sheet was produced by pressing at a press temperature of 170°C, a press pressure of 100 ka/cm2, and a press time of 4 minutes. Seats 1 to 1 produced under the above conditions were JIS 4
After punching with a dumbbell, the tensile strength was measured using a Strograph (manufactured by Shimadzu) at room temperature at a tensile speed of 200 mm/min, and the results were as shown in Graph 1.

The number of samples was 10, and the average value was taken. On the other hand, the required strength of sheets, tubes, and injection molded products was investigated using the same test data on commercially available medical devices and previous prototypes. As a result, the vitamin Effl having the required strength is 30 fold parts or less, preferably 20 fold parts or less for extrusion molded products such as sheets and tubes, and 50 fold parts or less for injection molded products.
Preferably, it was 30,000 parts or less.

Blood compatibility test-1 From artificial, Example 1.2.3.4.6.8.13, Comparative Example 1, and Example or Table ff21.22.
23 and Comparative Example 2, sheets with a wall thickness of 11Iffl were pressed at a press temperature of 170°C and a press pressure of 100°C.
kg/cm2 and press time was 4 minutes.

When platelet dilatation ability was evaluated for the sheet thus prepared, the results shown in FIG. 4 were obtained.

The platelet diastolic ability test was performed by the following method. That is, 4.5 mtl of venous blood of a red normal person was collected using a polypropylene syringe containing 0.5142 ml of 3.8% citric acid, and the blood was transferred to a polypropylene test tube. A dilution solution (saline: 3.8% sodium citrate - 9 = 1) was added to the obtained PI (P) to make a platelet suspension. This solution was dropped onto the sample. The plates were left for a certain period of time to allow platelets to adhere and expand.This was fixed with 2% glitaraldehyde, dehydrated stepwise in an ethanol series, and observed under a microscope after drying.

The evaluation method was to examine the number of platelets attached to 0.11 mad2 and changes in their morphology. Morphological changes were classified into the following three scales.

Type 1: The shape of the attached platelets is spherical or has 1 to 2 pseudopods.Type 2: Those with several pseudopods or 1 pseudopod.
Type 3: The platelets are expanded and have a flat plate shape. The number of platelets attached to the above sheet is shown in Figures 5A and 5B.
The morphological changes are shown in FIGS. 6A and 6B. As is clear from these figures, compared to the comparative example, Example 3.4
．． 6.8.13.21.22.23, the number of platelets adhering to the sheet was clearly small, and the morphological changes of the adhered platelets were also small.

Further, although some effects were observed in Example 2, no effects were observed in Example 1.

Blood podium test-2 In an artificial medium, the resins of Example 3.6 and Comparative Example 1 and the resins of Example 21.23 and Comparative Example 2 in Table 1 were molded using an extrusion molding machine at a molding temperature of 170°C to 185°C. Speed B
m/min, width 400m at roll temperature 40℃
m, a sheet with a wall thickness of 0.4n+a+ is formed, and ?
The main inlet or outlet member was sealed and joined at the same time as the sheet was sealed by high-frequency heating to form a blood bag (empty bag). As shown in FIG. 3, the blood bags drawn in this manner are connected as a three blood bag system by tubes 5, and two CPD liquids are added to the blood bag 1a.
After injecting 8 ml, sterilize with high pressure steam (120℃ 1.5k)
g/cm2 [gauge pressure] for 20 minutes) and examined. The blood bag prepared above was placed 200 m from a healthy person.
Blood was collected from & and centrifuged (1500 ppm
, 10 minutes) to obtain PRP, further centrifuge the PRP (3000 rpm, 10 minutes), and
．． The PCs were injected into the blood bags of Example 3.6 and Comparative Example 1, and the blood bags of Example 21.23 and Comparative Example 2 were injected into the blood bags of 10n142 each under aseptic conditions and stored. After storage for 24 hours, 48 hours, and 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 Coulter Counter 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 results are shown in Figures 7A and 7B. Note that the number of specimens was 5, and the average value was taken.

Next, in order to determine platelet aggregation ability, OP aggregation was measured using an ablebometer. The percentage 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. 8A and 8B.

[Effects of the Invention] As described above, the medical component according to the present invention has the effect of inhibiting platelet aggregation, and in a blood bag assembled using the medical component as a component, platelet components do not aggregate. Since the platelets are preserved without affecting their function and without causing shape change or destruction even if they adhere to the inner surface of the blood bag, there is less loss of platelets during storage within the blood bag.
Moreover, the survival activity of platelets is not inhibited even after long-term storage.
That is, when reinjected into the body, the ability of platelets is fully demonstrated, making it possible to perform effective treatment for blood transfusions, making it an extremely high quality medical device.

[Brief explanation of the drawing]

Fig. 1 is a front view of the medical device of the present invention 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 front view of the medical device of the present invention applied to a blood bag. Figure 5 shows the relationship between the tensile strength of the pull sheet and the vitamin E content.
Figures A and 5B are pictorial diagrams showing the relationship between the number of platelets attached and vitamin E content a, Figures 6A and 6B are diagrams showing changes in platelet morphology, and Figures 7A and 7B are platelet reduction rates. FIG. 8A and FIG. 8B are diagrams showing the ADP aggregation rate before and after storage. 1.1a, 1b, 1C...Blood bag, 2...Edge, 4...Vitamin E-containing resin. Applicant Takasu Takasu Figure 5A Blood fir's first release-1 piece Figure 5B Figure 6A Figure 6B I#112 @Total of Soto S Mouse - ~ - 11 @ + GiP Sai ~ 1; - One meeting

Claims (1)

[Scope of Claims] 1. A medical device for storing, preserving, and transporting blood, in which at least one part of the components that make up the main body of the device that comes into direct contact with blood contains vitamin E. A medical device characterized by: 2. The medical device according to claim 1, wherein the device body is a blood bag. 3. The medical device according to claim 1, wherein the device body is a tube used in a blood transport circuit. 4. The medical device according to claim 1, wherein the member that comes into direct contact with blood is a plastic sheet, and the resin forming the sheet contains vitamin E. 5. The medical device according to claim 1, wherein the member that comes into direct contact with blood is a tube that connects to another medical device. 6. The medical device according to claim 4, wherein the content of vitamin E is 0.5 to 50 parts by weight based on 100 parts by weight of the base resin. 7. The medical device according to claim 4, wherein the sheet has an average wall thickness of 0.1 to 1.0 mm. 8. The medical device according to claim 4, wherein the resin forming the sheet is substantially vinyl chloride resin. 9. The medical device according to claim 7, wherein the vinyl chloride resin has an average degree of polymerization of 400 to 3,000. 10 The resin forming the sheet has an average degree of polymerization of 700 to 3
000 vinyl chloride resin, 4 parts by weight of plasticizer
The medical device according to claim 7 or 8, containing 0 to 80 parts by weight.