JP2919514B2 - Manufacturing method of medical device - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a medical device used in contact with blood, for example, a component of a blood circuit.

<Conventional technology> The extracorporeal blood circulation circuit is composed of various tubes, connectors for connecting the tubes, artificial organs (artificial lung, artificial kidney), and the like. The constituent materials of the tubes are mainly polyvinyl chloride, connectors and As a constituent material of the casing of the artificial organ, polypropylene or polycarbonate is mainly used.

These materials are selected from the viewpoints of excellent physical properties and workability, high safety for human body (no leaching or toxicity), and low material cost.

However, some of these materials have problems with their compatibility with blood. That is, when blood circulation is performed for a long period of time, a thrombus is formed on a contact surface with blood.

Therefore, in order to perform long-term blood circulation, it is necessary to continuously inject an anticoagulant such as heparin into the circuit, but in consideration of adverse effects on the human body, for example, the tendency of bleeding after surgery, the anticoagulant is considered. Continuous administration of the agent is undesirable and should be avoided as much as possible.

Under such circumstances, development of a blood circuit component having antithrombotic properties without administration of an anticoagulant has been desired.

<Problems to be Solved by the Invention> The present invention has been made in view of the above-mentioned drawbacks of the related art, and an object of the present invention is to provide a method for manufacturing a medical device having antithrombotic properties. is there.

<Means for Solving the Problems> Such an object is achieved by the present invention described below.

The present invention, when manufacturing a medical device used in contact with blood, injection molding a polymer compound having a repeating structural unit represented by the following structural formulas I and II at 230 ~ 250 ℃ to form a substrate Then, the surface is treated by immersing the substrate in hexafluoroisopropyl alcohol for 5 to 30 seconds, and then dried at 40 to 80 ° C., whereby the average diameter of the substrate is 0.5 to 50.0 This is a method for producing a medical device, wherein a spherulite of μm is formed.

(Where R is a linear or branched alkylene group having 2 to 4 carbon atoms, R 'is a linear alkylene group or an aromatic ring residue having 2 to 10 carbon atoms, and R "is a linear alkylene group having 2 to 7 carbon atoms. Or n represents a branched alkylene group, n is 1 to 180, and m is 1 to 400.) Hereinafter, the configuration of the method for producing a medical device of the present invention will be described in detail.

The medical device manufactured according to the present invention has the following structural formulas I and II on the contact surface of the medical device (substrate) with blood.
The layer of the high molecular compound which consists of a repeating structural unit shown by this is formed.

Such a polymer compound is called a so-called segmented nylon.

The portion of Structural Formula I represents a polyether repeating unit, while the portion of Structural Formula II represents a polyamide repeating unit. The moiety of Structural Formula I and the moiety of Structural Formula II are linked by an ester bond.

R in the portion of the structural formula I is, for example, a linear or branched alkylene group having 2 to 4 carbon atoms such as ethylene, isopropylene and tetramethylene, and n is about 1 to 180, preferably about 0 to 60. .

R 'in the structural formula II is a linear alkylene group having 2 to 10 carbon atoms, preferably 4 to 8 carbon atoms or an aromatic ring-containing group such as a benzene ring, and R "is a straight-chain alkylene group having 2 to 7 carbon atoms. It is a chain or branched alkylene group, and the combination of R 'and R "is not particularly limited, but preferably forms a crystalline-amorphous microdomain structure from the viewpoint of improving antithrombotic properties. Is good.

For this purpose, the polyamide moiety (polymer) represented by the structural formula II is preferably one having a high crystallinity. For example, R ′ is an octamethylene group and R ″ is an even number of carbon atoms such as a hexamethylene group. Those having a straight-chain hydrocarbon group are preferred.

Further, m in the structural formula II is 1 to 400, preferably 1 to 120.
It is.

The quantitative relationship in the polymer of the polymerized units of the structural formulas I and II is not particularly limited, but it is preferable that the structural formula I portion is about 10 to 50% by weight of the whole.

The molecular weight of such a high molecular compound (segmented nylon) is not particularly limited, but is preferably 10,000 to 300,
000, more preferably 20,000 to 100,000.

Specific examples of the segmented nylon include the following.

Such segmented nylon itself has antithrombotic properties, and is also excellent in durability, moldability, workability,
Sufficient antithrombotic properties cannot be obtained simply by forming a segmented nylon layer on the surface of the substrate that contacts blood.

That is, in the present invention, it is important that the surface (blood contact surface) of the segmented nylon layer is a spherulite (spherical crystal). Thereby, excellent antithrombotic properties are exhibited.

Here, spherulite refers to the form of a polymer crystallized into a single sphere by growing fibrils around the nucleus. Observation with an electron microscope (SEM) shows that the projection has a hemispherical or similar shape. Appears as

Although the principle of obtaining excellent antithrombotic properties by using a spherulite is not clear, it is presumed that the arrangement of the crystalline part and the non-crystalline part is arranged and the microphase separation structure is clarified. .

The average diameter of the spherulite is not particularly limited, but 0.5 to 50.0 μ
m is preferred.

 This is because those in this range are particularly excellent in antithrombosis.

The medical device of the present invention is applied to a component of a blood extracorporeal circuit. The circuit components include various tubes such as a blood supply tube and a pump tube, connectors having different diameters for connecting tubes, arterial and venous insertion catheters, artificial lungs,
Examples include a gas exchange membrane and a dialysis membrane of an artificial organ such as an artificial kidney, a bubble trap, a blood bag, a chamber, a co-injection port, and a centrifugal pump.

In addition, artificial blood vessels, artificial hearts, intravascular indwelling catheters,
The present invention can also be applied to a device to be placed in a living body such as a catheter for accommodating a lead wire of a pacemaker or the like, and a blood transfusion or blood collection device such as a syringe, a blood collection tube, a blood bag, and an accessory thereof.

In addition, each said apparatus is an example and is not limited to these.

Next, a method for manufacturing the medical device of the present invention will be described.

 The medical device is manufactured by the following steps.

1) The segmented nylon is molded into a medical device (base material) such as a connector or a casing of an artificial organ using an injection molding machine or a press molding machine. At this time, the molding temperature is preferably about 230 to 250 ° C. Note that additives such as a heat stabilizer and a nucleating agent may be added to the segmented nylon.

2) Next, the surface of the molded product is treated with a solvent. Examples of the solvent include formic acid and hexafluoroisopropyl alcohol.

Examples of the treatment method include a method of spraying (showing) a solvent on a substrate, a method of immersing the substrate in the solvent, and a method of circulating the solvent in a flow path of a tubular medical device such as a connector.

The processing time is determined according to the thickness of the substrate. For example, for a film having a thickness of 5 mm, the time is preferably about 5 to 30 seconds. If the time is less than 5 seconds, no spherulites are formed on the surface, or even if spherulites are formed, the distribution becomes non-uniform. Also, 30
When the time exceeds seconds, the shape of the base material may be deformed.

3) After the treatment with the solvent is completed, drying is performed.

Drying conditions (drying temperature, drying time) are appropriately determined according to the type and concentration of the solvent used, the shape of the substrate, and the like.

Among these, the drying temperature is preferably set to 40 to 80 ° C. If it is out of this range, spherulites are not formed on the surface of the base material, or even if spherulites are formed, the distribution is uneven, or the diameter of the spherulites is out of the above range,
This is because the diameter may vary.

Such drying may be performed using any known drying device (oven and vacuum dryer).

Further, a medical device having a blood flow path can be dried by supplying warm air into the flow path. In this case, the supply amount of the warm air can be, for example, about 1 to 10 l / min.

<Example> Experiment 1 (Reference Example 1) A different-diameter connector made of polycarbonate was prepared as a base material, immersed in a 0.4% permanganic acid / sulfuric acid solution for 2 minutes, and then sufficiently washed and dried to obtain a surface. Was subjected to a hydrophilic treatment.

Next, a 6% (w / v%, the same applies hereinafter) polytetramethylene oxide-nylon 610 / formic acid solution was passed through the flow path inside the connector, and the coating liquid was coated on the inner surface of the flow path.

After that, a temperature of 70 ° C is supplied to the flow path inside the connector.
The coating solution was dried by supplying the solution at 3 l / min for 6 hours, and further vacuum-dried for 24 hours to form a segmented nylon layer having a thickness of 1.0 μm.

The state of the surface of the segmented nylon layer is referred to as the first state.
It is shown in the electron microscope (SEM) photograph (1000 times) of the figure. This shows that spherulites having an average diameter of about 5 μm are formed almost uniformly on the surface of the layer.

For comparison, an electron micrograph (× 1000) of the inner surface of the uncoated connector is shown in FIG.
Shown in the figure.

(Reference Example 2) As a base material, a tube for extracorporeal blood circulation circuit (outer diameter 9m)
m, inner diameter 6 mm). This tube is made of a PVC-EVA copolymer (manufactured by Sekisui Corporation). This material is a non-plasticized PVC material containing no plasticizer.

The inner surface of this tube was coated with 2% polytetramethylene oxide-nylon 610 / hexafluoroisopropyl alcohol. The coating method was as follows. One end of the tube was immersed in the coating solution, and the other end of the tube was pumped from the other end of the tube. Was sucked up to fill the tube with the coating solution, then the pump was stopped, and the coating solution level was lowered at a constant speed of 8.0 cm / min.

Thereafter, the coating solution was dried by supplying warm air of 70 ° C. to the inside of the tube at a supply rate of 3 l / min for 2 hours, and further dried in vacuum for 24 hours to form a segmented nylon layer having a thickness of 1.0 μm. .

The surface condition of this segmented nylon layer is
It is shown in the electron micrograph (× 1000) of the figure. according to this,
It can be seen that spherulites having an average diameter of about 5 μm are formed almost uniformly on the surface of the layer.

In addition, when a segmented nylon layer was formed under the same conditions on an arterial / vein insertion catheter of the same material instead of the circuit tube, similar results were obtained.

Experiment 2 (Example of the present invention) Polypropylene oxide-nylon 610 was used at a mold temperature of 240
Injection molding was performed at 10 ° C. to obtain a block of 10 × 3 × 50 mm, which was immersed in hexafluoroisopropyl alcohol for 10 seconds to treat the surface, and then dried in an oven at 40 ° C. for 6 hours.

The state of the surface before the treatment is shown in the electron micrograph of FIG.
FIG. 5 shows an electron micrograph (× 2000) of the surface after the treatment. According to this, it is understood that spherulites having an average diameter of about 5 μm are formed almost uniformly, although the surface is flat before the treatment.

Experiment 3 (Reference Example 3) A platelet dilatation ability test was performed by the following method.

 First, the following Nos. 1 to 4 were prepared as base material samples.

No.1: PVC sheet No.2: PVC-polyurethane copolymer sheet No.3: PVC-polyurethane copolymer with a layer of polytetramethylene oxide-nylon 610 (thickness: 1.0 μm, spherulite diameter: 5 μm) Sheet No.4: PVC-polyurethane copolymer sheet with a layer of polypropylene oxide-nylon 610 (thickness 1.0 μm, spherulite diameter 5 μm) The dimensions of each sample No. 1 to 4 are 8 × 8 mm is there.

Then, P was adjusted platelet count as specimen 10 ⁵ / [mu] l
Apply 200 μl of RP onto each of sample Nos. 1 to 4 at room temperature.
After leaving it for a minute, it was fixed with glutaraldehyde.

After washing and drying, the number of adhered platelets and the morphological classification (types I, II, and III) were calculated by observation with an electron microscope (SEM).

<Morphological Classification> I: Spheroidized from normal disk shape to pseudopodia 1-3
II: Stretched at least 4 pseudopods and extended the vesicles to half the length of the pseudofoot. Completely crushed The results of the test performed on three samples are shown in Table 1 below.

As is clear from Table 1, sample N having a spherulite on the surface
o.3 and 4 have a smaller number of adhered platelets and less morphological change than Samples Nos.1 and 2 without spherulites.

Experiment 4 In the same manner as in Experiment 3, the following samples were subjected to a platelet dilation ability test.

 Nos. 5 and 6 below were prepared as samples.

No.5: Injection molded sheet of polypropylene oxide-nylon 610 (without spherulites) No.6: No.5 treated with a solvent and spherulites (spherulite diameter 4μ)
m) formed sheet As is clear from Table 2, Sample No. 6 of the present invention has less adhered platelets and less change in morphology than Sample No. 5 which is a comparative example.

<Effect of the Invention> As described above, according to the method for manufacturing a medical device of the present invention, a medical device excellent in antithrombotic properties is provided.

Therefore, for example, when blood circulation is performed for a long time using a blood circuit, it is not necessary to administer an anticoagulant such as heparin, and the safety to the human body is enhanced.

[Brief description of the drawings]

1 to 5 are photographs as substitutes for drawings, each showing the structure of a crystal. FIG. 1 and FIG. 2 are electron micrographs (× 1000) showing the state of the surface of the segmented nylon layer relating to the reference example, respectively. FIG. 3 is an electron micrograph (× 1000) of the surface of the polycarbonate substrate. Figure 4 shows segmented nylon without spherulites
It is an electron micrograph (2000 times) of the injection molded sheet of No. 610. FIG. 5 is an electron micrograph (2000) showing the surface morphology of the segmented nylon of the present invention forming spherulites.
Times).

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shiro Endo 1500 Inoguchi, Nakai-machi, Ashigara-kami, Kanagawa Prefecture Inside Terumo Corporation (72) Inventor Mina Ishii 1500 1500 Inokuchi, Nakai-machi, Ashigara-gun, Kanagawa Prefecture Inside Terumo Corporation (72) Inventor Yasuhisa Sakurai 3-17-6, Eifuku, Suginami-ku, Tokyo (72) Inventor Naoya Ogata 6-29-6, Asaya-Kita, Suginami-ku, Tokyo (72) Inventor Kohei Sanai 4-29-8, Wakabayashi, Setagaya-ku, Tokyo (72) Inventor Nobuhiko Yui 2-3-22 Hinodai, Hino-shi, Tokyo (72) Inventor Kazunori Kataoka 2-40-102, Kotake-cho, Nerima-ku, Tokyo (72) Inventor Mitsuo Okano 6-12-9, Kokufudai, Ichikawa-shi, Chiba -101 (56) References JP-A-61-155426 (JP, A) JP-A-62-233165 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61L 33/00

Claims (2)

(57) [Claims] In producing a medical device used in contact with blood, a polymer compound comprising a repeating structural unit represented by the following structural formulas I and II is injection-molded at a temperature of 230 to 250 ° C. A substrate is manufactured, and then the substrate is immersed in hexafluoroisopropyl alcohol as a solvent for 5 to 30 seconds to treat the surface, and then dried at 40 to 80 ° C., whereby the surface of the substrate is Forming a spherulite having an average diameter of 0.5 to 50.0 [mu] m. (Where R is a linear or branched alkylene group having 2 to 4 carbon atoms, R 'is a linear alkylene group or an aromatic ring residue having 2 to 10 carbon atoms, and R "is a linear alkylene group having 2 to 7 carbon atoms. Or a branched alkylene group, wherein n is 1 to 180 and m is 1 to 400.) 2. The method for manufacturing a medical device according to claim 1, wherein the polymer compound is polypropylene oxide-nylon 610.