JPS628762A - Method and apparatus for producing synthetic resin tube having protein film formed to inner wall thereof - 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 "Field of Industrial Application" The present invention relates to a method for manufacturing a long synthetic resin tube having a thin, uniform protein coating on its inner wall, and an apparatus for manufacturing the same. More specifically, the present invention relates to a method for manufacturing a medical tube whose main component is a synthetic resin tube with excellent visibility and a protein coating formed on the inner wall of the tube, and an apparatus for manufacturing the same.

``Prior art'' Conventionally, soft materials have been used as materials for transport tubes used for collecting, transporting, or injecting blood or drug solutions from the human body in the medical field, such as blood collection, blood transfusions, infusion sets, and artificial kidney blood circuits. A composition based on vinyl chloride resin (hereinafter abbreviated as "soft vinyl chloride") is used. This is because soft PVC has a high level of performance required as a material for infusion pipes, such as transparency, flexibility, resiliency, chemical resistance, heat resistance, and cold resistance, and is also inexpensive and sanitary. As a disposable product, which is considered desirable from various aspects,
By being suitable.

However, when soft PVC is used for such purposes, it is recognized that plasticizers, stabilizers, and other resin additives blended into the base resin can be leached into the liquid during product use. In addition, problem 7α has also been pointed out, such as the tendency to cause hemolysis and coagulation when coming into contact with blood.

Synthetic resins other than soft vinyl chloride, such as polyethylene, polypropylene, polyamide, polyester, etc., have also been put into practical use as materials for transport pipes used in the medical field for collecting, transporting, or injecting blood or drug solutions into the human body. However, since these synthetic resins are hydrophobic,
It has no affinity even when it comes into contact with blood or medicinal solutions, and is water repellent, which tends to cause problems such as bubble adhesion and fluid flow fluctuations.

In order to solve these problems, attempts have been made to form a crosslinked protein coating with excellent biocompatibility on the inner wall of a synthetic resin tube. However, it is technically very difficult to uniformly form a protein coating on the inner wall of a long synthetic resin tube, and the method has had to rely on manual labor that requires a large amount of labor.

[Summary of the problem to be solved by the invention] In view of the current situation, the present inventors have aimed to continuously obtain long, large quantities of synthetic resin tubes that have fewer problems as described above and are highly safe. As a result of intensive studies aimed at this purpose, the present invention has been completed.

``Means for Solving the Problems'' That is, the gist of the present invention is that when manufacturing a synthetic resin tube having a protein coating on the inner wall, in an atmosphere adjusted to a temperature that does not cause gelation of the protein solution, A step of injecting a protein solution from one end of a flexible synthetic resin tube, and then pulling the tube almost vertically upward while allowing the protein solution in the tube to flow down by gravity to form a thin film of the protein solution on the inner wall of the tube; After completing this process, the tube is introduced into an atmosphere adjusted to a temperature at which the protein solution gels, and the protein solution is gelled. A step of continuously injecting the protein crosslinking agent solution from the other end of the tube. (first invention) The gist of the second invention is an apparatus used when carrying out the first invention.

The present invention will be explained in detail below.

In the present invention, a flexible synthetic resin tube refers to a tube made of a thermoplastic resin. Examples of the thermoplastic resin include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, and ethylene-acrylic acid copolymer. Combined, polystyrene, rubber reinforced polystyrene, ABS resin,
Examples include MBS resin, polymethyl methacrylate, polyacetal, polyphenylene oxide, polycarbonate, polyester, polyamide, polyvinyl chloride, polyvinylidene chloride, vinyl chloride-vinyl acetate copolymer, silicone rubber, fluororesin, and the like.

These can be used alone or in combination of two or more. Note that the above examples do not limit the present invention.

If necessary, the above thermoplastic resin may contain ordinary resin additives such as plasticizers, lubricants, heat stabilizers, antioxidants, light stabilizers, ultraviolet absorbers, dyes, pigments, flame retardants, fillers, etc. Can be blended.

In order to manufacture a synthetic resin tube from the above-mentioned thermoplastic resin, it is preferable to use an extrusion molding method. The tube should preferably have a circular cross-sectional shape, with an outer diameter of 1° or less and an inner diameter of 3 mm.
It is preferable that the thickness is in the range of mm or more, and the thickness is about lllll11.

The synthetic resin tube used in the present invention is
The thermoplastic resin obtained by extrusion molding may be used as is, but it is more preferable to use a tube whose inner wall is coated with an adhesive in order to impart tackiness or adhesion to the inner wall of the tube. be.

When using the method of the present invention, in the first step, the protein solution is injected into the tube from one end of the thermoplastic resin tube in an atmosphere adjusted to a temperature that does not gel the protein solution. While pulling the tube almost vertically upward, the protein solution inside the tube is allowed to flow down by gravity, forming a thin film of the protein solution on the inner wall of the tube. The thin film of protein solution that forms on the inner wall of the tube in this process is gelled in the next second process, and then dried in the post-processing process to form a film that has excellent affinity with blood and drug solutions. , it becomes a thick film to form a film that does not cause problems such as bubble adhesion and flow fluctuation.

The protein solution used in the present invention refers to a solution in which protein is dissolved in a solvent. Proteins refer to proteins that are induced and produced through lighter treatments than natural proteins, which are the main components of living cells. Specifically, gelatin, proteose, peptone, keratin, collagen, fibroin, etc. can be used. These can be used alone or in combination of two or more. Note that the above examples do not limit the present invention.

Solvents for dissolving proteins include water, methyl alcohol,
Examples include ethyl alcohol, n-propyl alcohol, i-propyl alcohol, S-propyl alcohol, t-propyl alcohol, glycerin, propylene glycol, and acetone.

These can be used alone or in combination of two or more.

If the concentration of the protein dissolved in the above solvent is too high, the viscosity of the protein solution will become too high when the temperature of the protein solution is increased, which is not preferable. That is, if the viscosity of the protein solution is high, it becomes difficult to form a uniform FF film of protein on the inner wall of the tube, or the thin film of protein becomes too thick, which is undesirable. If the ysg of this protein is too thick, the protein i membrane will be damaged when actually used for medical purposes, making it impossible to obtain a tube of good quality. On the other hand, if the concentration of protein in the protein solution is too low, the protein film will become too thin, making it impossible to improve the affinity with the inner wall of the synthetic resin tube when it comes into contact with blood or drug solution, which is undesirable. Under these circumstances, the concentration of the protein solution should be
The range is preferably 20% by weight, particularly preferably 8% by weight.
-15% by weight.

The protein solution is injected into the tube in an atmosphere whose temperature is adjusted so that the protein solution does not gel. This is to form a uniform thin film of protein solution on the inner wall of the tube.

When injecting a protein solution into a tube, an uncoated tube with a length of several tens to hundreds of meters is wound around a tube unwinding device, and the required amount is injected from one end of the tube. The amount of protein solution injected at this time is sufficient to uniformly wet the inner surface of the tube. Therefore, this amount can be appropriately selected depending on the diameter and length of the tube wound around the tube unwinding device, the viscosity of the solution, etc.

The tube wrapped around a tube unwinding device and filled with a protein solution is placed in an atmosphere whose temperature is adjusted so that the protein solution does not gel. For this purpose, it is preferable to store the tube wound around the tube unwinding device in a constant temperature oven and adjust the temperature. Specifically, the temperature of the constant temperature bath is 30 to 60
The temperature is preferably in the range of 35 to 60°C, and particularly preferably in the range of 35 to 60°C.

The inner wall of the tube is uniformly wetted with protein solution in a constant temperature bath, and then pulled upward. When pulling the tube upward, it is necessary to pull it up in a vertical direction, otherwise the thickness of the protein solution adhering to the inner wall of the tube will not be uniform, which is not preferable. As the tube is pulled up almost vertically, the protein solution flows down the tube by gravity, evenly wetting the inner wall. The speed at which the tube is pulled up is such that the position of the protein solution poured into the tube remains at a constant position within the thermostatic chamber.

When using the method of the present invention, the tube on which a thin film of protein solution has been formed on the inner wall in the above first step is immediately introduced into an atmosphere adjusted to a temperature at which the protein solution gels, and the thin film of protein solution is gelled. .

In order to gel a protein solution, a tube with a thin film of this solution formed thereon is guided into a cooling tank installed near the thermostatic chamber, and the inside of this cooling tank is pulled up almost vertically from bottom to top. good. The ambient temperature of the cooling tank is preferably 30°C or lower, preferably 10°C or lower.

When the second step above is completed, a tube in which a wet protein film is formed is obtained. When using the method of the present invention, in the next step, a protein crosslinking agent solution is injected into this tube to cause a crosslinking reaction. The protein crosslinking agent solution used in the present invention refers to an aqueous solution of a crosslinking agent. Examples of the crosslinking agent include aldehydes, incyanates, acid chlorides, sulfonyl chlorides, chloroformates, epoxies, and epichlorohydrin.

Among them, aldehydes such as formaldehyde, geltaraldehyde, and glyogysar are suitable.

The concentration of the crosslinking agent solution is preferably in the range of 0.1 to 2% by weight of the crosslinking agent.

After completing the third step above, the protein thin film becomes brittle when it dries, so it is best to pass a glycerin aqueous solution through the tube while the thin film is still wet to perform post-treatment to absorb glycerin into the thin film. , in this case,
Fill the tube with glycerin aqueous solution and leave it for 1 to 3 minutes.
Just leave it for 0 minutes.

After this post-processing is completed, the aqueous glycerin solution is discharged from the tube, the tube is washed with sterile water, and warm air is blown into the tube to dry it, thereby obtaining the desired tube with a protein coating formed on its inner wall.

Hereinafter, the method of the present invention will be explained in detail based on the drawings.

FIG. 1 is a front view of the apparatus used in carrying out the method of the present invention, FIG. 2 is a plan view of the m1 diagram, and FIG.
The figure is a front view of the tube unwinding device used in the apparatus according to the present invention, Figure vIJ4 is a side view of the longitudinal section taken along the line A-A' in Figure 3, and Figure 5 is a side view of the tube rewinding device used in the apparatus according to the present invention. B-
FIG.

In the figure, 1 is a tube winding device, 13 is a tube unwinding device, 2 is a tube, 12 is a constant temperature bath, 14 and 24
20 is a cooling tank, and 22 is a crosslinking agent solution supply section.

The apparatus used when carrying out the method of the present invention is a constant temperature bath 1
A cooling unit 20 is installed near the unit 2.

The constant temperature bath 12 is equipped with a tube unwinding device 13 in which the uncoated tube 2 is wound in advance, and the constant temperature bath 12 controls the temperature of the uncoated tube 2, the tube unwinding device 13, and the protein solution 15. Performs the function of regulation. It is preferable that the wall surface of the constant-temperature chamber [12] be made of a transparent material so that the inside can be observed with the naked eye. The cooling tank 20 functions to cool the protein solution to a temperature at which it becomes a gel.

The cooling tank 20 is also preferably constructed from a transparent material).

The tube winding device 1 is placed at a different location from where the constant temperature bath 12 is placed, with the cooling 1ffi 20 in between. The tube winding device is equipped with a crosslinking agent solution supply section 22 equipped with a rotary joint for supplying a protein crosslinking agent solution. 21 and 23 are a tube winding device 1 and a tube unwinding device 13, respectively.
These are the drive shafts for rotating the motor 1.
Driven by 9 and (/18).

A cover with holes or slits 14 for transferring the tubes is provided above and below the cooling tank 20. Furthermore, holes or slits 2 for transferring the tubes are also provided on the wall surface of the constant temperature layer adjacent to the canopy at the bottom of the cooling WI20.
Drill 4. The holes 14 and 24 are provided so that their central axes are aligned in the vertical direction in order to facilitate tube transfer.

On top of the cooling WI20, there is a cooling tube W! A roll 25 is installed to pull the inside of the tube vertically upward and to continuously transport the tube. Roll 25 is driven by motor 17. A roll 27 is installed at the bottom of the constant temperature bath 12 to change the transport direction of the tube leaving the tube unwinding device 13 to the vertical direction before entering the cooling WI 20.

The tube rewinding device used in the device of the present invention has a structure as described below.

FIG. 3 is a front view showing an example of an embodiment of the tube rewinding device used in the device of the present invention, and FIG. 4 is a
Fig. fi5, a side view taken in the direction of arrows in a longitudinal section in the A' portion, is a cross-sectional view taken in the direction shown in the arrows in the BB' portion of FIG.

The tube rewinding device 13 is composed of a plurality of guide plate members 9. The tube 2 is located between the guide plate members 9 of 2IIL':! - rolled and rolled into a single layer.

The guide plate member 9 is composed of two guide plates 3 and a guide plate connecting member 7 that connects these two guide plates 3. The guide plate member 9 can be given extremely high rigidity by having a rigid structure, and has a gap 8 formed by the two guide plates 3, the guide plate, and the connecting member 7, so that the tube 2 and is suitable for controlling the temperature of protein solutions.

FIG. 4 illustrates a tube rewinding device in which two tubes 2 are wound between three sets of guide plate members 9. A spacer 6 is installed between two adjacent sets of guide plate members 9 to ensure a gap for further winding the tube 2. The tube rewinding device 13 is formed by stacking these guide plate members 9 and spacers 6 alternately and then fixing them with the tightening members 5. Approximately in the center of the tube rewinding device 13, a tube introduction hole 10 is provided that passes through the entire guide plate 2 and spacer 6 so that the tube end can be taken out when the tube 2 is started to be wound around the tube rewinding device 13. It is provided. At the center of the tightening member 5 is a shaft hole 1 into which a drive shaft for rotating the tube rewinding device 13 is inserted.
1 is provided.

When winding a tube into the tube rewinding device 13, the tube rewinding device 13 is first attached to a drive shaft for rotating the tube rewinding device 13.

Next, one end of the tube is passed through the gap secured by the spacer 6 of the tube rewinding device 13 and inserted into the tube introduction hole 1.
A little bit from 0 to the outside. Subsequently, by rotating the tube rewinding device using the drive shaft, the tube can be easily wound into the tube rewinding device. At this time, it is recommended to feed the tube so that strong tension is not applied to the tube.Furthermore, in order to smoothly roll in the tube, it is necessary to make a large gap in the area where the tube 2 is wound, which is secured by the spacer 6. The diameter of the tube is at least 103 mm.
% is required. More preferably, the size is 110 to 130%.

The tube winding device 1 has almost the same structure as the tube unwinding device 13, but is equipped with a rotary joint in its center for supplying a protein crosslinking solution supply section 22. It is being

A specific embodiment of continuously manufacturing a synthetic resin tube having a protein layer formed on its inner wall using the method and apparatus of the present invention will be described below.

The tube unwinding device 13, in which the synthetic resin tube that forms the protein layer on the inner wall has been rolled up using the method described above, is kept at a constant temperature! Attach to the drive shaft 23 of P112.

Figures 1 and 152 show eight tubes being connected at the same time.
A loaded tube unwinding device 13 is illustrated. Constant temperature W! The temperature of 12 is adjusted in advance to a temperature at which the protein solution is melted. Then, the empty tube winding device 1 is attached to the drive shaft 21. The tube winding device 1 illustrated in FIGS. 1 and 2 also has a structure that allows eight tubes to be wound simultaneously. Next, one end of the separately prepared splicing tube 26 (eight tubes are required in the apparatus illustrated in FIGS. 1 and 2) is inserted into the tube introduction hole through the gap secured by the spacer of the tube winding device 1. and connected to the crosslinking agent solution supply section 22. Next, lift the other end of the splicing tube 26, pass it through the roll 25, and then pass it through the cooling tank 2o.
4 and the hole 24, and the splicing tube 26
The other end is introduced into the constant temperature bath 12. Next, in the fitting tube 26 previously connected to the crosslinking agent solution supply section 22,
A protein cross-linking agent solution 16 is injected from the cross-linking agent solution supplying part to fill the cross-linking groove file into the splicing tube 26 to a height slightly in front of the roll 25.

Next, from the end of the tube 2 that forms the protein layer, which is rolled into the tube unwinding device 13 in the constant temperature bath 12,
The molten protein solution 15 is injected into the tube 2 by press fit or vacuum suction. The amount of protein solution injected at this time is sufficient to coat the inner wall of tube 2.

Next, the end of the tube 2 into which the protein solution was injected is connected to the end of the splicing tube 26 introduced into the thermostatic chamber. Thereafter, the motor 17 drives the roll 25 to continuously transport the tube 2 from the tube unwinding device 13 toward the tube winding device at a constant speed. At this time, the rotational speeds of the tube winding device 1 and tube rewinding device 13 are adjusted so that strong tension is not applied to the tube 2.

Further, the level of the protein solution injected into the tube 2 is always between the roll 27 and the hole 24, and the level of the crosslinking agent solution 16 is in front of the roll 25.
It is preferable to control the supply amount of the crosslinking agent solution so that the crosslinking agent solution does not flow into the tubes in the cooling tank 20.

While the tube 2 is being transferred from the tube unwinding device 13 to the tube winding device 1, a uniform thin protein layer is formed on its inner wall. That is, the tube 2 whose entire inner wall is uniformly wetted by the protein solution 15 filled in the tube inside the constant temperature bath 12 passes through the rolls 27 and then is pulled vertically upward, and the holes 24 and 14 After passing through, it is cooled from the outside by cooling 'Mg20. At this time, the excess protein solution adhering to the inner wall of the tube flows down, and the protein solution adhering to the inner wall of the tube gels as the tube is cooled from the outside, forming a thin protein layer that forms the inner wall of the tube. Become one with. after that,
Cooling f! After passing through the tube 20, the tube passes through the a-rule 25, and then the inside of the tube is filled with the protein crosslinking agent solution 16 supplied from the crosslinking agent solution supply section 22. At this time, the protein layer adhering to the inner wall of the tube undergoes a crosslinking reaction and turns into a crosslinked protein layer that is less susceptible to deterioration.

Thereafter, the tube is subjected to the above-mentioned post-treatment to obtain the desired synthetic I (fatty tube) having a protein coating on its inner wall.

"Effects of the Invention" The present invention has the following particularly remarkable effects, and its industrial utility value is extremely large.

(1) When using the method of the present invention, a uniform coating of protein can be continuously formed on the inner wall of a long synthetic resin tube ranging from several meters to several hundred meters, and a product with stable quality can be produced. Efficient, sanitary! I! ! can be built.

(2) When using the method of the present invention, the step of applying the protein solution to the inner wall of the tube and the step of crosslinking the applied protein solution can be performed consecutively, so the time required for these steps can be greatly reduced. Can be shortened.

(3) The device of the present invention includes the step of applying a protein solution to the inner wall of the tube and the step of crosslinking the applied protein solution in one device, making it extremely compact and suitable for use in narrow spaces. can be installed.

"Examples" The present invention will be explained in detail based on Examples below.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Example: Artificial Dialysis Cera) l Made of soft polyvinyl chloride, commercially available as Tachikawa, with an outer diameter of 7 ml11. Inner diameter is 5111J
Eight tubes each having a length of 100I11 were prepared. After winding these tubes into a tube unwinding device, apply approximately 0.1 of acrylic resin-molding adhesive M (Olipine BPS-3233 from Toyo Ink Co., Ltd.!It!) to the inner wall of the tube.
It was applied to a thickness of μ and dried thoroughly.

After a tube unwinding device wound with eight tubes was attached to the drive shaft of the thermostatic oven, the temperature of the thermostatic oven was adjusted to maintain the temperature at 40°C.

Next, after the tube winding device was attached to the drive shaft, eight splicing tubes were attached to the tube winding device, and one end of the splicing tube was connected to a crosslinking agent solution supply section. Thereafter, the other end of the splicing tube was introduced into a constant temperature bath.

A 0.5% by weight aqueous solution of geltaraldehyde was used as the crosslinking agent solution. After injecting this geltaraldehyde aqueous solution into a tank connected to the crosslinking agent solution supply section, the geltaraldehyde aqueous solution was injected into eight joint tubes from the crosslinking agent solution supplying section to fill them up to a predetermined position.

Meanwhile, the temperature of the cooling tank was adjusted to 15°C.

A gelatin solution was used as the protein solution.

Gelatin (manufactured by Nitsupi Co., Ltd., JIS special grade) 12 parts by weight,
After mixing 60 parts by weight of sterile water and 28 parts by weight of ethyl alcohol to prepare a gelatin solution at 60°C, this gelatin solution was maintained at 40°C.

300 ml of this gelatin solution was injected into each of eight uncoated tubes in a constant temperature bath. Next: The gelatin solution inlet of the tube was connected to the end of the splicing tube that had been previously introduced into the thermostatic bath.

Next, drive the motor to rotate the tube unwinding device, tube winding device, and rolls to rotate the tube 211/
Transferred at a speed of 1 minute. At this time, the rotation speed of the motor was controlled so that strong tension was not applied to the tube. Furthermore, the amount of geltaraldehyde aqueous solution supplied was controlled so that the vertical portion of the tube in the thermostatic chamber was always filled with gelatin solution.

After almost all of the tubes in the thermostatic chamber were transferred, the open ends of the eight tubes were sealed, and the cross-linking agent solution was filled inside and left at room temperature for 1 hour to allow the cross-linking reaction to occur. I have done it enough.

After that, drain the cross-linking agent solution from the tube, remove the splicing tube, and fill the tube with 100% sterile water.
The flow was continued for 120 minutes at a flow rate of cc/min to wash away excess aldehyde.Then, while the crosslinked gelatin membrane was in a wet state, a 20% aqueous solution of glycerin was filled into the tube. This was left for a minute to allow the crosslinked gelatin membrane to absorb glycerin. Thereafter, the aqueous glycerin solution was discharged from the tube.

Thereafter, the tube was placed in a heating furnace whose temperature was adjusted to 80° C., and compressed air of 0.4 kg/am” was passed through one end of the tube for 10 minutes to dry the inside of the tube.

The thickness of the crosslinked gelatin membrane of the resulting tube was approximately 30 microns.

In addition, when the cross-linked gelatin film was peeled off from the inner wall of the tube and the concentration of glycerin contained in this film was measured, it was approximately 3.
It was 0% by weight. ' The synthetic resin tube thus obtained had good adhesion of the gelatin film to the inner wall of the tube, and had no uneven thickness.

[Brief explanation of drawings]

FIG. 1 is a front view of the device according to the present invention, FIG.
3 is a front view of the tube rewinding device used in the apparatus according to the present invention, and FIG.
- A side view of the vertical cross section taken along the line A', and FIG. fjS5 is a cross sectional view taken along the line BB' of FIG. 4. In the figure, 1 is a tube winding device, 13 is a tube unwinding device, 2 is a tube made of synthetic wood WI, 12 is a constant temperature bath, 1
4 and 24 are holes, 15 is a protein solution, 16 is a crosslinking agent solution, 20 is a cooling tank, and 22 is a crosslinking agent solution supply section.

Claims (2)

[Claims] (1) When manufacturing a synthetic resin tube with a protein coating on the inner wall, the protein solution is injected from one end of the flexible synthetic resin tube in an atmosphere controlled at a temperature that does not gel the protein solution. , a step in which the tube is pulled upward almost vertically and the protein solution inside the tube is allowed to flow down by gravity to form a thin film of the protein solution on the inner wall of the tube; after this step, the tube is heated to a temperature at which the protein solution gels. The tube has a protein coating on its inner wall. Method for manufacturing synthetic resin tubes. (2) A constant temperature bath is placed to adjust the temperature to a temperature range in which proteins do not gel, and a cooling bath is installed near this constant temperature bath to adjust the temperature to a temperature that gels the thin film of protein solution formed on the inner wall of the tube. A tube winding device is placed across the cooling tank at a location different from the location where the thermostatic oven is disposed, and the tubing is continuously wound inside the thermostatic oven. A returning device is provided, and holes or slits are bored in the wall surface of the thermostatic chamber for transferring the tubes, and holes or slits are bored in the lower and upper parts of the cooling bath for transferring the tubes almost vertically. the tube winding device is provided with a
1. An apparatus for producing a synthetic resin tube having a protein coating on its inner wall, comprising a protein crosslinking agent solution supply section.