JP2011193984A - Leak test method for hollow fiber membrane type medical instrument - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a leak test method for a hollow fiber membrane type medical instrument dispensing with, after the execution of a leak test, the drying and removal of liquid remaining in a hollow fiber membrane and a periphery of the hollow fiber membrane, eliminating energy loss and time loss, and showing a reduced performance change.SOLUTION: This leak test method for the hollow fiber membrane type medical instrument including a hollow fiber membrane 3 having a permselectivity includes: a step of coating the hollow fiber membrane 3 with coating liquid including radiation crosslinking hydrophilic polymer and polyalcohols; a leak test step of measuring the permeability of gas of the hollow fiber membrane 3, and an irradiation sterilization step of applying radiation to the hollow fiber membrane 3.

Description

  The present invention relates to a leak test method for a hollow fiber membrane type medical device.

  In recent years, medical application of hollow fiber membrane technology has progressed, artificial kidney used for hemodialysis therapy of patients with chronic renal failure, plasma exchange therapy that discards patient plasma and replaces it with fresh frozen plasma or albumin solution Hollow fiber membrane-type medical devices are frequently used in plasma separators used in the field, plasma fractionators used in double filtration plasma exchange therapy for removing high molecular weight substances in patient plasma, and the like.

The hollow fiber membrane type medical device includes a product in which the container is filled with liquid and the hollow fiber is completely filled with the liquid (hereinafter sometimes referred to as a wet product), and the container is not filled with liquid and is dry (hollow The product may be referred to as a product (hereinafter, “dry product”) in a state in which the yarn contains almost no liquid, or in a semi-dry state (the hollow fiber is wet with a liquid, but is not hydrated at a saturation liquid retention rate or higher). )
In particular, dry products have the advantage that they are not easily frozen during transportation and storage even in cold regions, and the products themselves are light.

In the hollow fiber membrane type medical device, if there is a pinhole in the hollow fiber membrane, a substance to be blocked by the hollow fiber membrane leaks to the filtrate side. Therefore, in the process of assembling the hollow fiber membrane type medical device, It is necessary to perform a leak test.
When the gas permeability of the hollow fiber membrane is low, the pressure of the gas is applied to one side of the hollow fiber membrane, and the pinhole of the hollow fiber membrane is controlled by the speed at which the gas escapes to the other side of the hollow fiber membrane. However, in the case of hollow fiber membrane medical devices using hollow fiber membranes with high water permeability in recent years, the gas permeability of the hollow fiber membrane is very high. Can not.

  For this reason, in order to perform a leak test of a hollow fiber membrane having high water permeability and high gas permeability, the hollow fiber membrane is once wetted with a liquid, and after having made no gas permeation without a pinhole, In a state where the leak test is performed (for example, see Patent Document 1) or in a state where the hollow fiber membrane is completely immersed in the liquid, the hollow portion of the hollow fiber membrane is pressurized with gas, and bubbles are generated from the hollow fiber membrane. A method of detecting the presence or absence of a pinhole by detecting whether or not it has occurred (see, for example, Patent Document 2) has been performed.

  As another leak test, a leak inspection method for a hollow fiber membrane module in which gas containing colorable particles is introduced into the inside of the hollow fiber membrane under pressure to detect leakage of the colored particles (see, for example, Patent Document 3). There is also.

Japanese Patent Laid-Open No. 2005-238096 JP 2003-190747 A JP 2009-183822 A

However, when the hollow fiber membrane type medical device is a dry product, applying a method of wetting the hollow fiber membrane with a liquid as in the methods described in Patent Documents 1 and 2, after performing a leak test, the hollow fiber membrane In addition, since it is necessary to dry and remove the liquid remaining around the hollow fiber membrane, it has a great disadvantage of requiring heat energy and time.
In addition, when adopting the process of wet-drying the hollow fiber membrane once, especially the process of performing hot air drying, the pore shape of the hollow fiber membrane changes, the average pore diameter, the pore diameter distribution change, the water permeability There is also a problem that the fractionation performance may be changed.
In addition, according to the method described in Patent Document 3, there is a problem that the colored particles remain in the hollow fiber membrane module and cannot be used in a medical device.

  Therefore, in the present invention, in view of the problem of the hollow fiber membrane type medical device as the dry product, it is not necessary to dry the liquid remaining around the hollow fiber membrane and the hollow fiber membrane after performing the leak test, It is an object of the present invention to provide a leak test method for a hollow fiber membrane medical device that has no loss of energy or time and can avoid performance changes due to such drying treatment.

As a result of intensive studies to solve the above problems, the present inventors coated a solution containing a radiation crosslinkable hydrophilic polymer and a polyhydric alcohol on a dense layer of a hollow fiber membrane having selective permeability, The inventors have found that the above-mentioned problems can be solved by conducting a leak test and sterilizing by irradiation, and have come to obtain a leak test method for a hollow fiber membrane medical device.
That is, the present invention is as follows.

[1]
A leak test method for a hollow fiber membrane type medical device comprising a hollow fiber membrane having selective permeability,
Coating the hollow fiber membrane with a coating solution containing a radiation-crosslinking hydrophilic polymer and a polyhydric alcohol;
A leak test step for measuring gas permeability of the hollow fiber membrane;
An irradiation sterilization step of irradiating the hollow fiber membrane with radiation;
A leak test method for a hollow fiber membrane type medical device.

[2]
The leak test method for a hollow fiber membrane type medical device according to [1], wherein the polyhydric alcohol is glycerin.

[3]
The leak test method for a hollow fiber membrane medical device according to the above [1] or [2], wherein the concentration of the polyhydric alcohol in the coating solution is 40 to 75% by mass.

[4]
The leak test method for a hollow fiber membrane medical device according to any one of [1] to [3], wherein the radiation-crosslinking hydrophilic polymer is polyvinylpyrrolidone.

[5]
The hollow fiber membrane medical according to any one of [1] to [4], wherein the concentration of the radiation-crosslinkable hydrophilic polymer in the coating solution is 0.01% by mass or more and less than 1.0% by mass. Tool leak test method.

[6]
The leakage test method for a hollow fiber membrane medical device according to any one of [1] to [5], wherein the irradiation sterilization is performed by irradiating γ rays or electron beams.

[7]
The hollow according to any one of [1] to [6], wherein in the irradiation sterilization step, the hollow fiber membrane-type medical device is packaged in an oxygen-impermeable sterilization bag together with an oxygen absorbent and subjected to irradiation sterilization. Leak testing method for thread membrane medical devices.

[8]
The leak test method for a hollow fiber membrane medical device according to any one of [1] to [7], wherein the selectively permeable hollow fiber membrane contains a hydrophobic polymer and a hydrophilic polymer.

[9]
A hollow fiber membrane type medical device subjected to a leak test by the leak test method according to any one of [1] to [8].

  According to the present invention, there is no need to dry the hollow fiber membrane and the liquid remaining around the hollow fiber membrane, there is no loss of energy and time, and there is no change in performance due to the drying treatment. A leak test method can be provided.

The partial cross section schematic model diagram of an example of the hollow fiber membrane type medical device of this embodiment is shown.

Hereinafter, a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described with reference to the drawings.
The present invention is not limited to the following description, and various modifications can be made within the scope of the gist thereof.
In the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. Further, the positional relationship such as up, down, left, and right is based on the positional relationship shown in the drawings unless otherwise specified, and the dimensional ratio in the drawing is not limited to the illustrated ratio.

[Leak test method for hollow fiber membrane type medical devices]
The leak test method for a hollow fiber membrane type medical device according to the present embodiment is a leak test method for a hollow fiber membrane type medical device comprising a selectively permeable hollow fiber membrane, and includes a radiation crosslinkable hydrophilic polymer and a multi-component hydrophilic polymer. A step of coating the hollow fiber membrane with a coating solution containing a monohydric alcohol, a leak test step of measuring gas permeability of the hollow fiber membrane, and an irradiation sterilization step of irradiating the hollow fiber membrane with radiation. It is the leak test method of the hollow fiber membrane type medical device which has.

FIG. 1 is a schematic partial cross-sectional view of a hollow fiber membrane medical device that is a target of the leak test method of the present embodiment.
In addition, in the right part of the dashed-dotted line shown in FIG. 1, the schematic sectional drawing of a hollow fiber membrane type medical device is shown, and in the left part of a dashed-dotted line, the schematic side view of a hollow fiber membrane type medical device is shown.
The hollow fiber membrane type medical device 1 is loaded with a bundle of hollow fiber membranes 3 along the longitudinal direction of the cylindrical container 9, and the hollow fiber membrane 3 is separated from the inside and the outside of the hollow fiber membrane 3. Both ends of the bundle are embedded in the resin 8 and are fixed to both ends of the cylindrical container 9.
Headers 2, 2 ′ having nozzles 4, 5 serving as fluid inlets / outlets are provided on the end face of the resin 8 opened inside the hollow fiber membrane 3.
On the side surface of the cylindrical container 9, at least one port 6, 7 serving as a fluid inlet / outlet port is provided.
A first space 10 is formed between the inner side of the hollow fiber membrane 3 and the inner surface of the header, and a second space 11 is formed between the outer side of the hollow fiber membrane 3 and the inner surface of the cylindrical container. .

  Examples of the hollow fiber membrane type medical device to be subjected to the leak test method of the present embodiment include a hemodialyzer, a hemodialysis filter, a blood filter, a continuous hemodialysis filter, a continuous blood filter, a plasma separator, Examples include plasma component fractionators, plasma component adsorbers, virus removers, blood concentrators, plasma concentrators, ascites filters, ascites concentrators, and medical devices that utilize the filtration characteristics of hollow fiber membranes. It becomes a target.

  As the selectively permeable hollow fiber membrane constituting the hollow fiber membrane type medical device to be subjected to the leak test method of the present embodiment, the hollow fiber membrane type medical device is a hemodialyzer, a hemodialysis filter, a blood filter, In the case of continuous hemodiafiltration, continuous hemofiltration, blood concentrator, plasma concentrator, ascites concentrator, etc., cellulose, polyacrylonitrile, ethylene vinyl alcohol, polymethyl methacrylate, polysulfone, etc. A dialysis membrane made of a hydrophilic or hydrophilic polymer can be applied, and the hollow fiber membrane medical device is a plasma separator, plasma component separator, plasma component adsorber, virus remover ascites filter, etc. Is a blood made of a hydrophilic or hydrophilic polymer such as polyethylene, ethylene vinyl alcohol, cellulose acetate, cellulose, polysulfone, etc. Separation membrane, the plasma fraction membrane, virus removal membrane or the like can be applied.

The hollow fiber membrane type medical device that is the target of the leak test method of the present embodiment includes both a dry type and a semi-dry type.
These refer to those in which the cylindrical container is not filled with a liquid and is in a dry state or semi-dry state, but the hollow fiber membrane is not immersed in a solution that cannot be held, that is, most of the solution is in the hollow fiber membrane. It is what is being held.

(Coating the coating solution on the dense layer portion of the hollow fiber membrane)
<Coating solution>
The coating solution contains a radiation crosslinkable hydrophilic polymer and a polyhydric alcohol.
The polyhydric alcohols refer to alcohols having a plurality of hydroxyl groups in the molecule. For example, glycerin, ethylene glycol, glucitol and the like can be mentioned.
The polyhydric alcohol is preferably a solution having a relatively low molecular weight that can be soaked in the hollow fiber membrane and giving a suitable viscosity to a solution that is a coating solution, for example, an aqueous solution.
Since the polyhydric alcohol permeates into the membrane wall of the hollow fiber membrane, the gas permeability can be greatly reduced, so that the hollow fiber membrane is preferable for the leak test.
Among the polyhydric alcohols, glycerin and ethylene glycol are preferable, and glycerin is particularly preferable.

Since the hollow fiber membrane medical device may be stored in a low temperature environment of 0 ° C. or less, it is preferable that the coating solution does not freeze even under such a low temperature condition.
A part of the coating solution is immersed in a selectively permeable hollow fiber membrane. For example, freezing under low temperature conditions can be prevented by using an aqueous solution containing 40 to 75% glycerin as a polyhydric alcohol.

The radiation-crosslinkable hydrophilic polymer refers to a polymer that is water-soluble hydrophilic polymer but crosslinks by radiation irradiation and becomes insoluble in water.
Examples thereof include polymers such as polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, and polypropylene glycol.
In particular, polyvinyl pyrrolidone and polyethylene glycol are preferable from the viewpoint of safety and the viscosity of the coating solution can be kept at a viscosity that can be uniformly applied to the coating, and polyvinyl pyrrolidone is more preferable.

The concentration of the hydrophilic polymer in the coating solution is preferably 0.01 to 1.0% by mass, and more preferably 0.1 to 1.0% by mass. If it is less than 0.01% by mass, it is difficult to stabilize the result of a leak test described later and it is difficult to obtain a result having good reproducibility. Since it becomes too high and the coating to the hollow fiber membrane becomes non-uniform, it is not preferable.
The weight average molecular weight of the radiation-crosslinkable hydrophilic polymer contained in the coating solution is preferably large to some extent because it is easily insoluble in water by crosslinking. On the other hand, if the molecular weight is too large, it takes time to dissolve in water, the solution viscosity tends to increase, and it is difficult to handle. From this viewpoint, the molecular weight of the radiation-crosslinkable hydrophilic polymer is preferably 40,000 to 800,000.

  The coating solution is a solution obtained by dissolving a radiation crosslinkable hydrophilic polymer in water, an organic solvent or the like together with the polyhydric alcohol, but is an aqueous solution in consideration of cleaning before actual use of the hollow fiber membrane medical device. It is preferable.

<Process for coating hollow fiber membrane>
The hollow fiber membrane exhibits selective permeability as a function, but may have a configuration in which a “dense layer” that exhibits selective permeability is provided in a part thereof.
Selective permeability means that only a water or small molecule substance is allowed to pass through without passing a polymer substance contained in the treatment liquid. For example, in artificial dialysis, it refers to the function of filtering water that is desired to be discharged outside the body, but not filtering proteins such as albumin necessary for the body.
Examples of the dense layer include a structure that exists in the vicinity of the inner surface of the hollow fiber membrane and has a denser network structure than the outer surface side.
The hollow fiber membrane or the dense layer preferably contains a hydrophobic polymer and a hydrophilic polymer as constituent components.
Hydrophobic polymers are water-insoluble polymer materials, and most engineering plastics can be used. For example, polymers such as polysulfone, polyamide, polyimide, polyphenylene sulfide, and polyphenyl ether can be used. Can be mentioned.
In particular, polysulfone and polyethersulfone are preferable, and polysulfone is more preferable.
The hydrophilic polymer is a polymer substance that is soluble in water, and examples thereof include polymers such as polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, and polypropylene glycol.
In particular, polyvinyl pyrrolidone and polyethylene glycol are preferable, and polyvinyl pyrrolidone is more preferable.

  For example, the hollow fiber membrane is prepared by adding a hydrophilic polymer to the above hydrophobic polymer and, if necessary, additives, discharging a spinning stock solution dissolved in a solvent from an annular slit base, and simultaneously injecting an inner solution from an injection hole. However, the film can be formed by a dry-wet method of passing through a dry part and then leading to a coagulation bath.

  As a method for coating the coating solution containing the radiation-crosslinkable hydrophilic polymer and the polyhydric alcohol described above on the hollow fiber membrane or the dense layer portion constituting the hollow fiber membrane, for example, the coating solution may be applied to the hollow fiber. A method of passing the liquid inside the membrane can be adopted. By this method, the coating solution contacts at least the inner surface of the hollow fiber membrane. The surplus solution can be removed by a method such as flushing (blowing away) with a gas or the like, or removing liquid by applying centrifugal force.

As described above, by impregnating the hollow fiber membrane with a coating solution containing a polyhydric alcohol, the gas permeability of the hollow fiber membrane can be greatly reduced, so that the hollow fiber membrane is in a preferable state for a leak test. However, in order to further reduce the gas permeability of the hollow fiber membrane and stabilize the leak test results, a radiation-crosslinkable hydrophilic polymer having a molecular weight that is difficult to enter the membrane wall of the hollow fiber membrane, It is necessary to coat the dense layer of the hollow fiber membrane. As a result, the result of a leak test described later is stabilized, and a reproducible result is obtained.
The reason why such an effect can be obtained by using the radiation-crosslinkable hydrophilic polymer is that the radiation-crosslinkable hydrophilic polymer masks the influence of the pore diameter and thickness unevenness of the dense layer portion of the hollow fiber membrane. This is probably because of this.

(Leak test process for measuring gas permeability)
As described above, after the coating solution is coated on the hollow fiber membrane or the dense layer constituting the hollow fiber membrane, a leak test is performed.
The leak test is an inspection for the presence or absence of pinholes in the hollow fiber membrane.
For example, a method of determining the presence or absence of pinholes by applying a gas pressure to the hollow fiber membrane, measuring the velocity of the gas passing through the hollow fiber membrane, and the like can be exemplified.
As a specific method, when a certain air pressure is applied to the inside of the hollow fiber membrane and then the pressurization is stopped and the gas pressure is applied to the piping, that is, the hollow fiber membrane, the gas is introduced into the hollow fiber membrane. A method of measuring the pressure drop inside the hollow fiber membrane after closing the pipe is common.

(Irradiation sterilization process)
After performing a leak test as described above, the hollow fiber membrane is sterilized by irradiation. As a result, the radiation-crosslinkable hydrophilic polymer is crosslinked and becomes insoluble in water. As a result, it is possible to prevent the hydrophilic polymer from eluting into a body fluid such as blood.
Since the polyhydric alcohol in the coating solution can be removed by washing before using the hollow fiber membrane-type medical device, it can be prevented from being eluted into the body fluid.

Irradiation sterilization refers to sterilizing an object by irradiating the object to be sterilized with radiation such as an electron beam or γ-ray.
In particular, electron beam sterilization is preferable because it has high energy and sterilization is completed in a short time.
The irradiation dose for sterilization is preferably 10 to 50 kGy, more preferably 20 to 35 kGy.

When sterilizing by irradiation with gamma rays, wrap the hollow fiber membrane type medical device in an oxygen-impermeable sterilization bag together with an oxygen absorbent and absorb the oxygen in the sterilizing atmosphere of the sterilized product before sterilizing. However, it is preferable for preventing breakage of the polymer chain and reducing the amount of eluate.
In the case of sterilization by irradiation with an electron beam, the sterilization atmosphere of the object to be sterilized may be air, but it is more preferable to sterilize after absorbing oxygen in order to reduce the eluate.
The oxygen scavenger is not limited as long as it has a oxygen scavenging function. For example, sulfite, bisulfite, dithionite, hydroquinone, catechol, resorcin, pyrogallol, gallic acid, longalit, ascorbic acid and / or its salts, sorbose, glucose, lignin, dibutylhydroxytoluene, dibutylhydroxyanisole, Examples thereof include oxygen scavengers using metal powders such as ferrous salts and iron powders as oxygen absorbing main agents.
In addition, oxygen scavengers for metal powders are used as an oxidation catalyst, if necessary, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium bromide, odor. One or two kinds of metal halides such as potassium iodide, magnesium bromide, calcium bromide, iron bromide, nickel bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, iron iodide, etc. The above may be added.
Moreover, adding a deodorant, a deodorant, and another functional filler is not restrict | limited at all.
Furthermore, the shape of the oxygen scavenger is not particularly limited, and may be any of powder, granule, lump, sheet, and the like, and a sheet or film in which various oxygen absorbent compositions are dispersed in a thermoplastic resin. It may be an oxygen scavenger.

The oxygen-impermeable sterilization bag is a sterilization bag that prevents the permeation of microorganisms and substantially prevents the permeation of oxygen.
Commercially available films for sterilization bags can be used, and laminated films for radiation sterilization can be used.
Oxygen permeation is also substantially blocked when the oxygen permeability at 23 ° C./50% RH is preferably 20 cc / m ² · day · atm or less, more preferably ^2.5 cc / m ² · day · atm. Or less, more preferably 1 cc / m ² · day · atm or less.
Since it is preferable that oxygen does not permeate, the lower limit of the oxygen permeation rate is zero.
As the material of the oxygen-impermeable sterilization bag, a bag advantageous in terms of storage and cost is preferable. For example, a polyvinylidene chloride film, a polyvinyl alcohol film, a biaxially stretched polyvinyl alcohol film, a polyvinylidene chloride coat 2 A film having an easy-to-seal property such as an axially stretched polyvinyl alcohol film, a polyester / aluminum / polyethylene laminate sheet, or an aluminum foil is preferred.
Among these, a polyester / aluminum / polyethylene laminate sheet, that is, an outer layer of polyester, an intermediate layer of aluminum foil or aluminum vapor deposition, and an inner layer of polyethylene laminate sheet are more preferable.

[Hollow fiber membrane medical device]
By performing the leak test method of the present embodiment, for example, a configuration as shown in FIG. 1, that is, a bundle of hollow fiber membranes is loaded along the longitudinal direction of a predetermined cylindrical container, and the inside of the hollow fiber membranes Both ends of the bundle of hollow fiber membranes are embedded with resin and fixed to both ends of the cylindrical container so that the outer and outer sides are separated from each other, and the end surface of the resin has a nozzle serving as a fluid inlet / outlet port It is a hollow fiber membrane type medical device provided with a header and provided with at least one port serving as a fluid inlet / outlet on the side surface of the cylindrical container, and has been applied in a leak test that has been conventionally performed. Thus, a hollow fiber membrane type medical device that exhibits excellent permselectivity in the medical field without any fear of performance change due to the dry treatment can be obtained.

Hereinafter, although a specific Example and a comparative example with this are given and demonstrated, this invention is not limited to a following example.
First, various measurement methods used in Examples will be described.

[Leak test method for measuring gas permeability]
Using a Cosmo leak tester (COSMO AIR LEAK TESTER LS-1842, manufactured by Cosmo Keiki Co., Ltd.), pressure was applied to the inside of the hollow fiber membrane at 250 kPa, the pipe was closed after 2.5 seconds, and the subsequent 3.5 seconds. The pressure fluctuation (drop) inside the hollow fiber membrane was measured. The measurement environment temperature was 25 ° C.
If the pressure drop was less than 580 Pa, the hollow fiber membrane had no pinholes.
This criterion is an experimental value obtained while confirming whether hemoglobin in blood leaks or does not leak in the hollow fiber membranes used in the following examples and comparative examples.

[Evaluation method for elution amount of polyvinylpyrrolidone (hereinafter PVP)]
Inside the hollow fiber membrane of the hollow fiber membrane type medical device, 500 mL of distilled water for injection is flowed at a flow rate of 100 mL / min, and then the outlet side is closed, and 500 mL of distilled water for injection at the same flow rate is outer surface of the hollow fiber membrane. The ultrafiltered side was washed, and then the distilled water for injection in the module (hollow fiber membrane medical device) was discharged with pressurized air.
Next, 300 mL of distilled water for injection heated to 70 ° C. was circulated for 1 hour at a flow rate of 200 mL / min inside the hollow fiber membrane. After the circulation, all distilled water for injection in the module was recovered, and this was extracted. It was.
The PVP concentration of the extract was determined by liquid chromatography (RID-6A manufactured by Shimadzu) and column (manufactured by GF-710HQ Shodex), and converted to the amount of PVP eluted per module.

[Example 1]
A uniform spinning solution comprising 17 parts by mass of polysulfone (Solvay Advanced Polymers, P-1700), 4 parts by mass of polyvinylpyrrolidone (BASF, K-85) and 79 parts by mass of dimethylacetamide (hereinafter referred to as DMAC) Produced.
A 42% aqueous solution of DMAC was used as the hollow inner solution, and was discharged from the spinneret together with the spinning stock solution.
At that time, the discharge amounts of the spinning solution and the hollow inner solution were adjusted so that the film thickness after drying was adjusted to 35 μm and the inner diameter was adjusted to 185 μm.
The discharged stock solution for spinning is immersed in a 60 ° C. coagulation bath made of water provided below 50 cm, passed through the coagulation step and the water washing step at a speed of 30 m / min, introduced into a dryer, and dried at 160 ° C. The crimped polysulfone-based hollow fiber membrane was wound up.
Next, a bundle of 10,000 wound hollow fiber membranes is loaded into a plastic cylindrical container designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ^2, and both ends thereof are urethane resin Then, both ends were cut to form an open end of the hollow fiber membrane.
From the opening end, 0.1 w / w% polyvinylpyrrolidone (BASF, K-85) is dissolved in a 63 w / w% glycerin (special grade, manufactured by Wako Pure Chemical Industries) solution as a coating solution. 60 mL of the solution was injected into the hollow fiber membrane at a speed of 5 mm / s, flushed with 0.3 MPa air for 10 seconds, and then header caps were attached to both ends.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was determined by the leak test method for measuring the gas permeability of the module (hollow fiber membrane medical device) described above.
As a result of the measurement, the pressure drop was 475 ± 12 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
After plugging the nozzle on the liquid inflow / outflow side, wrapping with oxygen absorbent in an oxygen-impermeable sterilization bag, and performing an irradiation sterilization step of irradiating 20 kGy of γ-ray, a hollow fiber membrane type with an effective membrane area of 1.5 m ² A medical tool was obtained.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP. The amount of PVP elution was 0.48 mg, which was found to be sufficiently small for practical use.

[Example 2]
As the coating solution, a solution in which 0.01 w / w% polyvinylpyrrolidone (manufactured by BASF, K-85) was dissolved in a 63 w / w% glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) solution was used.
Other conditions were the same as in Example 1, and a hollow fiber membrane type medical device was produced.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 505 ± 17 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP. The PVP elution amount was 0.44 mg, which was found to be sufficiently small for practical use.

Example 3
As a coating solution, a solution in which 1.0 w / w% polyvinyl pyrrolidone (BASF Corp., K-85) was dissolved in a 63 w / w% glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) solution was used.
Other conditions were the same as in Example 1 to produce a hollow fiber membrane type medical device.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 455 ± 7 (standard deviation) Pa, and the number of hollow fiber membrane type medical devices judged to have pinholes was 0 out of 50.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP. The elution amount of PVP was 4.28 mg.

Example 4
As a coating solution, a solution in which 0.1 w / w% polyvinyl pyrrolidone (BASF K-85) was dissolved in 40 w / w% glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was used.
Other conditions were the same as in Example 1, and a hollow fiber membrane type medical device was produced.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 490 ± 15 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP. The PVP elution amount was 0.52 mg, which was found to be sufficiently small for practical use.

Example 5
As a coating solution, a solution obtained by dissolving 0.1 w / w% of polyvinylpyrrolidone (manufactured by BASF, K-85) in a 75 w / w% aqueous solution of glycerin (special grade manufactured by Wako Pure Chemical Industries, Ltd.) was used.
Other conditions were the same as in Example 1 to produce a hollow fiber membrane type medical device.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 462 ± 10 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP. The amount of PVP elution was 0.45 mg, which was found to be sufficiently small for practical use.

Example 6
In the irradiation sterilization process, a hollow fiber membrane type medical device was packaged without putting an oxygen absorbing material in the sterilization bag, and an electron beam was irradiated with 35 kGy.
Other conditions were the same as in Example 1, and a hollow fiber membrane type medical device was produced.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 482 ± 13 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
About the hollow fiber membrane type medical device after irradiation sterilization, the elution amount of PVP was measured according to the evaluation method of the elution amount of PVP.
The amount of PVP elution was 1.53 mg, which was found to be sufficiently small for practical use.

[Comparative Example 1]
As the coating solution, a 63 w / w% aqueous solution of glycerin (special grade manufactured by Wako Pure Chemical Industries, Ltd.) was used.
Other conditions were the same as in Example 1, and a hollow fiber membrane type medical device was produced.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 550 ± 25 (standard deviation) Pa, and 4 out of 50 were judged to have pinholes.

[Comparative Example 2]
The irradiation sterilization process was not performed.
Other conditions were the same as in Example 1, and a hollow fiber membrane type medical device was produced.
Fifty of these were prepared, and the pressure fluctuation for 3.5 seconds was obtained by the leak test method described above.
As a result of the measurement, the pressure drop was 473 ± 13 (standard deviation) Pa, and there was no hollow fiber membrane type medical device judged to have a pinhole.
About the hollow fiber membrane type medical device after the leak test, the elution amount of PVP was measured according to the evaluation method of the PVP elution amount. The amount of PVP elution was as large as 11.4 mg.

  The leak test method for a hollow fiber membrane medical device of the present invention has industrial applicability as a manufacturing technology for a hollow fiber membrane medical device.

DESCRIPTION OF SYMBOLS 1 Hollow fiber membrane type medical device 2, 2 'Header 3 Hollow fiber membrane bundle 4, 5 Nozzle 6, 7 Port 8 Resin 9 Cylindrical container 10 First space 11 Second space

Claims (9)

A leak test method for a hollow fiber membrane type medical device comprising a hollow fiber membrane having selective permeability,
Coating the hollow fiber membrane with a coating solution containing a radiation-crosslinking hydrophilic polymer and a polyhydric alcohol;
A leak test step for measuring gas permeability of the hollow fiber membrane;
An irradiation sterilization step of irradiating the hollow fiber membrane with radiation;
A leak test method for a hollow fiber membrane type medical device.   The leak test method for a hollow fiber membrane type medical device according to claim 1, wherein the polyhydric alcohol is glycerin.   The leak test method for a hollow fiber membrane type medical device according to claim 1 or 2, wherein the concentration of the polyhydric alcohol in the coating solution is 40 to 75 mass%.   The leak test method for a hollow fiber membrane type medical device according to any one of claims 1 to 3, wherein the radiation-crosslinking hydrophilic polymer is polyvinylpyrrolidone.   The hollow fiber membrane medical device according to any one of claims 1 to 4, wherein the concentration of the radiation-crosslinkable hydrophilic polymer in the coating solution is 0.01 mass% or more and less than 1.0 mass%. Leak test method.   The leak test method for a hollow fiber membrane type medical device according to any one of claims 1 to 5, wherein the irradiation sterilization is performed by irradiating γ rays or electron beams. In the irradiation sterilization step,
The leak test method for a hollow fiber membrane type medical device according to any one of claims 1 to 6, wherein the hollow fiber membrane type medical device is packaged in an oxygen-impermeable sterilization bag together with an oxygen absorbent and sterilized by irradiation. . The permselective hollow fiber membrane is
The leak test method for a hollow fiber membrane type medical device according to any one of claims 1 to 7, comprising a hydrophobic polymer and a hydrophilic polymer.   A hollow fiber membrane type medical device subjected to a leak test by the leak test method according to any one of claims 1 to 8.

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