JP2000229123A - Medical instrument - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the water resistance of a polymer, remove leukocytes and viruses from blood and blood preparations and realize safe use by providing a cationic agent whose counter ion is an alkyl sulfonate ion or an alkyl sulfate ion. SOLUTION: A cationic agent whose counter ion is an alkyl sulfonate ion or an alkyl sulfate ion is provided in an immobilized state on the surface of a medical instrument such as a leukocyte removing filter to remove nosogenetic substances such as leukocytes, viruses or the like, a virus removing filter, a blood bag, an indwelling needle, a catheter, a stent, a tube connector, an effluent bag, an endoscope cover or a blood circuit. Preferably, the alkyl sulfonate ions are methane sulfonate ions, the alkyl sulfate ions are methyl sulfate ions and the cationic agent should contain a quaternary amino group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device for removing pathogenic substances such as leukocytes and viruses from blood and blood products. More specifically, such as a leukocyte removal filter, a virus removal filter or a blood bag, in which a polymer having a quaternary amineno group having an alkylsulfonate ion or an alkylsulfate ion as a counter ion is fixed on the surface of a medical device by coating or the like. Related to medical equipment

[0002]

2. Description of the Related Art Various treatments have been conventionally performed on the surface of a medical device, but a medical device that removes and adsorbs specific components such as leukocytes and viruses from blood such as a blood filter and an adsorbent. In such a method, cationization of a material surface is performed to exhibit an adsorption / removal function.
As a specific example, US Pat. No. 3,420,033 and US Pat. No. 3,352,424 show a method of removing platelets by treating a filter material with a cationic material. Also, JP-A-10-817
No. 17 shows a method of applying a similar cationic material to a medical device to prevent bacterial infection.

[0003] In order to easily and inexpensively perform the surface modification of these treatments, coatings without ionic or covalent bonds have been performed. Especially in the cationization of the material surface,
Coating of a cationic polymer or the like has been mainly performed. Particularly in the case of a quaternary ammonium salt among cationic polymers, the counter ion of the polymer is Cl, Br
And the like. Originally, a quaternary ammonium salt is easily soluble in water, and when these halogen ions are used as counter ions, the molecule has high water solubility and is easily soluble in water.

[0004] As another means, an operation of chemically introducing a crosslinkable functional group into a coating agent or the like and performing thermal denaturation after coating or the like has been performed. The heat denaturation operation after coating not only increases the number of operation steps, but also causes problems such as coloring of the cationizing agent. Particularly in medical materials, denaturation such as coloring must be avoided as much as possible, which has been a problem. Further, when a cross-linking agent or the like is introduced into the polymer, there is a problem that attention must be paid to the storage stability of the polymer.

In methods other than coating, JP-A-10-8
There is a method of graft-polymerizing a cationic polymer to a polymer serving as a base material as exemplified in No. 1717, but these methods are complicated and difficult to say.

[0006]

As described above, when coating a medical device with a cationic polymer or the like as described above, the conventional method that has been performed to prevent the elution of the polymer requires complicated treatment, There was a risk that the polymer was denatured and colored by the treatment.

Therefore, an object of the present invention is to solve the above-mentioned problems, improve the water resistance of the polymer by improving the counter ion, and provide a simple and safe medical treatment with little effect on blood. To provide tools.

[0008]

Investigations have been made to solve the above-mentioned problems, and it has been found that the present invention can be achieved as follows.

[0009] (1) A medical device characterized in that a cationizing agent having an alkylsulfonate ion or an alkylsulfate ion as a counter ion is fixed on the surface.

(2) The medical device according to (1), wherein the alkylsulfonic acid ion is methanesulfonic acid ion.

(3) The medical device according to (1), wherein the alkyl sulfate ion is a methyl sulfate ion.

(4) The medical device according to (1), wherein the cationizing agent contains a quaternary amino group.

(5) The medical device is a leukocyte removal filter, a virus removal filter, a blood bag, an indwelling needle, a catheter, a stent, a tube connector, a drainage bag, an endoscope cover, or a blood circuit.
-The medical device according to any one of (4).

Is solved.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The base material constituting the leukocyte removal filter or virus removal filter most preferably used in the present invention is a porous body, a flat membrane, a hollow fiber, a nonwoven fabric, a woven fabric,
A knitted fabric or a composite thereof, having a porosity of 75% to 95%
% (More preferably 80 to 95%), and the pore size is 0.1 to 30 μm (more preferably 2 to 20 μm) as measured by a mercury intrusion method.
m) are preferred.

When the porosity is 75% or more, the filtration time is short, and when the porosity is 95% or less, the strength as a filter can be maintained. Further, if the pore size is less than 0.1 μm, clogging is likely to occur during the removal operation, making it difficult to withstand use.
If it exceeds m, the frequency of contact between the filter and white blood cells or viruses in blood or blood products may decrease, and the capture rate may decrease.

In general, it is considered that the leukocyte-removing filter or the virus-removing filter is preferably such that the substrate itself is cationic or the surface thereof is cationic. This is because pathogens such as leukocytes and viruses have a negative charge on their cell surfaces, and if the surface of these blood filters is cationic, they are trapped by them.

The base material constituting these filters is made of natural polymers such as cotton and hemp, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polysulfone, polyethersulfone, poly (meth) acrylate, ethylene Polyvinyl alcohol copolymer, butadiene-a fibrous or sponge-like one made of a synthetic polymer such as a acrylonitrile copolymer or a mixture thereof,
A sponge-like polyurethane porous body is preferred from the viewpoint of processability, blood compatibility and the like.

However, these blood filters typified by polyurethane can have excellent leukocyte removal and virus removal performance due to processability and blood compatibility, but have high hydrophobicity as they are, so that It is difficult to pass through the pores and requires some hydrophilic treatment.

At this time, if the cationization treatment can be performed simultaneously with the hydrophilization treatment, only one operation is required, and the work process is simplified, and the production capacity is improved. Therefore, if the present invention is used, the hydrophilicity can be improved by a simple operation, and at the same time, the leukocyte removal performance can be improved, and an improvement in production capacity is expected. Next, specific examples of the coating agent suitably used in the present invention are shown below.

More specifically, the coating agent suitably used in the present invention is a polymer compound having a quaternary amino group having an alkylsulfonate ion or an alkylsulfate ion as a counter ion.

As the alkylsulfonate ion or alkylsulfate ion as a counter ion, methanesulfonate ion or methylsulfate ion is preferably used because of easy availability and synthesis. It is considered that an acid or an alkyl sulfate ion having more than the number of carbon atoms further increases the hydrophobicity and is excellent in elution resistance.

Examples of such a polymer include a random or block polymer of (meth) acrylic acid and a known monomer polymerizable with (meth) acrylic acid and having a quaternary amine as an ester group. . Such a polymer is known as an antistatic agent, but no attempt has been made to apply it to a blood filter as in the present invention.

By the way, the method described in US Pat. No. 2,732,256 is applied to a method for synthesizing a polymer using such an alkylsulfonate ion as a counter ion.
For example, it can be synthesized by adding a polymerization initiator to a solution of a dialkylamine ester of (meth) acrylic acid and a dialkyl sulfate, and then adding sodium alkylsulfonate.

The polymer having a halogen ion or an alkyl sulfate ion as a counter ion can be derived from a polymer having an alkyl sulfonate ion as a counter ion. That is, a polymer having a halogen ion as a counter ion can be obtained by substituting an alkyl sulfonate ion with a halogen ion using an ion exchange resin. Next, by adding an aqueous solution of sodium alkyl sulfate or potassium alkyl sulfate to the aqueous solution of the substituted polymer, a polymer having an alkyl sulfate ion as a counter ion is obtained.

These polymers are substances having high hydrophilicity, and can impart hydrophilicity at the same time as imparting cationicity (cationization).

The method of fixing (holding) these polymers on a blood filter is only to perform simple operations such as coating, dipping, spraying or spin coating, and then heating and drying at 60 to 100 ° C. . It is more preferable to wash with water after heating and drying to wash out eluted substances.

In addition to the blood filter, these polymers are fixed to the surface of a virus removing membrane, a dialyzer, a blood bag, an indwelling needle, a catheter, a stent, a tube connector, a drainage bag, an endoscope cover, and a blood circuit. It is also preferred.

This is because, when applied to the medical tools and medical instruments described above for the reasons described above, the effect of removing the pathogenic substance is obtained.

[0030]

EXAMPLES Next, the present invention will be described in detail with reference to examples performed on a porous polyurethane material or the like, but the present invention is not limited to only these examples.

Example 1 Polyacrylamide-Poly 2
-(Acryloyloxy) ethyldiethylmethylammonium methylsulfate (Product name: Calgon K 400, Ca
lgon) was repeatedly precipitated and purified three times in tetrahydrofuran.

Next, a polyurethane porous material having an average pore diameter of 5.2 μm and a porosity of 86% (product name: Rubicell, manufactured by Toyo Polymer Co., Ltd.) was ultrasonically washed in hexane for 1 hour. After drying the porous body, a 0.3 wt% Calgon K400 (purified) aqueous solution was prepared and immersed in this. After immersion, remove the porous
Dry for 2 hours at ° C. Thereafter, shower washing at room temperature was performed for 4 hours to remove excess Calgon K400, followed by drying.

The obtained porous membrane is punched to a diameter of 25 mm,
The solution was set in a holder having a liquid inlet / outlet, and a trypan blue aqueous solution adjusted to 0.02 mM (using Trypan Proof manufactured by Merck) was flowed through an approximately 20 ml pump. Thereafter, excess trypan blue was washed by flowing 50 ml of RO water. The stained sample was measured for reflection absorbance at 570 nm using a CS-930 flying spot scanning densitometer manufactured by Shimadzu Corporation to determine the amount of the canionization agent fixed on the surface.

Example 2 Polyacrylamide-Poly 2
-(Acryloyloxy) ethyldiethylmethylammonium methylsulfate (Product name: Calgon K 400, Ca
lgon) was repeatedly precipitated in tetrahydrofuran three times to purify the cationic polymer.

A polyurethane of 0.2 × 10 × 50 mm (product name:
Milactran E380, manufactured by Nippon Milactran Co.)
It was immersed in a 3 wt% Calgon K400 (purified) aqueous solution. After immersion, the porous body was dried at 80 ° C. for 2 hours. Thereafter, the plate was washed with running water for 2 hours to remove excess Calgon K400.

The obtained sheet was added to an aqueous trypan blue solution (adjusted to 0.02 mM) using trypan blue (Merck).
After immersion for a minute and washing with RO water, the cationizing agent on the material surface was measured.

A sample punched to a diameter of 25 mm was set in a holder having a liquid inlet / outlet, and an approximately 20 ml pump of a trypan blue aqueous solution (using Trypan Blue manufactured by Merck) adjusted to 0.02 mM was flown. Thereafter, excess trypan blue was washed by flowing 50 ml of RO water, and the amount of the canthionizing agent fixed on the surface was examined in the same manner as in Example 1.

Comparative Example 1 Polyacrylamide-Poly 2
-(Acryloyloxy) ethyldiethylmethylammonium methylsulfate (Product name: Calgon K 400, Ca
lgon) was repeatedly precipitated and purified three times in tetrahydrofuran. The purified polymer was converted to a 3 wt% aqueous solution, and 5
Amberlite IRA 402BL Cl (manufactured by Organo) filled in a 50 mm x 300 mm chromatographic tube for 0 ml of the aqueous solution
To exchange the counter ion for Cl. Amberlite IRA 402BL Cl was subjected to ion exchange according to a conventional method, and used as Cl type. Thereafter, the precipitate is repeatedly reprecipitated three times in tetrahydrofuran and purified, and the counter ion is Cl.
Calgon K 400, which became an ion, was synthesized.

Next, a polyurethane porous material having an average pore diameter of 5.2 μm and a porosity of 86% (product name: Rubicell, manufactured by Toyo Polymer Co., Ltd.) was ultrasonically washed in hexane for 1 hour. After drying, the porous material was reprecipitated with tetrahydrofuran, and then immersed in a 0.3 wt% Calgon K400 (purified) aqueous solution in which the counter ion was exchanged for Cl. After immersion, it was dried at 80 ° C. for 2 hours. Thereafter, shower washing at room temperature was performed for 4 hours and dried.

Using the obtained porous membrane as a sample, the amount of the canionization agent fixed on the surface of the substrate was examined in the same manner as in Example 1.

Example 3 The polymer obtained by exchanging the counter ion obtained in Comparative Example 1 for Cl ion was converted into a 3 wt% aqueous solution.
A 10 wt% aqueous solution of lauryl sulfate chloride was added dropwise to 0 ml of the aqueous solution. An insoluble polymer in which Cl ions were exchanged for lauryl sulfate ions gradually precipitated. This was recovered by filtration, and Calgon K400 having a counter ion of alkyl sulfate was synthesized.

Next, a polyurethane porous material having an average pore diameter of 5.2 μm and a porosity of 86% (product name: Rubicell, manufactured by Toyo Polymer Co., Ltd.) was ultrasonically washed in hexane for 1 hour. After drying the porous body, the precipitate was reprecipitated with tetrahydrofuran, and the counter ion was exchanged for lauryl sulfate ion.
It was immersed in a 00 aqueous solution. After immersion, it was dried at 80 ° C. for 2 hours. Thereafter, shower washing at room temperature was performed for 4 hours to remove the eluate from the porous body, followed by drying.

The obtained sheet was used as a sample, and Example 1 was used.
The amount of canthionizing agent fixed on the substrate surface was examined in the same manner as in the above.

Comparative Example 2 First, polyacrylamide-
Poly 2- (acryloyloxy) ethyldiethylmethylammonium methylsulfate (Product name: Calgon K 40
0, Calgon) was reprecipitated three times in tetrahydrofuran to purify the cationic polymer.

Polyurethane of 0.2 × 10 × 50 mm (Product name:
Milactran E380, manufactured by Nippon Milactran Co., Ltd.) The sheet was reprecipitated with tetrahydrofuran, followed by the same method as in Comparative Example 1.
It was immersed in a 0.3 wt% Eretat U52 (purified) aqueous solution in which the counter ion was exchanged for Cl. After immersion, the sheet was dried at 80 ° C. for 2 hours. Thereafter, the plate was washed with running water for 2 hours to remove elutes and dried.

The obtained sheet was immersed in a trypan blue aqueous solution adjusted to 0.02 mM (using Trypan Blue manufactured by Merck) for 5 minutes, washed with RO water, and measured for a cationizing agent on the surface of the material.

Table 1 summarizes the above results.

[0048]

[Table 1]

From the above results, a polymer containing a quaternary amino group having an alkyl sulfonate ion or an alkyl sulfate ion as a counter ion is more excellent in counter-eluting property than a polymer having a halogen ion as a counter ion. In other words, it was found that the material was more firmly fixed (held) on the substrate surface.

Next, the leukocyte removal performance was examined.

For the measurement of the leukocyte removal rate and the platelet recovery rate, each leukocyte removal filter was punched out to a size of 25 mm in diameter and mounted in a dedicated module. CPD-added fresh blood collected from healthy volunteers was prepared to prepare a red blood cell concentrate. This was flowed 5 ml at a head of 10 cm to measure the amount of white blood cells and the amount of plasma plate before and after passing through the leukocyte removal filter,
The removal rate and the recovery rate were determined from the following equations.

Leukocyte removal rate (%) = (1− (number of white blood cells after filtration / number of white blood cells before filtration)) × 100 Platelet recovery rate (%) = (number of platelets after filtration / number of platelets before filtration) × 100 The blood count and platelet count were determined using an automatic blood cell counter (SYSMEX E-9000, Toa Medical Electronics Co., Ltd.).

Example 4 Using the filter obtained in Example 1, the leukocyte removal rate and the platelet recovery rate were determined by the methods described above.

Table 2 shows the results.

Comparative Example 3 Using the same filter as used in Comparative Example 1, the leukocyte removal rate and the platelet recovery rate were determined by the above-described methods.

Table 2 shows the results.

[0057]

[Table 2]

[0058]

The medical device of the present invention can remove pathogenic substances such as leukocytes and viruses from blood or blood products because a cationizing agent having an alkyl sulfonate ion or an alkyl sulfate ion as a counter ion is fixed on the surface.

Further, the medical device of the present invention is excellent in elution resistance because a cationizing agent having an alkylsulfonate ion or an alkylsulfate ion as a counter ion is immobilized on the surface.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61M 5/158 A61M 5/14 369Z

Claims (5)

[Claims] 1. A medical device wherein a cationizing agent having an alkylsulfonate ion or an alkylsulfate ion as a counter ion is fixed on the surface. 2. The medical device according to claim 1, wherein the alkyl sulfonate ion is methane sulfonate ion. 3. The medical device according to claim 1, wherein the alkyl sulfate ion is a methyl sulfate ion. 4. The medical device according to claim 1, wherein the cationizing agent contains a quaternary amino group. 5. The medical device according to claim 1, wherein the medical device is a leukocyte removal filter, a virus removal filter, a blood bag, an indwelling needle, a catheter, a stent, a tube connector, a drainage bag, an endoscope cover, or a blood circuit. 2. The medical device according to claim 1.