JP2003010655A - Porous membrane and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a porous membrane reduced in or inhibited from the elution of an endotoxin adsorbent from a porous surface, being highly safe, and stably having an excellent endotoxin adsorptivity and to provide a simple method for producing the porous membrane. SOLUTION: The porous membrane is the one coated with a quaternary ammonium salt in which the four aliphatic alkyl groups are independent of each other, the total of the numbers of carbon atoms of the aliphatic alkyl groups is 22-40, and at least two of the aliphatic alkyl chains have each 10 carbon atoms. The method for producing the porous membrane comprises dissolving the quaternary ammonium salt in which the four aliphatic alkyl groups are independent of each other, the total of the numbers of carbon atoms of the aliphatic alkyl groups is 22-40, and at least two of the aliphatic alkyl chains have each 10 carbon atoms in an organic solvent and bringing a porous membrane into contact with the solution to coat at least a part of the surface of the porous membrane with the ammonium salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a porous membrane used for removing endotoxin from an aqueous liquid, and a filter incorporating the same.

2. Description of the Related Art Endotoxin is a constituent component of the outer membrane of the cytoplasmic membrane of Gram-negative bacteria, and is known to exhibit various physiological activities on the living body. Endotoxin is a lipopolysaccharide (LPS) with a complex structure in which lipid A in the active site, R core polysaccharide and O antigen-specific polysaccharide are bound to each other. It is a substance that exhibits an action, an antitumor action, a decrease in white blood cells and platelets, a bone marrow hemorrhage necrosis, etc. and causes shock of infectious diseases.

[0002] Therefore, it is necessary to avoid the contamination of pharmaceuticals, medical devices, infusions, etc. with endotoxin and the invasion of endotoxin into the living body. If it is mixed in the manufacturing process, it is necessary to surely remove it. is there. In addition, in the case of an infusion solution, endotoxin may be mixed during use, and it is desirable to perform the removal step immediately before the infusion solution enters the living body.

As a method for removing endotoxin,
For example, water used in the manufacturing process of pharmaceuticals, etc. is brought into contact with porous fine particles such as activated carbon or ion exchange resin or water-insoluble fibers and adsorbed on the surface, or water or aqueous solutions, and endotoxin adsorption of aqueous liquids such as infusions. There is a method of adsorbing endotoxin by filtering with a porous membrane having the ability.

In addition, for example, in the method using fine particles or water-insoluble fibers, a method of immobilizing substances such as polymyxin B and polyethyleneimine which are antibiotics, and endotoxin-adsorbing ability such as histidine and chitosan on polystyrene or polypropylene fibers is used. Is being considered. Further, as a method of filtering a porous membrane, it is known that a microporous membrane of polysulfone or polyethersulfone is dipped in an aqueous solution containing a quaternary ammonium salt such as polyamide epichlorohydrin resin and coated. However, since quaternary ammonium salts such as polyamide / epichlorohydrin resin are water-soluble, they are easily eluted. Generally, a durable capacity required as a filter for removing endotoxin is, for example, about 1 liter per one use for infusion, but even if it is used at such a capacity, substances that are toxic to living organisms are of course available. In particular, it is necessary to prevent the elution of the endotoxin-adsorbing substance, even if the substance has low toxicity to the living body.

Further, there is a drawback that heat treatment is required to immobilize a quaternary ammonium salt-containing substance such as polyamide-epichlorohydrin resin on the microporous membrane, which is troublesome and costly. Further, there is a problem of toxicity when immobilizing substances such as quaternary ammonium salts such as polymyxin and polyamide-epichlorohydrin resin are eluted, and further, there is a problem that the endotoxin adsorption capacity is small. In addition, depending on the type of immobilization substance, it can be quite expensive.

[0006]

The problem to be solved by the present invention is to suppress or prevent the elution of the endotoxin adsorbing substance from the porous surface, and to provide a highly safe and stable endotoxin adsorbing ability. The present invention is to provide a porous membrane having the above, and the porous membrane by a simple method.

[0007]

Means for Solving the Problems As a result of intensive studies by the present inventors in order to solve these problems, as a result, a porous membrane coated with a quaternary ammonium salt having a specific long-chain alkyl group was adsorbed on endotoxin. The present invention was found to be stable coating on the surface of the porous membrane, and to stably exhibit excellent endotoxin adsorption ability, even though it is a simple production method such as applying a substance having ability to the porous membrane. It came to completion.

That is, the present invention has four independent aliphatic alkyl groups each having a total number of carbon atoms of 22 to 40, and at least two aliphatic alkyl chains each having 10 carbon atoms. It was found that the above-described porous membrane coated with a water-insoluble quaternary ammonium salt has a stable and high endotoxin adsorption capacity.

The present invention also has four independent aliphatic alkyl groups, each of which has 22 to 20 carbon atoms.
40, quaternary ammonium salt having at least two aliphatic alkyl chains having 10 or more carbon atoms is dissolved in an organic solvent, the solution is brought into contact with a porous membrane, and the solution is dried to remove the porosity. We have found a method for producing a porous membrane, which is characterized by coating at least a part of the surface of the porous material.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION First, the present invention has four independent aliphatic alkyl groups, the total number of carbon atoms in the aliphatic alkyl group is 22 to 40, and at least two aliphatic alkyl chains are included. A porous membrane obtained by coating a quaternary ammonium salt having 10 or more carbon atoms on at least a part of the surface of the porous membrane will be described.

The quaternary ammonium salt used in the present invention has four independent aliphatic alkyl groups, and the total number of carbon atoms in the alkyl group is 22 to 40, preferably 22 to 40.
32 is a quaternary ammonium salt in which at least two aliphatic alkyl chains have 10 or more carbon atoms. Further, it is preferable that two of the aliphatic alkyl groups have the same carbon number and have 10 or more carbon atoms, and further that two of the aliphatic alkyl groups are methyl groups and Two of them are more preferably aliphatic alkyl groups having 10 or more carbon atoms.

Since the quaternary ammonium salt of the present invention is hydrophobic, it is bound to the porous membrane by a hydrophobic binding interaction and is stably retained in the porous membrane without being eluted into infusion solution or water. It

When the total number of carbon atoms of the aliphatic alkyl group of the quaternary ammonium salt is less than 24, the bond between the quaternary ammonium salt and the porous material is weak, and elution from the porous surface occurs, resulting in long-term endotoxin. It becomes difficult to maintain the adsorption capacity. If the total number of carbon atoms of the aliphatic alkyl group of the quaternary ammonium salt is more than 40, the hydrophobicity is too high, and the bond with the endotoxin dissolved in the water contacting the porous membrane is less likely to occur.

As such a quaternary ammonium salt,
Examples thereof include tridecylmethylammonium salt, tritetradecylmethylammonium salt and didodecyldimethylammonium salt. The total number of carbon atoms in the alkyl group is 22
Examples of the quaternary ammonium salt having 40 to 40 and two alkyl groups being methyl groups include didecyldimethylammonium salt and dihexadecyldimethylammonium salt.

From the viewpoint of synthesis and quality control, the above-mentioned aliphatic alkyl group having 10 or more carbon atoms is preferably an alkyl group having the same carbon number, which is easy to control.

The porous membrane used in the present invention will be described. The material of the porous membrane used in the present invention is not particularly limited as long as it has a hydrophobic portion on the membrane surface among the materials for the porous membrane generally used for filtration applications, for example, polyamide. , Polysulfone, cellulose acetate, polyvinylidene fluoride, polycarbonate, polypropylene and the like. The quaternary ammonium salt used in the present invention comprises these porous film-constituting polymers,
Although the hydrophobic portion is bonded, if the hydrophobic bond is weak, the quaternary ammonium salt will be eluted when the porous membrane comes into contact with the aqueous liquid. From this, polyamide-based polymers, polysulfone-based polymers and cellulose-based polymers are preferable as the polymer constituting the porous membrane. These polymers are preferably used because they have a high binding property with the quaternary ammonium salt and are less likely to be eluted. Polyamide-based polymers include nylon 6 and nylon 6,
In addition to aliphatic polyamides such as No. 6, aromatic polyamides, alicyclic polyamides and the like can be mentioned. Examples of the polysulfone-based polymer include polysulfone, polyether sulfone, and polyphenylsulfone. As a cellulosic polymer, cellulose acetate,
Examples include nitrocellulose and ethyl cellulose. Among these, aliphatic polyamide, aromatic polyamide, polysulfone, polyether sulfone, or cellulose acetate polymer is preferable. The pore diameter of the above-mentioned porous material is not particularly limited, but is preferably 0.5 μm or less, more preferably 0.2 to 0.5.
μm.

In the present invention, the amount of the quaternary ammonium salt coating the porous membrane is not particularly limited. However, in order for the porous membrane to sufficiently exhibit endotoxin adsorption ability, it is preferable that it is coated with as much quaternary ammonium salt as possible. Depending on the concentration, it does not increase, and there is a case where the filtration rate of the membrane decreases due to the clogging of the inner pores of the porous membrane. Therefore, the solution concentration of the quaternary ammonium salt applied to the surface of the porous film is preferably 0.01 to 5% by mass, and 0.1 to 3%.
Is more preferable, and the water permeation flux as a porous membrane for removing endotoxin is 7,000 to 1 at this concentration.
2,000 L / m ² · hour · kg · cm ⁻² can be maintained, and endotoxin adsorption capacity can be sufficiently exerted.

The filter incorporating the porous membrane is not particularly limited as long as it is a filter formed by a known technique. For example, in a cartridge made of synthetic resin such as polypropylene or polycarbonate or stainless steel. Examples of the filter include the porous membrane placed on the substrate and integrated by welding. Further, a filter formed by folding the porous membrane into a pleated shape and incorporating it into a housing made of synthetic resin or stainless steel can be given.

Next, a method for producing a porous film coated with the quaternary ammonium salt used in the present invention will be described below.

First, the total number of carbon atoms in the aliphatic alkyl group is 2
2 to 40, and two aliphatic alkyl chains have 10 carbon atoms
The above quaternary ammonium salt is dissolved in an organic solvent.

The organic solvent that dissolves is preferably one that does not damage the porous membrane as much as possible. Examples thereof include alcohol solvents such as methanol, ethanol, isopropyl alcohol, and normal propyl alcohol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone. Among these, alcoholic solvents having a small number of carbon atoms such as methanol, ethanol and isopropyl alcohol are particularly preferable.

At this time, if precipitation of the quaternary ammonium salt occurs, the solution is heated to a temperature above the temperature at which it can be dissolved to bring it into a completely dissolved state. Next, the porous membrane is immersed in this solution. At that time, before the porous membrane is immersed in the solution of the quaternary ammonium salt used in the present invention, if it is previously immersed in the same solvent in which the quaternary ammonium salt is dissolved, Is filled with a solvent, and the solution of the quaternary ammonium salt is easily impregnated inside the porous membrane, which is preferable. Then, the porous membrane is taken out from the quaternary ammonium salt solution, and the solvent is completely evaporated to dryness. The drying may be carried out at room temperature or in a dryer up to a temperature at which the porous membrane is not affected.

The porous membrane of the present invention is mainly used for medical treatment, food industry, and other applications for adsorbing endotoxin which requires the removal of endotoxin from purified water. Ammonium salts are disclosed, for example, in JP-A-11
As described in Japanese Patent Publication No. 164882, it is recognized that it has high biocompatibility and can be used for the above-mentioned applications without problems.

[0024]

EXAMPLES The present invention will be described below with reference to examples, but these are merely examples of representative aspects of the present invention, and the present invention is not limited thereto. Unless otherwise specified, “part” or “%” is in terms of mass.

The details of the test method used in the examples are as follows. 1. Membrane filtration test method-Ultrafiltration test device S manufactured by Sartorius as a water permeation flux filter
M-165-26, distilled water, pressure 98
Water was filtered under conditions of kilopascal (kPa) and temperature of 25 ° C., and the amount of water permeation through the membrane was measured. Filtration measurement time was set to 5 minutes from 5 minutes after the start of filtration.

2. Test method for endotoxin adsorption capacity ~ porous membrane immersion test control standard endotoxin (E. col
i UKT-B strain-derived, manufactured by Wako Pure Chemical Industries, Ltd.) was completely dissolved in water for injection to prepare a 3 EU / ml solution. Further, this solution was diluted 5-fold (0.6 EU / ml), 10-fold (0.3 EU / ml), 15-fold (0.2 EU / ml) with water for injection. 10 ml for each 100 ml of this diluted solution
² porous membrane was immersed. Stir the solution for 2 hours at room temperature,
After that, the porous membrane was taken out. The endotoxin concentration of this solution was measured to measure the endotoxin adsorption ability of the porous membrane. To measure the endotoxin concentration, an endotoxin measurement kit "Limulus HS-J Single Test Wako" (manufactured by Wako Pure Chemical Industries, Ltd.) was used, and the concentration was measured by a gelation time comparison method by a fall test. The measurement result is expressed in three steps, and "+" is positive, and when gelled completely,
“±” is a false positive, and when it gelled slightly, “−” was a negative, indicating that it did not gel.

3. Measurement of endotoxin adsorption capacity-filtration test A cartridge filter was prepared using a porous membrane coated with a quaternary ammonium salt. Next, control standard endotoxin (E, coli UKT-B strain origin, Wako Pure Chemical Industries, Ltd.) was completely dissolved in water for injection, and 3EU was added.
500 ml of / ml solution was made. Next, the infusion tube was connected to a water bottle for injection containing an endotoxin aqueous solution, and a cartridge filter was connected to the end of the tube so that the drop from the water surface in the bottle was 1 m. After the connection, the endotoxin aqueous solution was dropped at a flow rate of 500 ml per hour to filter the inside of the porous membrane. The filtrate was collected and the endotoxin concentration before and after filtration was measured. For the measurement, an endotoxin quantification kit "endospacey" (manufactured by Seikagaku Corporation) was used.

Example 1 Preparation of Quaternary Ammonium Salt-Coated Porous Membrane Three-layer nylon microfiltration (MF) membrane (CUNO, upper mean pore size 0.65 μm) sandwiching a non-woven fabric support.
The lower layer (0.2 μm) was immersed in ethanol for 10 minutes. In addition, 5 parts of distearyldimethylammonium chloride (manufactured by Lion Akzo Co., Ltd., trade name: ARCARD 2HT-75) was dissolved in 370 parts of ethanol to obtain a 1% ethanol solution. Next, a nylon MF membrane immersed in ethanol was immersed in the solution and stirred at room temperature for 1 hour. Then M
The F membrane was taken out of the solution, dried at room temperature for 1 hour, and further dried in a drier at 40 ° C. for 5 hours to obtain a porous membrane A. When the water permeation flux of this porous membrane A was measured,
It was 7,500 L / m ² · hour · kg · cm ⁻² .

Example 2 2.5 parts of distearyldimethylammonium chloride was dissolved in 372.5 parts of ethanol to obtain a 0.5% ethanol solution. Similar to Example 1, the MF membrane that had been immersed in ethanol was immersed in this solution, and the same treatment as in Example 1 was performed to obtain a porous membrane B. The water permeation flux of this porous membrane is 9,000 L / m ^2
-It was hour-kg-cm- ² .

(Example 3) 5 parts of trilauryl monomethylammonium chloride (manufactured by Lion Akzo Co., trade name: Arcade 312-85) was dissolved in 395 parts of ethanol,
A 1% ethanol solution was obtained. As in Example 1, the MF membrane immersed in ethanol was immersed in this solution, and the same treatment as in Example 1 was performed to obtain a porous membrane C. The water permeation flux of this porous membrane is 7,500 L / m ² · hour · kg.
^-It was cm- ² .

Comparative Example 1 1 part of benzyldimethylstearyl ammonium chloride was dissolved in 99 parts of ethanol to prepare 1 part.
% Ethanol solution was obtained. Similar to Example 1, the MF membrane that had been immersed in ethanol was immersed in this solution, and the same treatment as in Example 1 was performed to obtain a porous membrane D. The water permeation flux of this porous membrane is 9,000 L / m ² · hr · kg ·
It was cm ^-2 .

Comparative Example 2 The same nylon MF membrane as that used in Example 1 was immersed in ethanol and stirred for 1 hour at room temperature. Then, the MF membrane was dried in the same manner as in Example 1 to obtain a porous membrane E. The water permeation flux of this porous membrane was measured to be 10,000 L / m ² · hour · kg.
^-It was cm- ² .

(Test Example 1) Measurement of endotoxin adsorption capacity Porous membranes A to C obtained in Examples 1 to 3 and Comparative Examples 1 to 3
Each of the porous membranes D and E obtained in Example 1 was evaluated for endotoxin adsorption capacity by an immersion test, and Table 1
As a result, endotoxin was most adsorbed on the porous A.

[0034]

[Table 1]

(Example 5) Measurement of endotoxin adsorption capacity by filtration test Porous membranes A to C obtained in Examples 1 to 3 and Comparative Examples 1 and 2
When the endotoxin adsorption capacity of each of the porous membranes D and E obtained in 1. was measured by a filtration test, the results shown in Table 2 were obtained.

[0036]

[Table 2]

Example 6 Evaluation Test of Quaternary Ammonium Salt Fixation Porous Membranes A to C obtained in Examples 1 to 3 and Comparative Examples 1 and 2
A cartridge filter was prepared using each of the porous membranes D obtained in. Next, an infusion tube was connected to a 1-liter physiological saline bottle, and a cartridge filter was connected to the tip of the tube so that the difference with the water surface in the bottle was 1 m. After connection, at a flow rate of 500 ml per hour,
The physiological saline was dropped and passed through the porous membrane. The liquid that passed through was collected in a flask, sealed tightly, stirred well, and the state of the liquid was visually confirmed. There was no change in the passing liquid of the porous membranes A to C, and no elution into the passing liquid was observed. On the other hand, the passing liquid of the porous membrane D was considerably foamed, and the quaternary ammonium salt was found to be eluted into the passing liquid.

[0038]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a porous membrane having high safety and a high endotoxin adsorption capacity, particularly an endotoxin adsorption porous membrane and a filter incorporating the same.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) B01D 71/68 B01D 71/68 B01J 20/26 B01J 20/26 H C08J 9/36 CEZ C08J 9/36 CEZ // C08L 101: 00 C08L 101: 00 F Term (reference) 4C077 AA12 BB03 CC06 EE01 KK11 LL02 LL12 MM03 NN14 NN15 PP02 PP13 4D006 GA02 HA72 HA77 HA80 HA95 MA03 MA06 MB14 MC11 MC45 MC54 MC55 MC62 MC78X NA10 NA45 NA60 NA42 PB12 PB12 PB12 PB12 PB12 PB12 PB12 PB12 AA24 AA38 AA70 AA71 AA87 AD13 AF03 CE15 CE35 CE98 DA43 4G066 AC26C AC31C AD06B BA03 CA54 DA07

Claims (8)

[Claims] 1. Water having four independent aliphatic alkyl groups, the total number of carbon atoms of the aliphatic alkyl groups is 22 to 40, and at least two aliphatic alkyl chains have 10 or more carbon atoms. A porous membrane in which at least a part of the surface of the porous membrane is coated with a quaternary ammonium salt which is insoluble in. 2. The porous membrane according to claim 1, wherein two of the aliphatic alkyl groups have the same carbon number and the carbon number is 10 or more. 3. Two of the aliphatic alkyl groups are methyl groups, and two of the aliphatic alkyl groups have 1 carbon atoms.
The porous membrane according to claim 1 or 2, which has 0 or more aliphatic alkyl groups. 4. The porous membrane according to claim 1, wherein the polymer constituting the porous membrane is a polyamide type, a polysulfone type, or a cellulose type. 5. The porous membrane according to any one of claims 1 to 4, which is a porous membrane for adsorbing endotoxin. 6. A filter incorporating the porous membrane according to any one of claims 1 to 5. 7. A water-insoluble first group having four independent aliphatic alkyl groups each having a total number of carbon atoms of 22 to 40, and at least two aliphatic alkyl chains having 10 or more carbon atoms. A method for producing a porous membrane in which a quaternary ammonium salt is dissolved in an organic solvent, the solution is brought into contact with the porous membrane, and the solution is dried and removed to coat at least a part of the porous surface. 8. The production method according to claim 7, wherein the organic solvent is alcohol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, or N-methylpyrrolidone.