JPH0611318B2 - Hemophilic cellulose-based dialysis membrane and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a cellulose-based artificial dialysis membrane having excellent blood affinity, and this membrane is useful as a membrane for artificial kidney and other artificial dialysis membranes.

[Conventional technology]

Certain polymer membranes are widely used in the treatment of patients as artificial kidney membranes, artificial lung membranes, plasmapheresis membranes and the like. The greatest feature of these polymer membranes is their direct contact with the blood of the patient. Since even the currently used medical polymer membranes generate some thrombus upon contact with blood, heparin, which is an anticoagulant, is administered into the blood of a patient during treatment to prevent thrombus formation. However, the use of such an anticoagulant should be avoided in hemorrhagic patients, and if it is repeatedly used over a long period of time, various disorders occur. Furthermore, it has been pointed out that various defense mechanisms of the living body are activated by the contact of blood with the surface of the polymer membrane. When hemodialysis is performed with a polymer membrane made of regenerated cellulose, transient leukopenia and activation of complement components occur. Although the relationship between these phenomena and clinical symptoms or their clinical significance is not clear, it is desired to reduce these phenomena without impairing other excellent performances of the polymer membrane made of regenerated cellulose.

Therefore, attempts have been made to improve the blood affinity of polymer membranes. The two major flows are as follows.
One is a method in which a drug that enhances the affinity of blood, that is, an anticoagulant or an antiplatelet agent is included in a polymer film or adsorbed to the polymer film, and an extremely small amount is gradually released into the blood. The other is a method of imparting blood affinity by improving the physicochemical properties of the surface of the polymer membrane that comes into contact with blood by chemical modification or the like. However, both have advantages and disadvantages.

The former method has problems that the contained drug is exhausted and that it is difficult to use for hemorrhagic patients.
As the latter method, a method of coating various polymers or vitamins on the surface of a polymer film made of regenerated cellulose has been already proposed, but there is a problem that the sterilization method is limited due to the stability of the film. In addition, JP-A-61-81
No. 05 proposes a method of reacting a regenerated cellulose membrane with an isocyanate prepolymer, and JP-A No. 60-118203 proposes a method of chemically bonding a polymer acid via a bridging agent. There are problems such as material stability and complexity of reaction process. Furthermore, JP-A-61-11
No. 3459 proposes a dialysis membrane formed using a modified cellulose such as diethylaminoethyl cellulose.
Improvements in terms of reducing blood coagulation are not sufficient.

[Problems to be solved by the invention]

As described above, there are merits and demerits in the attempt to improve the blood affinity of the polymer membrane made of regenerated cellulose. Therefore, an object of the present invention is to provide a cellulose-based polymer membrane having improved blood affinity without impairing the excellent dialysis performance of the polymer membrane made of regenerated cellulose, and a method for producing the same.

[Means and Actions for Solving Problems]

Hydroxyl groups are present on the surface of the polymer film made of regenerated cellulose. Therefore, it has the downside that the complement component is activated, but on the other hand it has the positive side that it can be used as a scaffold to implant graft chains. That is,
By reacting a graft chain having a functional group capable of reacting with a hydroxyl group, such as a carboxyl group and its derivative, an isocyanate group, or a halogen group at the main chain or chain end with the surface of a polymer membrane made of regenerated cellulose, the graft chain is Planted.

Here, the “graft chain” refers to a molecular chain in which at least one end is chemically bonded to the film surface. The number of functional groups that react with hydroxyl groups is not limited to one, and may be two or three. Further, as a repeating unit of the graft chain, Can be considered as a candidate. The unit of repeating carboxyl-containing groups mentioned last should be contained in a small amount as a copolymer from the viewpoint of antithrombogenicity.

Although many combinations of functional groups and graft chains are possible in this way, the present invention is completed as a result of various studies in consideration of biosafety, biocompatibility, economic efficiency, chemical reactivity and the like. Came to.

That is, in one aspect thereof, the present invention provides a blood-affinity cellulosic dialysis membrane characterized in that a polyethylene glycol biocarboxylic acid or an acid chloride thereof is ester-bonded to a polymer membrane composed of regenerated cellulose.

In another aspect, the present invention provides a polyethylene glycol carboxylic acid by treating a polymer membrane composed of regenerated cellulose with a solution in which a polyethylene glycol carboxylic acid or its acid chloride and an esterification catalyst are dissolved or dispersed in a reaction medium. Provided is a method for producing a blood-affinity cellulosic dialysis membrane, which comprises performing an esterification reaction between an acid or an acid chloride thereof and a membrane surface.

As the polyethylene glycol carboxylic acid used in the present invention, a carboxylic acid represented by the general formula: HO ₂ CCH _2- (OCH ₂ CH ₂ ) n-OCH ₂ CO ₂ H (n = 1 to 150), and general _{expression, HO 2 CCH 2 - (OCH} 2 CH 2) n-oR; include monocarboxylic represented by (n = 1~150 R = CH ₃ or CH ₂ CH _3).

As described above, not only a monocarboxylic acid but also a dicarboxylic acid can be used as the polyethylene glycol carboxylic acid. In the latter case, it is possible to increase the polyethylene glycol carboxylic acid content by condensation or the like before reacting with the hydroxyl groups on the membrane surface. The molecularization may proceed, and the reactivity of esterification may decrease. Further, in the case of dicarboxylic acid, there is a possibility that a loop-shaped graft chain bonded to the surface at two points may be formed, but as will be described later, it is preferable that one end of the graft chain is bonded to the surface, and The monocarboxylic acid of equolcarboxylic acid is more preferably used.

The ester bond to the surface of the polymer film made of regenerated cellulose is carried out by an esterification reaction with a hydroxyl group existing on the film surface, and a well-known low-molecular alcohol and low-molecular carboxylic acid or its acid chloride The reaction can be applied. As treatment conditions, it is preferable to keep the treatment temperature low and the treatment time as short as possible so as not to affect the physical properties of the polymer film made of regenerated cellulose.
These items are also advantageous from the economical aspect, and it is preferable to use an esterification catalyst to promote the esterification.

As an esterification catalyst for promoting the reaction, in the case of carboxylic acid, a sulfuric acid, a mineral acid such as hydrochloric acid, an organic acid such as an aromatic sulfonic acid, a Lewis acid such as boron fluoride ether, pyridine, 4-dimethylaminopyridine, dimethyl An organic base such as aniline, a carbodiimide derivative such as dicyclohexylcarbodiimide, a mixed catalyst of a carbodiimide derivative and 4-dimethylaminopyridine and / or 4-pyrrolidinopyridine, and the like are used. These catalysts may be used alone or in appropriate combination. In the case of an acid halide, in order to remove a by-product halide, pyridine, dimethylaniline, triethylamine, tetramethylurea, magnesium metal, or a remover thereof and 4-dimethylaminopyridine and / or 4-pyrrolidone is used. A mixed catalyst with dinopyridine or the like is used. From the viewpoint of smoothly proceeding the reaction, those soluble in the reaction medium are preferable,
It is appropriately selected depending on the reaction medium used.

The amount of the catalyst used should be appropriately selected depending on the type of the carboxylic acid or its acid chloride, that is, its reactivity, the composition of the reaction system, the form and type of the target polymer membrane, etc. Is good.

As the reaction medium, do not react with the polyethylene glycol carboxylic acid used or its acid chloride,
It is necessary that the esterification catalyst is not deactivated and that the polymer membrane composed of the regenerated cellulose membrane does not undergo a major morphological change. Therefore, as the reaction medium, any solvent that satisfies the above requirements and disperses or dissolves the polyethylene glycol carboxylic acid or its acid chloride and the esterification catalyst is used. From the viewpoint of uniformity and smoothness of reaction, a solvent that dissolves polyethylene glycol carboxylic acid or its acid chloride and an esterification catalyst is preferable. As such a reaction medium, for example, n
-Hexane, n-heptane, cyclohexane, petroleum ether, petroleum benzine, benzene, toluene and other hydrocarbons, acetone, methyl ethyl ketone and other ketones, methyl acetate, ethyl acetate, propyl acetate and other esters, ethyl ether, isopropyl ether , Ethers such as dioxane, and the like. These reaction media can be used alone or as a mixture, and are appropriately selected from the viewpoints of safety to living bodies and removal after reaction.

There are various methods for treating a polymer film made of regenerated cellulose. That is, a method in which a polymer film made of regenerated cellulose is added to a treatment liquid in which polyethylene glycol carboxylic acid or acid chloride and an esterification catalyst are dissolved or dispersed and stirred, and the polymer film is placed in a dipping tank filled with the treatment liquid. A method of dipping, a method of circulating a treatment liquid in a treatment tank filled with a polymer film, and the like can be adopted. further,
A method of assembling a polymer membrane made of regenerated cellulose in a dialyzer or the like and then circulating or filling the treatment liquid at least on the blood circulation side and allowing it to stand can be naturally adopted.

After the completion of the esterification reaction, the polymer membrane made of regenerated cellulose is separated from the treatment liquid, and is omitted if the reaction reagent, esterification catalyst, side reaction product, etc. used in the esterification reaction do not remain in the membrane. Usually, washing is performed to remove them. In this washing operation, the solvent used for the reaction or a solvent such as methyl alcohol or ethyl alcohol that does not cause a large change in the shape of the polymer film made of regenerated cellulose is subjected to immersion extraction or Soxhlet extraction. Finally, the residual solvent is removed by vacuum drying, blast drying or the like.

In the polymer membrane composed of regenerated cellulose whose membrane surface is esterified in this way, the activating effect of the complement component is not impaired without impairing the excellent dialysis performance of the polymer membrane used as shown in the examples. Suppressed. Such an effect is
It is considered that in the present invention, the esterification reaction occurs only on the surface of the polymer film, and the chemical and physical structure inside the film is maintained. Also, the amount grafted on the surface is
It is considered that the amount is sufficient to improve the physicochemical and biochemical properties of the surface, but is small enough not to adversely affect the permeation of water and substances.

The effect of improving the physicochemical and biochemical properties of the membrane surface can also be pointed out for other hemophilicities. That is, in the present invention,
The graft chain is hydrophilic and the adsorption of plasma proteins is suppressed. One rationale for this phenomenon is
Y. Ikada: Advance in Polymer
Science (Advance in Polymer Science), 5th
Vol. 7, 1984, p. 103 et seq., But briefly summarized, on a blood-contacting surface implanted with hydrophilic graft chains, the graft chains, which contain a large amount of water, are the substantial surface of the material. The idea is to prevent protein adsorption to cells and adhesion of cells such as platelets. Therefore, adhesion and activation of platelets, which cause blood coagulation, to the blood contact surface are unlikely to occur, and contact phase activation of coagulation factors is unlikely to occur.
That is, it is considered that thrombus formation is suppressed on the blood contact surface where such protein adsorption is suppressed.

In order to suppress the adsorption of proteins as described above, it is better that one end is bound and the other end is free to move than in the state where the graft chain is bound to the polymer membrane surface at two or more places and the chain movement is suppressed. preferable. This is because the free graft chain shields the substantial surface of the polymer membrane and suppresses protein adsorption. In the case of the hydrophilic graft chain, the effect of increasing the water content is added.

〔Example〕

 Next, the present invention will be described more specifically with reference to Examples.

The measurement items described in the following examples are measured by the following methods.

(1) Water permeation amount A module in which both ends of a bundle of 100 hollow fibers are fixed with an adhesive is made, and after filling the hollow portion with water, one end is closed,
Water is added while applying a pressure of 200 mmHg from the opening, and the amount of water permeation per unit time is measured. The membrane area of the hollow fiber is
Calculate by measuring the inner diameter and the effective length of the module.

(2) Clearance Make a module similar to (1) and use 1000 ppm urea aqueous solution or 100 ppm vitamin B-12 (VB ₁₂ ) aqueous solution instead of water in the dialysate by the same method as (1). The concentration is calculated from the absorbance, and the clearance is calculated from the following formula.

(3) Complement consumption rate If the sample is a hollow fiber, cut it into 2 mm lengths, and if it is a film, cut it into 2.5 x 2.5 mm ² pieces, put them in a polyethylene tube, and dilute them 4 times with GV buffer. Add 200μ of guinea pig complement (Cordis Labo) at 37 ° C
Incubated with stirring for hours. Complement value is determined according to the modified Mayer method (see MM Mayer: Immunochemistry, 2nd edition, page 133, published by CC Thomas, 1961). I asked. That is, 50% hemolysis value of complement (CH50
Value), and the rate of complement consumption (% CH5
0) was calculated.

(4) Protein adsorption amount Bovine serum albumin was radiolabeled with ¹²⁵ I, and the sample was soaked in its aqueous solution (bovine serum albumin concentration 0.3 mg / mml) at 37 ° C for 3 hours, and the non-adsorbed protein was removed by washing. The amount of protein adsorbed was determined by measuring the radioactivity of the protein.

(5) Contact angle Place a small drop of water on the film sample and use a microscope to
The contact angle was measured at 5 ° C.

Example 1 In a flask having a content of 500 ml, 0.25 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 400 in the polyethylene glycol portion, 0.04 g of dimethylaminopyridine and 350 ml of benzene were added, and the mixture was stirred and dissolved at 10 ° C.
Cooled to room temperature, and the cellulose hollow fiber (membrane thickness 11 μm, outer diameter 222 μm, inner diameter 200 μm, length 15 cm, under a nitrogen stream,
100 pieces of average weight 0.0017g) were added, and after passing 10 minutes, 30
After reacting at ℃ for 15 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, 20 pieces each were sampled, and they were first immersed in the benzene used for the reaction, then immersed in methyl alcohol, washed, and further methylated. After being immersed in alcohol overnight, it was dried under reduced pressure at room temperature to obtain a cellulosic dialysis membrane.

Example 2 In the same manner as in Example 1, 1.65 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 980 in the polyethylene glycol portion, 0.40 g of dicyclohexylcarbodiimide and 350 ml of benzene were used for 100 hollow fibers,
Esterification was performed at 15 ° C., 30 minutes, 1 hour, 3 hours, 5 hours, sampled, and post-treated to obtain a cellulose-based dialysis membrane.

Example 3 As in Example 1, 0.23 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 400 in the polyethylene glycol portion was used per 100 hollow fibers, 0.01 g of 4-dimethylaminopyridine, and dicyclohexylcarbodiimide.
0.13g and 350ml of toluene are used at 35 ° C for 15 minutes, 3
Esterification was performed for 0 minutes, 1 hour, 3 hours, and 5 hours, sampling was performed for each, and post-treatment was performed to obtain a cellulose-based dialysis membrane.

Example 4 As in Example 2, with respect to 100 hollow fibers, 0.22 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 400 in the polyethylene glycol portion, 0.02 g of pyrrolidinopyridine, 0.15 g of dicyclohexylcarbodiimide and 350 ml of ethyl acetate. For 5 minutes, 10 minutes, 15 minutes at 30 ℃
Min, 20 min, 30 min, esterification, sampling, and post-treatment to obtain a cellulosic dialysis membrane.

Example 5 In the same manner as in Example 2, 1.65 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 980 polyethylene glycol units per 100 hollow fibers, 0.01 g of 4-dimethylaminopyridine, 0.3 of dicyclohexylcarbodiimide.
Using 9g and toluene 350ml, 15 minutes at 30 ℃, 30
Esterification was performed for 1 minute, 3 hours, 5 hours, sampling was carried out, and post-treatment was carried out to obtain a cellulose-based dialysis membrane.

Example 6 As in Example 1, with respect to 100 hollow fibers, 6.12 g of polyethylene glycol dicarboxylic acid having an average molecular weight of polyethylene glycol of 3700, 4-dimethylaminopyridine 0.02 g, dicyclohexylcarbodiimide 0.1
Use 4g and 350ml of toluene for 15 minutes at 30 ℃, 30
Esterification was performed for 1 minute, 3 hours, 5 hours, sampling was carried out, and post-treatment was carried out to obtain a cellulose-based dialysis membrane.

Example 7 In the same manner as in Example 1, 13.24 g of polyethylene glycol dicarboxylic acid having an average molecular weight of polyethylene glycol of 7800 per 100 hollow fibers, 13.24 g of 4-dimethylaminopyridine, 0.03 g of dicyclohexylcarbodiimide 0.3
Using 8g and toluene 350ml, 15 minutes at 30 ℃, 30
Esterification was performed for 1 minute, 3 hours, 5 hours, sampling was carried out, and post-treatment was carried out to obtain a cellulose-based dialysis membrane.

Example 8 In a beaker having a content of 500 ml, 34.10 g of polyethylene glycol dicarboxylic acid having an average molecular weight of polyethylene glycol of 3700, 0.04 g of 4-dimethylaminopyridine,
2.58 g dicyclohexylcarbodiimide and 300 toluene
Add ml, stir and dissolve, cool to 10 ℃, and add cellulose film (membrane thickness 17μm, 5cm × 10Mcm).
(10 pieces, average weight 0.04 g) 8 sheets were added, the temperature was raised to 30 ° C. after 10 minutes, and the esterification was performed at that temperature for 15 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, and each sampled. Then, they were post-treated in the same manner as described above to obtain a cellulosic dialysis membrane.

Example 9 In the same manner as in Example 8, 9.94 g of polyethylene glycol dicarboxylic acid having an average molecular weight of polyethylene glycol of 3700, 0.09 g of paratoluenesulfonic acid and 300 ml of toluene were used for 4 sheets of the film at 50 ° C. Was esterified, and after 30 minutes, 1 hour, 3 hours, and 5 hours, sampling was performed and post-treatment was performed to obtain a cellulose-based dialysis membrane.

Example 10 In the same manner as in Example 8, 0.45 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 400 of polyethylene glycol portion, 0.004 g of dimethylaminopyridine, 0.26 g of dicyclohexylcarbodiimide and 300 ml of toluene were used per sheet of the above film. Then, after esterification at 50 ° C. for 5 hours, the film was taken out and post-treated to obtain a cellulose-based dialysis membrane.

Example 11 In the same manner as in Example 8, 1.67 g of polyethylene glycol dicarboxylic acid having an average molecular weight of polyethylene glycol of 3700, 57 ml of pyridine, and 43 ml of toluene were used for 1 sheet of the above-mentioned film, and the time ester was applied at 80 ° C. After conversion, the film was taken out and post-treated to obtain a cellulose-based dialysis membrane.

Example 12 As in Example 1, with respect to 100 hollow fibers, 0.27 g of polyethylene glycol dicarboxylic acid chloride having an average molecular weight of polyethylene glycol of 400, dimethylaminopyridine 0.02 g, pyridine 1 ml and toluene 350 were used.
Esterification was performed using 30 ml at 30 ° C. for 10 minutes, 20 minutes, 30 minutes, 1 hour, 3 hours, sampled, and post-treated to obtain a cellulose-based dialysis membrane.

Example 13 In the same manner as in Example 1, 0.63 g of polyethylene glycol dicarboxylic acid chloride having an average molecular weight of polyethylene glycol of 980 with respect to 100 hollow fibers, 0.63 g of dimethylaminopyridine, 0.01 g of pyridine, and 350 ml of toluene.
Esterification was performed using 30 ml at 30 ° C. for 10 minutes, 20 minutes, 30 minutes, 1 hour, 3 hours, sampled, and post-treated to obtain a cellulose-based dialysis membrane.

Example 14 In the same manner as in Example 1, 0.27 g of polyethylene glycol dicarboxylic acid chloride having an average molecular weight of 400 in the polyethylene glycol portion, 100 ml of pyridine, 150 ml of pyridine and 200 ml of toluene were used at 100 ° C. for 10 hollow fibers at 10 ° C. Minutes, 2
Esterification was carried out for 0 minutes, 30 minutes, 1 hour and 3 hours, sampling was carried out and post-treatment was carried out to obtain a cellulose-based dialysis membrane.

Example 15 In the same manner as in Example 1, 0.10 g of methoxydiethyleneglycolcarboxylic acid having an average molecular weight of 106 of polyethylene glycol portion was 100 g of the hollow fibers, 0.01 g of dimethylaminopyridine and 0.13 g of dicyclohexylcarbimide.
And toluene (350 ml) at 35 ° C for 15 minutes, 30
Esterification was performed for 1 minute, 3 hours, 5 hours, sampling was carried out, and post-treatment was carried out to obtain a cellulose-based dialysis membrane.

Example 16 As in Example 1, 0.02 g of ethoxydiethyleneglycolcarboxylic acid having an average molecular weight of polyethyleneglycol of 106, 0.26 g of dicyclohexylcarbodiimide and 350 ml of ethyl acetate were used at 50 ° C. for 100 hollow fibers. 15 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, esterification was performed, and each was sampled and post-treated to obtain a cellulose-based dialysis membrane.

Example 17 As in Example 1, 0.26 g of methoxyethylene glycol carboxylic acid chloride having an average molecular weight of polyethylene glycol of 106 with respect to 100 hollow fibers, 0.26 g of pyrrolidinopyridine 0.05 g, pyridine 2 ml and toluene 350 ml.
At 40 ℃ for 10 minutes, 20 minutes, 30 minutes, 1 hour,
Esterification was carried out for 3 hours, each sampled, and post-treated to obtain a cellulosic dialysis membrane.

Example 18 In the same manner as in Example 1, 0.36 g of ethoxyethylene glycol carboxylic acid chloride having an average molecular weight of 106 in the polyethylene glycol portion was 100% of the hollow fibers, 0.03 g of pyrrolidinopyridine, 2 ml of pyridine and 350 ml of toluene.
At 40 ℃ for 10 minutes, 20 minutes, 30 minutes, 1 hour,
Esterification was carried out for 3 hours, each sampled, and post-treated to obtain a cellulosic dialysis membrane.

Example 19 The complement consumption rate of the cellulosic dialysis membranes obtained in Examples 1 to 18 was measured. The test results are shown in Table 1.

Example 20 The esterification reaction was carried out under the same conditions as in Example 3,
The amount of adsorbed protein was measured for the samples collected at 60, 120, 180, 240 and 300 minutes. The results are shown in Table 2.

Example 21 The esterification reaction was carried out under the same conditions as in Example 10 to give 1
Samples of cellulose film were obtained after reacting for 5, 30, 60, 120, 180, 240 and 300 minutes. The contact angle was measured using this. The results are shown in Table 2.

Example 22 Cellulose hollow fiber (membrane thickness 11 μm, outer diameter 222 μm
m, inner diameter 200 μm, length 30 cm) (around 7,000 pieces)
Was filled in a stainless tube equipped with nozzles at the top and bottom. In addition, the content of polyethylene glycol in the flask having a content of 1,000 ml is 0.44 g of polyethylene glycol dicarboxylic acid having an average molecular weight of 400, dimethylaminopyridine 0.02 g,
Dicyclohexylcarbodiimide 0.26g and toluene 700
ml was added to prepare a treatment solution. This treatment liquid was circulated for 30 minutes by a system in which a tube pump was used to introduce the solution from the lower nozzle into the stainless steel tube, and the effluent from the upper nozzle was returned to the flask. At this time, the stainless tube and the flask were placed in a water bath so that the temperature of the treatment liquid was kept at 35 ° C.

The treated cellulose hollow fiber bundle was immersed in methyl alcohol for one day and then dried under reduced pressure at room temperature to obtain a cellulose-based dialysis membrane.

Table 3 shows the results of measuring the dialysis performance and the complement consumption rate of the esterified hollow fibers and the untreated hollow fibers.

[Effects of the Invention] The present invention has the following remarkable effects.

I. As is clear from Table 2, even when the polyethylene glycol chain is bound, the protein adsorption amount is still as low as 0.2 μg / cm ² or less, and the purpose of inhibiting thrombus formation can be achieved.

B. As shown in Table 2, there is no change in contact angle, the surface of the film is kept hydrophilic, and the physicochemical properties of the film are not changed.

C. As shown in Table 1, activation of complement can be almost completely prevented.

D. Since the temperature of the esterification reaction required for the production is low and the esterification reaction time is short, the physical properties of the cellulose polymer membrane do not change in this respect as well.

E. It is an economical dialysis membrane because it is easy to manufacture.

Claims (2)

[Claims] 1. A blood-affinity cellulosic dialysis membrane comprising a polymer membrane made of regenerated cellulose and polyethylene glycol carboxylic acid or its acid chloride ester-bonded thereto. 2. A polyethylene glycol carboxylic acid or its acid is obtained by treating a polymer membrane made of regenerated cellulose with a solution prepared by dissolving or dispersing polyethylene glycol carboxylic acid or its acid chloride and an esterification catalyst in a reaction medium. A method for producing a blood-affinity cellulosic dialysis membrane, which comprises performing an esterification reaction between chloride and a membrane surface.