JPS596062A - Artificial kidney excellent in polypeptide permeability - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a hemodialyzer, particularly a hemodialyzer with a molecular weight of 5.000 to 67.0.
This invention relates to an artificial kidney with excellent polypeptide removal performance between 0.0 and 0.00.

Traditionally, cuprophane membranes have been widely used as artificial kidneys, but some long-term dialysis patients using this type of artificial kidney have complained of bone pain, itching during dialysis, and a feeling of irritation. The cause of this phenomenon is the low permeability of medium-molecular weight substances with a molecular weight of 500 to 5,000.

In order to improve these points, Japanese Patent Application Laid-Open No. 57-59548. Same 5
7-55154, a membrane made of polyether-polycarbonate block copolymer was investigated, and vitamin B12
(molecular weight 1.355) is described to improve the permeability. These membranes especially have a molecular weight of 500 to 5,000.
It is designed to preferentially transmit substances up to 0.0, has the ability to substantially block serum albumin, and has low pressure resistance, so it is not sufficient for practical use. The same applies to JP-A-57-57553, which uses a combination of two or more types of membranes to improve the permeability of so-called medium molecular weight substances.

Japanese Patent Publication No. 57-51805. In 57-5/1806,
A hollow fiber membrane made of a reaction product of a polymer having a carboxyl group and cupro-7 has been described. The attack has been thwarted.

Japanese Patent Publication No. 57-50506. 57-50507. Same 57
-50508 describes an aromatic polysulfone membrane, but No. 50506 has an albumin rejection rate of 90%.
This is high, and there is no mention of protein fractionation at all. The same applies to No. 50508, which has a high inhibition rate of 90% or more for hemoglobin with a molecular weight of 68,000, and does not mention fractionation.

No. 50507 has a low albumin rejection rate of 82 to 85%, but has high water permeability and is unsuitable as an artificial kidney for dialysis.

Japanese Patent Publication No. 54-128983. A polymethyl methacrylate membrane is described in Japanese Patent Publication No. 52-3616, but
A product with a 7μ pumin inhibition rate of 90% or less and low water permeability has not been obtained. In JP-A-57769860, which describes a cyanoethylated cuglophane membrane, the rejection rate of ovalbumin with a molecular weight of 45,000 is 9.
It is as high as 0% or more, and the permeability of polypeptide is insufficient.

The present inventors have conducted research on improving the symptoms of patients with difficult dialysis and have found that, surprisingly, regardless of the membrane material, so-called medium molecular weight substances have specific fractionation performance regarding the permeability of even larger polypeptides. We have also discovered that an artificial kidney using a membrane with water permeability within a specific range is highly effective against difficult dialysis without requiring fluid replacement. That is, in the present invention, the inhibition rate of lysozyme with a molecular weight of 14,000 is 50% or less.2 The inhibition rate of α-chymotrypsin with a molecular weight of 25,000 is 70% or less.1 The inhibition rate of bovine serum albumin with a molecular weight of 6 to 7,000 is 60%. % or more and 90% or less, and the water permeability is 2.0 to 7,5 Mt, /
An artificial kidney consisting of a membrane with performance in the mNHg, 1-hr range.

If such an artificial kidney is used, it will be possible to easily relieve the symptoms of pain, itching, etc. complained of by long-term dialysis patients through 1 to 12 dialysis sessions.
It can relieve bone pain.

The rejection rate here is 1.7 v% of Linsan-2.
- Suisopotassium and 1.77% rinsanssuin-2
- adjusted to pH 7.4 with sodium 0,
Using a 1% protein solution, 20 D''/gi was placed at 67°CVc in an artificial kidney made at 1,0*/
This value was calculated according to the following equation (1) by collecting the permeate obtained at a pressure F of 100 MMHg.

・・・・・・(1) Water permeability means that distilled water at 37°C is allowed to flow at 200 MMHg into an artificial kidney with a membrane area of approximately Measure the amount of permeated water under the pressure of , and calculate the amount of permeated water per unit time and unit membrane area,
The slope of a straight line obtained by plotting the relationship with pressure.

The inhibition rate of lysozyme is 50% or less, preferably 40% or less. If it exceeds 50%, the permeability of medium molecular weight substances evaluated by vitamin Bo2 etc. will be insufficient and the performance as an artificial kidney will be poor.

The inhibition rate of α-chymotrypsin is 70% or less, preferably 60% or less. Above 70%, retinol-binding protein (which is thought to accumulate in the body of long-term dialysis patients)
(molecular weight 21,000) becomes insufficient and does not lead to improvement of difficult dialysis, which is the objective of the present invention.

The inhibition rate of bovine serum albumin is 60% or more and 90% or less, preferably 79% or more and 90% or less.

Conventionally, it has been believed that the loss of serum albumin due to dialysis is a burden on the patient and should be avoided as much as possible, but according to the results of the research conducted by the present inventors, it is possible to remove some of the albumin from the body. However, long-term dialysis patients experience itching, irritation,
It is effective in relieving bone pain. However, excessive removal of fulbumin leads to a low blood protein concentration that cannot be recovered by daily diet, so special treatment such as supplementation with albumin preparations is required, which is a burden on the patient and is costly. It costs a lot. In order to avoid most of these problems, the inhibition rate of serum albumin must be at least 60% or higher.

Water permeability is 2.0” AtHg・nf-hr or more*
7.5” AmHg-rf-hr or less, preferably 4
, OMl/xml1g, rtl, hr or more, 7.0m
// It is necessary that it is less than 1%-vl-hr. 2
．． Under 0LJ, it is difficult to remove the 1 to 2 kg of water that is required to be removed from the patient's body in one dialysis session in the normal dialysis time (4 to 5 hours). In addition, if it is 7.5 or more, the water permeability is too high, and when dialysis is performed using a normal method, water will be rapidly and excessively lost from the patient's body, which may be life-threatening. Therefore, when using an artificial kidney with such high water permeability, it is necessary to perform dialysis while replenishing water (fluid replacement), and special operations and equipment are required for this purpose, making it not versatile.

As shown above, the artificial kidney of the present invention simply consists of molecules 315
．． Not only is the permeability of polypeptides in the range of 000 to 67.000 excellent, but also the molecular weight is 500 to 5.000.
It has sufficiently satisfactory performance in terms of permeability to so-called medium molecular weight substances, lower molecular weight substances, and water permeability. Fully satisfactory permeability here means that the dialysance of urea (molecular weight 60), which is an indicator of low molecular weight substances, is 100"/in or more, and the dialysance of vitamin B12 (molecular weight 60), which is an indicator of medium molecular weight substances, is 100"/in or more.
) has a dialysance of 20 mt/H or more.

The artificial kidney of the present invention can use a membrane as thin as the pressure resistance of the dialysis membrane used, but if it is made thinner than 5μ, it is preferable that the pressure resistance of the membrane is less than the normally required 500ymHg. do not have. Further, when a membrane thicker than 100 μm is used, diffusion resistance to permeability of low-molecular weight substances or medium-molecular weight substances becomes too large, which is not preferable.

Although a flat membrane may be used as the dialysis membrane, a hollow fiber membrane is preferred because it is easy to assemble into an artificial kidney. In the case of hollow fibers, the inner diameter is preferably 50 μm or more and 300 μm or less in a wet state. When using a 50μ pongee, the pressure loss during use is too large, and hemolysis and residual blood are likely to occur. If it is thicker than 300μ, the artificial kidney itself will be too thick and difficult to handle.

As mentioned above, the material of the membrane is not particularly limited.

Examples include films such as cuprophane, regenerated cellulose, hexafluoroester, polyacrylonitrile, and polymethylene. Copolymers containing these polymers as the main component or derivatives of these polymers may be used, but ethylene vinyl alcohol/synonymous copolymers are preferred from the viewpoint of blood compatibility. When used clinically, a strong and transient decrease in white blood cells is often observed when using functional materials, especially ce/thiolose-based membranes.

Ethylene-vinyl alcohol-based copolymers with an ethylene content of 1 to 9 V% are more suitable.

The saponification degree is 80% or higher, which is the most preferable.
Ethylene content 25-50 mo/L/%, saponification i95 mo/
It is 1/1 or more. The ethylene vinyl 7μ copolymer may be a random, block, or graft copolymer, but if the ethylene content is less than 10%, the mechanical properties when wet are insufficient. Also, it is not preferable because it increases the amount of eluate.
If it is more than 0.0 m/l/%, the biocompatibility and permeability will decrease, which is not preferable. Therefore, 10-90 moA/%
Among these, 25 to 50 mo/L'% is preferable. If the degree of saponification is not 80 mo) I/% or more, the mechanical properties during wet conditions will be insufficient, and a degree of saponification of 95 mo) I/% or more is more preferable.

Even if the ethylene vinyl alcohol copolymer is copolymerized with a copolymerizable monomer such as methacrylic acid, vinyl chlorophyte, methyl methacrylate, acrylonitrile, or vinyl pyrrolidone in an amount of 15 mol% or less. It is also common to treat the ethylene vinyl alcohol copolymer with an inorganic cross-linking agent such as a boron compound or an organic cross-linking agent such as diisocyanate or di-aldehyde before or after film formation. It also includes those into which crosslinking has been introduced or those in which the functional hydroxyl group of the vinyl alcohol unit is acetalized with an aldehyde such as formaldehyde, acetaldehyde, butyraldehyde, benzaldehyde, etc. within 30 mo/L'%. The ethylene vinyl alcohol copolymer used in the present invention is measured by measuring the viscosity of a dime-4-sulfoxide solution (3% by weight concentration) v sulfoxide solution (temperature: 30°C) using a B-type viscometer. ]The value obtained from my sister is 1.0~
It is preferable to use a voice within the range of 50 centimeters. If the viscosity is lower than this, that is, if the degree of polymerization is low, the mechanical performance required for the membrane cannot be obtained;
If the viscosity is higher than this, it will be difficult to form a film.

Examples of solvents that can dissolve ethylene vinyl alcohol-based co-N combinations include monohydric alcohols such as methanol and ethanol, and polyhydric alcohols such as ethylene glycol, propylene glycol, and glycerin.

Phenol, metacresol, methylpyrrolidone.

Formic acid and hydrated products thereof are known, but in order to obtain a hemodialysis membrane with a good balance of water permeability and solute permeability, which is the object of the present invention, dimethyl sulfoxide, dimethylacetamide, or a mixture thereof may be used. Preferably, it is used as a solvent. Among these, dimethyl sulfoxide, which exhibits high solubility in ethylene vinyl alcohol, is preferred. When dissolving the ethylene vinyl alcohol copolymer in the above-mentioned solvent, especially dimethyl sulfoxide, the precipitation temperature (after the ethylene vinyl alcohol copolymer is completely dissolved in the solvent, it is gradually cooled and the copolymer is Even if the above-mentioned solvent contains a solvent such as water or methanol, isopropanol or dimethylformamide, or a liquid having good miscibility with the solvent and an inorganic salt within a range of 60°C or less (temperature at which precipitation begins). good.

When the ethylene vinyl alcohol compound is dissolved in the above-mentioned solvent, its concentration is in the range of 5 to 50% by weight, preferably 10 to 35% by weight. Further, the temperature of the polymer solution is 0° to 120°C, preferably 5 to 60°C. If the temperature is higher than this, there is a risk that the polymer may deteriorate, and if the temperature is lower than this, the viscosity of the stock solution is too high, making it difficult to form a film.

An aqueous medium is used as a coagulant for the coagulation bath.

The aqueous medium may be water alone, or a mixture of water with a water-miscible organic solvent, usually the same solvent as the polymer solution, within a range of 70% by weight, or a system in which an inorganic salt such as mirabilite is further dissolved in water. May be used.

When attempting to obtain a membrane having excellent polypeptide permeability and water permeability suitable for dialysis, which is the object of the present invention, from an ethylene vinyl alcohol copolymer, the selection of coagulation conditions is particularly important. Solidification temperature is 0°C or higher and 10°C
It is preferable that the temperature is lower than this, because at lower temperatures, the water permeability is too low and the albumin rejection rate is higher than 90%. Moreover, at higher temperatures, the water permeability becomes too high.

The ratio of the raw solution discharge speed into the coagulation bath ■o and the coagulation bath exit roller speed ■L is also important, and the bath draft (-■L7/v
o) is preferably in the range of 1.5 to 4.0. If it is less than this, the rejection rate of polypeptide will be too high, and if it is more than this, the water permeability will be too high, which is unsuitable.

Moist heat stretching after leaving the coagulation bath is also important in achieving fractionation and water permeability of polypeptide. In order to exhibit the performance of the present invention, it is necessary to stretch 3 to 40% in water at a temperature of 15°C to 75°C. At lower temperatures, the polypeptide rejection rate is too high, and on the contrary, at higher temperatures In this case, the permeability of the membrane itself to substances including low molecular weight substances decreases. Further, if the stretching ratio is lower than this, the rejection rate of bovine serum albumin exceeds 90%, and if it is higher than this, the water permeability becomes too high.

As detailed above, 1. Inhibition rate of bovine serum albumin is 60
% or more-f: 90% or less, α-chymotrypsin inhibition rate 7
0% or less, a lysozyme inhibition rate of 50% or less, and a water permeability of 2.0 to 7.5 hours, 2.0 to 7.5 hours, the artificial kidney has a relaxation rate that is not Long-term dialysis, patients with bone pain, etc.

It has the effect of relieving symptoms such as itchiness and itching through normal dialysis techniques that do not require fluid replacement.

The present invention will be explained below with reference to Examples.

Examples 1-2. Comparative Examples 1 to 6 Using four types of membrane materials: cuprophane, cellulose acetate, polymethyl methacrylate, and ethylene/vinyl alcohol, eight types of artificial kidneys with a hollow fiber internal area of approximately 1.0i were created and applied clinically. .

Table 1 shows the water permeability, polypeptide inhibition rate, and clinical application results of each artificial kidney measured by the method described in the specification.
Shown below. The clinical application results were evaluated by comprehensively evaluating the level of pain relief, irritation, and itching in the bones of patients with difficult dialysis. ++ means 'significant mitigation or elimination.

In the Replacement fluid column, cases where fluid replacement was essential when a predetermined amount of urea was removed were marked as "necessary." The overall ranking was determined by taking into account clinical effectiveness and operability.

As is clear from Table 1, the permeability of polypeptide in Comparative Examples 1 and 2 is good, but the high water permeability requires fluid replacement, which does not meet the purpose of the present invention. Also, comparative example 3
Although it is suitable in terms of water permeability, the inhibition rate of bovine serum albumin was somewhat high, and no significant efficacy was obtained in clinical evaluation. Comparative Example 4 has the lowest α-chymotrypsin inhibition rate and satisfactory lysozyme inhibition rate, but
Bovine serum albumin was not penetrated at all, and in clinical evaluation, it was only slightly effective and fluid replacement was required. Comparative Example 5 had no problem with water permeability, but the overall inhibition rate of polypeptide was too high and had no clinical effect at all. In Comparative Example 6, the water permeability was too high, the polypeptide rejection rate was also high overall, and no clinical effect was observed.

Example 3 An ethylene vinyl alcohol copolymer with an ethylene content of 52 moyv% was heated and dissolved in dimethyl sulfoxide to give a concentration of 2.
Two solutions were obtained. This was discharged through a circular nozzle at 7) 3.5, and dimethyl sulfoxide was cooled to 4.0°C while injecting 9Nz gas into the inside of the nozzle.
It was spun vertically upward into a coagulation bath of 1 weight water-struck solution. Next, the film was stretched 20% in hot water at 55°C, replaced with acetone, dried, and rolled up to a predetermined length. This material was bundled so that the inner diameter membrane area of the hollow fibers was 1.0, and formed into a cylindrical artificial kidney by a known method.

The resulting artificial kidney had an inner diameter of 202μ and an outer diameter of 272μ.

Made of 164 hollow fibers with a membrane thickness of 65μ, the water permeability measured using the method described above is 6.511IAysfJg-n? −
hr *The bovine serum apmin inhibition rate was 82.9%, the α-chymotrypsin inhibition rate was 47.5%, and the +)zozyme inhibition rate was 22.1%. In addition, as a result of applying this artificial kidney to clinical practice, bone pain, phlegm, and itching in patients with difficult dialysis were resolved after two rounds of dialysis, and fluid replacement was not required at all.

Claims (1)

[Claims] ■ Water permeability at 37°C 2.0 to 7.5 Gin-H4,i
・hr. Inhibition rate of bovine serum albumin: 60 to 90%, α-
An artificial kidney comprising a membrane having a blocking rate of chymotrypsin of 70% or less and a lysozyme blocking rate of 50% or less. (2) The artificial kidney according to claim 1, wherein the inhibition rate of the bovine serum albumin is 70 or more and 90% or less, the α-chymotrypsin inhibition rate is 60% or less, and the lysozyme inhibition rate is 40 or less. . (2) The artificial W organ according to claim 1 or 2, wherein the water permeability is 4.0 to 7.0 hours. ■ The film has a thickness of 5 to 100μ and an inner diameter of 5 when wet.
Patent which is a hollow fiber having a diameter of 0 to 300μ - Artificial kidney according to any one of claims 1 to 6 ■ The membrane has an ethylene content of 10 to 90 mol%, a degree of saponification of 80 mol% V% The artificial kidney according to any one of claims 1 to 4, which is a membrane of the above ethylene vinyl alcohol copolymer. (2) The membrane is an ethylene vinyl alcohol copolymer membrane having an ethylene content of 25 to 50 mo/I/% and a degree of saponification of 95 mole % or more, according to any one of claims 1 to 5. artificial kidney. (2) Dissolve the membrane ethylene vinyl alcohol/'-based copolymer in a solvent containing 4-/l/sulfoxide as a main component, adjust the polymer concentration to a solution in the range of 10 to 65% by weight, and dissolve the polymer solution. is discharged into a water-based coagulation bath at 0-10°C with a bath draft of 1.5-4.0, and then in a substantially water-based medium at 15-75°C.
The artificial kidney according to any one of claims 1 to 6, which is a membrane obtained by stretching 40 times.