JPS6244264A - Polypropylene porous membrane - 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 [Field of Industrial Application] The present invention relates to a polypropylene porous membrane that substantially prevents serum albumin from passing through. More specifically, the present invention relates to a polypropylene porous membrane suitable for artificial dialysis in an artificial kidney.

[Conventional technology]

In recent years, separation technologies using membranes have been developed in a wide range of areas, such as microfiltration, ultrafiltration, and reverse osmosis, and are attracting attention. Application fields include wastewater treatment, food industry, electronic industry, precision industry, etc. The development is particularly remarkable in the medical field, which by its nature requires extremely high performance, precision, and safety. Among the membranes used in the medical field, membranes for blood purification, particularly for artificial dialysis, account for an overwhelmingly large proportion.

Such artificial dialysis membranes still require various performances, but basically serum proteins do not pass through them, but
It must be able to pass through low-molecular or medium-molecular toxic substances with a slightly higher molecular weight such as urea, have appropriate water permeability, and have high strength when wet. on the other hand,
Membrane forms include flat membranes and hollow fiber membranes, and the latter has the advantage of being able to provide a large membrane area within a unit volume. For this reason, hollow fiber membranes are more commonly used than flat membranes.

Cellulose-based hollow fiber membranes are excellent in meeting these requirements, and it is no exaggeration to say that cellulose-based hollow fiber membranes currently account for most of the membranes used for artificial dialysis.

However, in recent years, the drawbacks of such cellulose-based films have been pointed out. It is a problem of activation of complement contained in the blood.

In other words, when performing artificial dialysis using a cellulose membrane,
Symptoms such as a temporary decrease in blood pressure and a temporary decrease in white blood cells have been reported. It has been found that this is caused by the complement contained in the blood reacting with cellulose, which constitutes the membrane, and being activated. Furthermore, the activation reaction with cellulose does not occur only with cellulose, but generally occurs with the polymers that make up the membrane, and although there is more than one pathway for this activation reaction, in any case, the It has also become clear that there is a strong relationship between the properties of the surface and the hydrophilicity, that is, the critical surface tension, and that activation is remarkable in relatively highly hydrophilic polymers with a critical surface tension of 40 to 45 dya/cs or higher.

Under these circumstances, the emergence of a dialysis membrane that does not cause complement activation reactions is awaited. In order to realize such a membrane, it would be sufficient to manufacture a dialysis membrane from a hydrophobic polymer, as can be seen from the above-mentioned circumstances, but such a membrane has not yet been completed.

[Problem that the invention seeks to solve]

In view of the current situation, the present inventors have conducted intensive research and succeeded in producing a porous membrane suitable for artificial dialysis from polypropylene, which is a typical hydrophobic polymer, and have thus arrived at the present invention. In addition to the fact that the porous membrane of the present invention is manufactured from polypropylene, one of its major features is that it has high water permeability. In other words, it can be easily inferred that the porous membrane has relatively large through holes from one side to the other. Conventionally, porous membranes with such large through holes were used for artificial dialysis. Although it was thought that the porous membrane of the present invention was not suitable for use as a membrane, it was surprisingly found that the porous membrane of the present invention satisfies the performance required for an artificial dialysis membrane. Furthermore, as expected, it was confirmed that the membrane of the present invention does not activate complement, and was found to be superior to the cellulose-based membranes that are currently widely used.

[Means for solving problems]

Membranes suitable for artificial dialysis according to the invention have a molecular weight of at least 0.89
0 Preferably made of polypropylene having a density of 0,900P/α1 or more and a melt index of 0.5 to 10, and a water permeability of 5 to 300 d/α.
hr-? F! '-vai, a polypropylene porous membrane having a serum albumin rejection rate of 99.5% or more at Hp, preferably a polypropylene porous membrane having a serum permeability of 2 or a urea clearance of 100 ml/m1n-y1 or more. It is. Furthermore, in terms of morphology, it is most preferable that the porous polypropylene membrane has a hollow fiber membrane shape.

As a method of manufacturing the membrane of the present invention, there is a method of manufacturing a porous membrane by mixing additives such as a plasticizer and a pore-forming agent, molding the mixture, and then removing the additives by an extraction method or the like. However, there is also a method of manufacturing a porous membrane without using any such additives. The porous membrane of the present invention can be obtained by any method, but since the porous membrane is intended for use in blood purification by artificial dialysis, components other than the polymer should be present as little as possible. This is desirable. Judging from this point of view, the former of the above two methods cannot be said to be completely free of residual additives, and the latter method can be said to be more preferable in terms of safety. As a method for manufacturing such a porous membrane,
For example, among the more preferable methods of shining an electron beam onto a homogeneous film, we will mainly discuss the stretching method to make it porous.In this method, polypropylene is heated above its melting point and extruded to form a film. Next, after constant length heat treatment under a temperature condition below the melting point of the polypropylene and above the glass transition point, stretching by 10 to 350% under a temperature condition above the glass transition of the polypropylene and lower than the constant length heat treatment temperature, Next, there is a method E in which a relaxation heat setting of 10 to 40% is carried out under a temperature condition lower than the melting point of the polypropylene and higher than the stretching temperature. In this case, stretching is performed by 2 times as necessary.
It can be done in stages or more. Further, in order to obtain a hollow fiber membrane shape, after extruding using a hollow fiber manufacturing nozzle, it may be subjected to fixed length heat treatment, stretching, and heat setting in the same manner.

However, in order to manufacture the porous membrane of the present invention by the method shown here, the polypropylene used as a raw material must satisfy specific conditions. One of them is density. The density of polypropylene is an indicator of its crystallinity. The process of stretching a melt-molded membrane to make it into a porous membrane is as follows:
The principle is that the crystal layers are separated by stretching.
It is essential that the melt-cast film has sufficient crystallinity. In other words, as will be explained later, what controls the permeability of urea is the proportion occupied by pores, that is, the porosity, and the porosity is determined by the proportion occupied by the crystalline phase, that is, the degree of crystallinity is required to be high. It is. In order for the urea clearance of the porous membrane to be produced to be at least 100 rnl/mlts・i, the density of polypropylene must be at least 0.89
0 P/an” or more, preferably 0.900 J’/
An” or more is required.

Another condition that the raw material polypropylene must satisfy is melt index (hereinafter referred to as MI). M
I is an indicator of the fluidity of polypropylene as well as an indicator of molecular weight. The pores in the porous membrane of the present invention allow urea molecules and water molecules to pass through and move out of the porous membrane, but they need to have the ability to remain in the blood without allowing serum proteins such as albumin and globulin to pass through. , this function is determined by the size of the pores. In other words, for example, albumin, the main component of serum protein, has a molecular weight of approximately 6900.
It is said that the radius of gyration in serum at 0 is approximately 50X, and the pore size of the porous membrane for artificial dialysis must roughly correspond to this. However, according to research conducted by the present inventors, there is an interaction between serum proteins and the porous membrane, so even when serum proteins are substantially blocked, the pore size must not necessarily be 50A or less. Although this is not inevitable, it can be easily inferred that the smaller the size, the higher the blocking function. To further explain the research results of the present inventors, it was found that the size of the pores in the porous membrane produced is closely related to the molecular weight of the raw material polypropylene, and the higher the molecular weight, the smaller the pores. . In other words, it was necessary that the MI be 10 or less. However, on the other hand, if the MI is too low, the flow of the melt will be poor, making melt molding impossible.

Therefore, it was necessary that MI be 0.5 or more and 10 or less.

The porous membrane of the present invention is characterized by extremely high water permeability, and clearly has pores that penetrate from one side of the membrane to the other.

In this respect, it not only has a distinct morphological difference from previous p-cellulose-based membranes, but also can be said to be a new dialysis membrane in which dialysis proceeds through a mechanism different from that of previous cellulose-based membranes when dialyzing blood. In other words, the previous cellulose membrane is a homogeneous membrane, and in blood dialysis, urea molecules are removed from the blood and removed to the dialysate using water molecules bonded to cellulose molecules or free water between cellulose molecules as a diffusion medium. In contrast, in the porous membrane of the present invention, urea molecules move using the water molecules filled in the through holes as a diffusion medium. In such a porous membrane, blood filtration occurs through the above-mentioned through holes, and it was thought that it was unsuitable as a membrane for artificial dialysis due to its excessive water permeability, but when hemodialysis was actually performed, unexpected results occurred. However, due to the interaction between the pores of the porous membrane and blood, especially serum,
It has been confirmed that the material exhibits appropriate permeability to water in serum, and that appropriate water removal occurs. However, if the water permeability is too high, it is natural that excessive water removal will occur, and on the other hand, it is easy to imagine that if the water permeability is too low, the urea permeability will also be low.

After all, it is appropriate that the water permeability is 5 to 300 d/hr.

Polypropylene was selected here because it does not activate complement activity in blood and because it is easy to form small pores with appropriate water permeability and albumin rejection by melt molding, stretching, etc.

The porous membrane of the present invention not only exhibits excellent dialysis performance, but also
It can be said that it is extremely superior in terms of biocompatibility as it does not activate complement in the blood.

Incidentally, various indicators described in the claims and the present specification were obtained by the measurement method described below.

Density: Density gradient tube method MI: Compliant with ASTM D-1238, however, temperature 200°C, load 2.16 kg Water permeability: A membrane with an effective membrane area of 20 cm is used as a module; in the case of a hollow fiber membrane, it is a loop-shaped module), After making the membrane hydrophilic with alcohol, etc., water at 20°C and 50111HJI is supplied from between one side of the membrane (from the hollow interior in the case of a hollow fiber membrane), and the view of the water passing through the hollow fiber membrane wall is observed. measure,
Calculate the water permeability according to the formula below.

Water permeability (11t/hr-m"-smH7) = permeation amount (b) / permeation time (hr) x membrane area (m') x transmembrane pressure differential (txH) serum protein rejection rate: effective membrane area 300 cm” membrane as a module,
From one side of the membrane (from the hollow interior in the case of hollow fiber membranes)
Ethanol was press-injected, circulated for 15 minutes, and then sufficiently replaced with water, and then serum was press-injected from one side of the membrane (from the hollow interior in the case of a hollow fiber membrane) at 37°C and an abdominal pressure difference of 200 mHP, The protein concentration in the serum and permeate is determined by the Bradford method, and the serum protein inhibition rate is calculated according to the following formula.

Rejection rate (%) = 100X (1 - protein concentration in permeate / protein concentration in permeate) Serum permeability: Inject serum in the same way as in the case of serum protein inhibition rate measurement,
The permeation rate at this time is measured, and the serum permeability is calculated according to the following formula.

Serum permeability (mlhr-i・douh/) = permeation amount C/permeation time (hr) x membrane area -) x transmembrane pressure differential (ms + Hp)
Urea clearance: In the same way as in the case of serum protein rejection rate, the membrane was attached to a dialysis machine after ethanol treatment and water replacement, and one side of the membrane (
In the case of hollow fiber membranes, from the hollow interior) 50 per membrane area
While flowing the dialysate at a flow rate of 0 atj/min, a concentration of 0.1% was applied to the other surface of the membrane (in the case of a hollow fiber membrane, to the hollow outside) at a flow rate of 200111/mln per membrane area.
urea aqueous solution. The urea concentration before and after the dialysis treatment is determined by the baladimethylaminobenzaldehyde method, and the urea clearance is calculated using the following formula.

Urea clearance = Activated complement C5a: Quantitated by two-antibody RI method.

〔Example〕

The present invention will be specifically explained below using Examples.

Example 1 Polypropylene with a density of 0,915 and a melt index of 5 was melted at 200°C and a linear velocity of 8c was produced from a slit for film production.
m/win while cooling with extruded air flow 80
It was withdrawn at 0 ml min. Then 100 at 135℃
After heat treatment for a fixed length of seconds, it was stretched by 150% at 30°C and further stretched for 1
Relaxation heat setting was performed at 35° C. so that the total stretching ratio was 100%.

The water permeability of the membrane thus obtained was 15 tul/hr.
.

i ・OH7, serum permeability is 4.1 rd/hr-y
/.III HP, serum protein inhibition rate was 100%, and urea clearance was 140 mj/m1n-1.

In addition, as a result of a complement activation test, the activated complement C5m was 3.5 rsp/rd after 120 minutes, and at the same time, as a control, the value of activated complement C5m was 0.5 rsp/rd.
m is 3.8 m//mA, which indicates that the hollow fiber membrane of the present invention does not activate complement and has excellent biocompatibility.

Comparative Example 1 A porous membrane was obtained in exactly the same manner as in Example 1, except that polypropylene having a density of 0.880 and a melt index of 7 was used.

The membrane has a water permeability of less than 1 d/hr, a serum permeability of less than 0.1 g/hr, mHz, and a urea clearance of less than 10 mj/min-m'', which is not suitable for artificial dialysis. It wasn't suitable.

Example 2 Polypropylene with a density of 0.915 and a melt index of 5 was melted at 195° C. and a linear speed of 8 c was applied from a nozzle for manufacturing hollow fibers.
800 m/min while cooling with extruded air flow.
? It was withdrawn at n/mln. Then 110 at 135℃
After heat treatment for a fixed length of seconds, it was stretched by 120% at 30°C and further stretched for 1
Relaxation heat setting was carried out at 35° C. so that the total stretching ratio was 120%, '1.

The water permeability of the porous i hollow fiber membrane thus obtained was 22
ml/hr -nX -11LHP, serum permeability is 5
．． 0TRV'hr-ml wHp, serum protein inhibition rate is 100%, urea clearance is 140 d/mln
-yj.

Furthermore, as a result of a complement activation test, it was found that activated complement C5m was 3.3 g/yJ after 120 minutes, and at the same time, it was also measured in the case without a membrane as a control.

Comparative Example 2 A porous membrane was obtained in exactly the same manner as in Example 2, except that polypropylene having a density of 0.885 and a melt index of 15 was used.

The water permeability of the membrane is 1 mj/hr-m”・OH/ or less,
Serum transmittance is 0.11 fLl/hr -m' -mH
Below p, urea clearance is 10 M/min -m'
The following conditions were not suitable for artificial dialysis.

Claims (1)

[Claims] 1. Made of polypropylene having a density of at least 0.890 g/cm^3 or more and a melt index of 0.5 to 10, and a water permeability of 5 to 300 ml.
/hr・m^3・mmHg and serum albumin inhibition rate is 9
A polypropylene porous membrane having a content of 9.5% or more. 2. Serum permeability is 2 to 200ml/hr・m^3・m
2. The porous polypropylene membrane according to claim 1, wherein the porous polypropylene membrane has a temperature of mHg. 3. The porous polypropylene membrane according to claim 2, which has a urea clearance of 100 ml/min·m^3 or more. 4. The porous polypropylene membrane according to claim 1, 2 or 3, wherein the porous polypropylene membrane is a hollow fiber membrane.