Dialyzers for blood treatment and processes for production thereof

Dialyzers for the treatment of blood and processes for their production.

The present invention refers to a semipermeable membrane for the treatment of blood that it shows little variation in the realization after drying and reduced elution of a hydrophilic polymer thereof; and a process for the production of a dialyzer that has built-in a semipermeable membrane that undergoes few changes in the realization before and after drying and reduced elution of a hydrophilic polymer of the same.

As a material for a semipermeable membrane for the treatment of blood as in an artificial kidney, it They have used various materials. For example, initially used as a natural material, cellulose and its derivatives, for example, cellulose diacetate and cellulose triacetate, and subsequently synthetic polymers such as the polysulfone, polymethylmethacrylate (PMMA) and polyacrylonitrile. Lately, cellulose membranes have also been used modified, which have been prepared by treating the cellulose with polyethylene glycol (PEG), or similar, to modify its blood compatibility In semipermeable membranes for the treatment of blood in patients suffering from renal failure Chronically, attempts have been made to minimize the albumin loss at the same time that proteins were removed of low molecular weight other than albumin. In addition to these membrane improvements, development processes have been developed hemodifiltration (HDF) and handling or use processes for increase dialysis efficiency and positive elimination of low molecular weight proteins undesirable. Polysulfone, which It has high water permeability, it is widely used in the actuality since it meets the requirements above mentioned. In a polysulfone membrane, it is usually mixed a hydrophilic polymer to transmit an affinity for blood to the membrane However, the polysulfone membrane has a defect since once it dries its properties tend to change in great magnitude Therefore, it is difficult to produce a type of dialyzer Dry polysulfone membrane that is lightweight and easy to drive.

In accordance with the above, we have treated the problem of providing a dialyzer that has a membrane semipermeable of dry or semi-dry type and that presents the advantages of be lightweight and resistant to freezing, where they are improved the water permeability of the semipermeable membrane and the dialysis performance (which is poor in a dialyzer that has a dry or semi-dry membrane) at the same level as a dialyzer with a wet type membrane.

We have also addressed the problem of provide a dialyzer membrane of the dry or semi-dry type that not only presents the above advantages but also exhibits a reduced elution of a hydrophilic polymer thereof.

Surprisingly we find that these advantages they can be achieved thanks to the following respective aspects of the invention.

Therefore, according to an aspect of the In the present invention, a dialyzer is provided for the blood treatment that has a membrane incorporated semipermeable hollow fiber comprising a hydrophobic polymer and a hydrophilic polymer, membrane permeabilization semipermeable after drying at 100 ° C for 24 h is 1/2 or more compared to the one before drying, and the dialyzer satisfies the following requirements:

(A) Vitamin A clearance is not less than 135 ml / min per 1.6 m2; and

(B) the amount of hydrophilic polymer that is elutes from the semipermeable membrane is not more than 10 ppm.

In accordance with another aspect of this invention, a process for producing a dialyzer is provided which incorporates a semipermeable membrane comprising a hydrophobic polymer and a hydrophilic polymer, said process includes:

the production of a semipermeable membrane of hollow fiber from a solution comprising 10 to 20% in weight of a hydrophobic polymer and 2 to 10% by weight of a hydrophilic polymer,

The drying of the semipermeable membrane without the treatment with a moisture retention agent; and

semipermeable dry membrane saturation with a proportion of water not less than 100% according to the dry weight of the semipermeable membrane [ie (water weight alone / dry weight of the semipermeable membrane alone) x 100%], which provides a atmosphere of inert gas inside the dialyzer, and then the irradiation of the semipermeable membrane with gamma rays in atmosphere of inert gas.

In accordance with the embodiments of this invention, a process is provided for the production of a hollow fiber membrane to use as a semipermeable membrane in a dialyzer, for the treatment of blood through a dry / wet circulating system of a spinning solution that comprises 15-18% by weight of a polymer hydrophobic and 4-8% by weight of a polymer hydrophilic, without treatment with a retention agent of moisture in which a dry area is filled with dry steam.

Preferred embodiments of the invention are described below.

In an embodiment on a dialyzer of the present invention, the hydrophobic polymer that can be used in The semipermeable membrane includes a number of plastics of engineering, such as polysulfone, polyamide, polyimide, polyphenyl ether and polyphenylene sulfide. Preferably, the Hydrophobic polymer is the polysulfone represented by the formula from below, which shows the polysulfone skeleton. The polysulfone derivatives in which the benzene ring is modified in the skeleton they are also useful in the realization of a dialyzer of the present invention.

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The hydrophilic polymer that can be used in the semipermeable membrane includes, for example, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose and polyvinyl pyrrolidone, which can be used alone or in combination. Polyvinyl pyrrolidone (referred to herein in forward as "PVP") since its industrial availability is relatively older It is preferable to use two or more polymers hydrophilic having different molecular weights. In this case, hydrophilic polymers preferably have molecular weights different from each other in 5 or more times.

The spinning solution to use for the semipermeable membrane preparation comprises a polymer hydrophobic, a hydrophilic polymer, a solvent and an additive. He solvent can be an amphiphromic solvent that can dissolve completely all the hydrophobic polymer, the hydrophilic polymer and the additive. Specific examples of the solvent include the dimethylacetamide, dimethyl formamide, dimethyl sulfoxide, acetone, acetaldehyde and 2-pyrrolidone additive Dimethylacetamide is particularly preferred since the Safety, stability and toxicity point of view. Additive it can be one that is a poor solvent for the polymer hydrophobic but that is miscible with the hydrophilic polymer, such as alcohol, glycerin, water and an ester. The water is particularly preferred from the point of view of suitability.

The viscosity of the spinning solution for the membrane production may depend on the molecular weight of the hydrophilic polymer, since the available hydrophilic polymers commercially they have low molecular weights. A viscosity Decreased spinning solution could cause breakage or oscillation of the fibers during the preparation of a membrane of hollow fibers, leading to a decrease in the stability of the resulting hollow fiber membrane. According to that, when use PVP as the hydrophilic polymer, PVP with a high molecular weight. When two or more types of PVP are used in a mixture, the PVP mixture has an average weight preferably of 200,000 or higher.

The respective components of the hydrophobic and hydrophilic polymers in the solution of spinning As indicated above, as the polymer content, one more membrane can be formed effectively although the porosity of the resulting membrane decreases, producing less water permeability. According to that, there is an optimal range of polymer content. To get one membrane that can exert both a high perme-selectivity as a permeability goes down to albumin when it dries, just like in the realization of a membrane of the present invention, the concentration of hydrophilic polymer is preferably 12 to 18% by weight, and the Hydrophilic polymer concentration is preferably from 2 to 20% by weight, more preferably 10 to 20% by weight, more preferably from 3 to 15% by weight. In the case of using two or more hydrophilic polymers with different molecular weights, is preferable that the content of hydrophilic polymers with weights molecular values ​​of 100,000 or higher in the spinning solution from 1 to 10% by weight. If the content is excessive, increase the viscosity of the spinning solution, which can cause difficulties in the formation of a membrane, as well as decreases the water permeability and diffusion. On the contrary, if this content is too small, it is impossible to build a desirable network structure for uremic protein permeation medium to high molecular weight toxic.

A process of realization of the invention for semipermeable membrane preparation is described more ahead. A spinning solution having such a composition as mentioned above, along with a core solution, it extrude from a row through a tube with double slit for form a membrane of hollow fibers. The membrane is washed with water, It dries and then shrinks. The shrunk membrane is collected and collected. Cut to an appropriate length. The cut membranes are placed in a module cartridge, in which both sides of the bale of the membranes are sealed with a material that wraps and insulates it. This Thus, a hollow fiber membrane module is produced.

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Preferably, according to an aspect of the process of the invention, the membrane is formed by a process of dry / wet circulation, in which a dry area is filled with steam dry. Dry steam refers to the vapor type material that it comprises aqueous particles of 10 µm or less. The Introduction of dry steam in the dry zone can generate about cores that can play an important role in the process to form an outer surface of the hollow fiber membrane. The PVP can coagulate around the cores to form PVP phases; So the separation takes place in the dry zone. TO then the fully formed PVP phases are extracted of the coagulation bath, generating wider pores. A conventional polysulfone dialysis membrane generally has an asymmetric structure, where the permeation material is controls only through the inner surface. Nevertheless, by providing said pores on the outer surface of the membrane, an external support layer can be formed with a rough porous structure. This structure allows a substance more easily transferred through the membrane by diffusion, facilitating greater permeation in the dialysis membrane finished

According to an aspect related to the process of the invention, for the formation of the hollow fiber membrane (not the "module"), a conventional process includes the treatment of the hollow fiber membrane with a moisture retaining agent but that does not include any drying of the membrane it does not uses and, instead, a process that includes drying is used membrane positive. As a result, a fiber membrane hollow will allow a permeation of water after drying 1/2 or more than that allowed by a membrane before drying. Preferably, it should be equal to or greater than 75%, and more preferably it should be equal to or greater than 90%. Since, in a Embodiment process of the present invention, the membrane is dry without treatment with a moisture retention agent, the spinning solution should be designed taking into account the shrinkage of the dry membrane. When the membrane is used semipermeable in this state, particularly in an artificial kidney, however, a considerable amount of the hydrophilic polymer It can diffuse from the membrane. For the reduction of said elution, the membrane undergoes a crosslinking treatment with gamma ray irradiation. If gamma rays are irradiated in presence of air (for example, oxygen), the Breakage of the hydrophilic polymer skeleton by the action of excited oxygen radicals, resulting in polymer decomposition. To solve this problem, it is it is preferable to saturate the membrane with a proportion of 100% and not greater than 1000%, more preferably 100 to 600%, even more preferably from 100 to 400% according to the dry weight of the membrane, replace atmospheric air with an inert gas and then radiate the membrane with gamma rays. Therefore, it is possible to prevent effectively elution of the hydrophilic polymer from the membrane. As Inert gas is preferably used nitrogen, argon, helium and carbon dioxide. Nitrogen, which is cheaper, is the favorite. The gamma ray exposure dose is preferably from 10 to 50 KGy, more preferably from 10 to 30 KGy. Since the crosslinking treatment induces the bond between the polymer Hydrophobic and hydrophilic, elution of hydrophilic polymer of the membrane can be reduced. The forced elution test of the membrane as described below showed that it was not observed no peak indicating the presence of the polymer Hydrophilic membrane chosen. According to it, it is possible to manufacture a semipermeable membrane that has an amount of elution not greater than 10 ppm. The term "amount of elution" makes reference to the amount of hydrophilic polymer of an extract that it is prepared by dispersion or dissolution in a certain amount of hollow fibers in a solvent for both hydrophobic polymers such as hydrophilic, since both polymers have a solubility not less than 0.5 g / ml and the solvent is not miscible in Water, and then the hydrophilic polymer is extracted from the solution with a certain amount of aqueous phase (chloride solution 0.1N ammonium, pH 9.5) to provide the extract. In the case of that the hydrophilic polymer be a mixture of polysulfone and polyvinyl pyrrolidone, the suitable solvent is preferably the methylene chloride

The semipermeable membrane prepared as it is mentioned above presents the characteristics of being functionally a membrane suitable for the treatment of blood, enough to present a good diffusion capacity of the substances causing uremia and a resistance of albumin diffusion, which is a useful protein, such as having a reduced elution of the hydrophilic polymer due to the structure network formed with hydrophobic and hydrophilic polymers. If the Albumin permeability exceeds 3%, may be affected the physical conditions of patients with hypoalbuminemia or the Nutritional conditions of the elderly. In consecuense, albumin permeability is preferably equal to or less at 3%. The causative substance of uremia or uremic toxin can be urea, creatinine or uric acid. As an indicator of permeation of the substance, that of vitamin B12 can be adopted. In the semipermeable membrane of the present invention, the Vitamin B12 clearance is preferably equal to or greater than 135 ml / min per 1.6 m2. From a practical point of view, the Urea, creatinine and uric acid clearance is preferably equal to or greater than 188, 175 and 165 ml / min per 1.6 m2, respectively.

In order to achieve the mentioned properties above, the content of the hydrophilic polymer in the membrane after cross-linking it is preferably 2 to 6% by weight. Very small content may cause a reduction in capacity water moisturizer and coagulation may occur after contact With the blood It is preferable that the membrane after cross-linking contains insoluble substances at a concentration from 5% to 15% by weight.

As indicated above, a membrane semipermeable for the treatment of the blood of the present invention has a water permeability after drying 1/2 or more in relation to the membrane before drying, and it can be achieved using a stage of drying the membrane in the state in which no moisture retention agent is attached to the membrane and a cross-linking stage of the dry membrane after conditioning to moisture (i.e. saturation with Water). As a result, the membrane can be applied to a dialyzer that has good properties such as reduced permeability of water and less loss of eluted substances from the membrane yet when it is used after drying. The membrane of the The present invention can be used in a semi-dry or dry state (as used here, the term "semi-dry state" makes reference to a state where water is present in the membrane but where the spaces between the hollow fibers are filled with a gas). Accordingly, a membrane can be provided semipermeable with a light weight, almost free from the problem of frozen, easy to use and with excellent performance. The production of such a semipermeable membrane can contribute to reduced cost of dialysis In addition the membrane can present high performance at various temperatures and conditions of sterilization since degradation can occur in the dialysis performance by extreme drying. Moreover, in the application to the treatment of a human body, the elution of the hydrophilic polymer (a foreign substance to the body), thus increasing the safety of the membrane as medical equipment. The dialyzer, according to the present invention, is applied to the medical devices for the treatment of blood, such as a kidney artificial, comprising a plasma separating membrane and a vehicle for adsorption separation from circulation extracorporeal

Specific embodiments of the invention will be will describe in more detail below regarding Following Examples of work. The determination procedures Used are as follows.

(1) Determination of water permeability

A hydraulic pressure of 100 mmHg was applied to the inside each hollow fiber in a glass tube mini-module (comprising 36 hollow fibers, effective length of 10 cm) where both ends of the beam hollow fibers were sealed), and then the Outgoing permeate quantity of mini-module tube per unit of time.

Water permeation was calculated according to The following equation:

UFR (ml / h / m2 / mmHg) = Q_ {W} / PxTxA

Where Qw is the amount of the filtrate (ml); T is the flow time (h); P is the pressure (mmHg); and A is the area of the membrane (m 2) (in terms of internal surface of the hollow fiber).

(2) Determination of change in performance after of drying

When the hollow fiber to analyze is not present no moisture retention agent, the fibers They can be dried under the conditions indicated below. Without However, when a retention agent is present moisture, soak 10 g of hollow fiber in 150 ml of pure water and Leave for 24 hours. This process is repeated twice and then dried in the form of a fiber bundle at 100 ° C for 24 hours. The Water permeability is determined before and after drying.

(3) Determination of solute clearance

This determination is made in accordance with the description of "The Performance Evaluation Criteria for Dialyzers "(The Japanese Society of Artificial Organs, ed., published in September 1982). In this post, they are shown two determination procedures for clearance. In this For example, the clearance is determined according to the value of 0 mmHg for TMP. Among the solutes analyzed, vitamin B12 can decompose by irradiation with light. According to it, it is Preferably determine the clearance of vitamin B12 the same day of sampling, preferably immediately after of sampling. The clearance is determined as the rate of liquid inlet to the QB module of 200 ml / min and the flow rate of water through the dialyzer section of the 500 QD module ml / min, using the equation below. If the areas of the membranes used for this analysis are different, it is possible calculate the global mass transfer coefficient according to the clearance value of each solute and the calculated value can Become in terms of area.

Clearing:

Cl \ (ml / min) = CB_ {i} -CB0 / CB_ {i} \ x \ QB

Where, CBi is the concentration at the entrance of the module; CB0 is the concentration at the module output; and QB is the liquid feed rate in the module (ml / min).

(4) Determination of albumin permeability

Bovine blood (treated with heparin) is used with a hematocrit value of 30% and a total protein content 6.5 g / dl, which has been maintained at a temperature of 37 ° C) in a blood tank Bovine blood is introduced into the hollow fibers through a pump at a speed of 200 ml / min. During this process, the pressure at the output of the module is adjusted to achieve a filtration rate of 20 ml / min per m2 of area of the module (which is equivalent to 32 ml / min per 1.6 m2), and the filtered and blood from the outlet are reintroduced to the tank of blood. After an hour of having started the reflux, it is taken a sample of the blood at the entrance and exit of the module and the filtered out. Blood samples are centrifuged to separate the serum. The serum is analyzed using BCG equipment (green bromocresol) from A / G B-Test Wako (one brand patented, Wako Pure Chemical Industries, Ltd.), and the albumin permeability (%) of individual samples at from serum concentrations. For the determination of the concentration of albumin in the filtrate at high sensitivity, a calibration curve is established for albumin a low concentrations making the relevant dilutions of the serum albumin included in the equipment.

Permeability \ a \ la \ albumin \ (%) = 2 \ x \ C_ {F} / (CB_ {i} \ + \ CB_ {0}) \ x \ 100

Where, CF, CB and C0 are the concentrations of albumin in the filtrate, at the module input and at the output of the module, respectively.

(5) Determination of the concentration of a polymer Hydrophilic PVP transferred to an aqueous layer in the elution test forced

A liter of pure water was passed through the dialyzer module from the blood side to the dialyzer side to wash the module. 1 g of hollow fiber from the module was dissolved in 10 ml of methylene chloride (10% w / v). The solution was extracted with 10 ml of 0.1N ammonium chloride solution (pH 9.5), and the solution resulting aqueous methylene chloride was centrifuged at high speed (20,000 rpm x 15 min). The aqueous layer was passed through a filter (pore size: 0.5 µm) until a solution is obtained of the sample.

The analysis of the sample solution is performed at 23 ° C using two Tos columns TSK-gel-GMPWXL connected in series with a theoretical number of stages (8,900 x 2) in the conditions following: mobile phase - 0.1N ammonium chloride solution (pH 9.5); flow rate-1.0 ml / min; load of the sample-0.2 ml. Nine products of monodisperse polyethylene glycol as standard material for molecular weight calibration and a curve of concentration-area calibration for a given PVP product. The concentration of PVP transferred in the aqueous layer (5 ml) is determined from the area of ​​the PVP peak of each solution of the sample. Samples containing a detectable amount of PVP were determined according to the PVP recovery (i.e. the rate of transfer in the aqueous layer) of the reference, and the amount of PVP eluted in the aqueous layer was calculated from the concentration of PVP in the aqueous layer from its recovery.

(6) Determination of PVP content by analysis elementary

Sample irradiated with gamma rays at temperature ordinary with a vacuum pump. 10 mg of the sample was analyzed dry with a CHN elemental analyzer. PVP content was calculated from the nitrogen content.

(7) Determination of material content insoluble

10 g of a fiber irradiated with gamma rays in 100 ml of dimethylformamide. The solution is centrifuged at 1500 rpm for 10 min to separate materials insoluble, and the supernatant was discarded. This process was repeated. three times. The insoluble material was washed with 100 ml of pure water and It was then centrifuged three times as mentioned above. The resulting solid material was evaporated to dryness and then It was dried with a vacuum pump. The weight of the dry solid material is used to calculate the content of insoluble material.

Example 1

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts polysulfone (Amoco, Udel-P1700), 4 parts polyvinyl pyrrolidone (International Special Products, referred to hereinafter as "ISP"; K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90) are dissolved in 77 parts of dimethylacetamide and 1 part of water with heat, until a spinning solution is obtained for the formation of the membrane

The viscosity of the spinning solution was 13.4 Pa.s at 50 ° C. The spinning solution was introduced in a row at 50 ° C and extruded, along with a core solution that It comprises 65 parts of dimethylacetamide and 35 parts of water, from the row through a tube with double annular slit with a diameter outer 0.35 mm and an internal diameter of 0.25 mm, so formed a membrane of hollow fibers. The membrane was subjected to conditioning to humidity at 30 ° C and a dew point of 28 ° C The conditioned membrane was passed through an atmosphere of dry area that was 250 mm long and contained particles of dry steam of size equal to or less than 10 µm, then at through a coagulation bath at 40 ° C comprising 20% ​​by weight of dimethylacetamide and 80% by weight of water. The resulting membrane is subjected to a water wash stage at 80 ° C for 60 seconds, a drying process at 135 ° C for 2 min and then at a stage of shrinkage at 160 ° C. The resulting membrane was adjusted in a beam. The bundle of hollow fiber membranes was packaged in a cartridge modules so that the hollow fiber membrane area was 1.6 m2 and was isolated with a coating. The beam thus isolated is provided with open faces at both ends to form a dialyzer module Consequently, the blood side was filled with tempered water (37 ° C) degassed at a filling rate of 200 ml / min for 1 min and then an inert gas was introduced (nitrogen) to the module at a pressure of 0.1 MPa for 15 seconds to expel the filling water. By this procedure, the side of the dialyzer was also replaced with inert gas. In this state, the water content in the hollow fiber membrane was 320%

The module was irradiated with gamma rays (25KGy) in a state where the membrane was wet and the module had filled with inert gas. The permeation was then determined of water, the clearance of each solute and the permeability of the albumin. As a result, it was shown that the module had a clearance of urea, creatinine, uric acid, phosphoric acid and VB12 195 ml / min, 185 ml / min, 186 ml / min and 145 ml / min, respectively, a permeation of water of 756 ml / h / m2 / mmHg and an albumin permeability of 1.5%. After drying, the Water content in the membrane was 0%, water permeation of the hollow fiber was 772 ml / h / m2 / mmHg and no observed degradation. The PVP content in the hollow fiber membrane determined by elementary analysis was 3.5%. The content of Insoluble material in the hollow fiber after irradiation with Gamma rays were determined at 7.2%. When the forced elution test to determine the concentration of PVP transferred from the hollow fiber membrane in the aqueous layer, no peak was detected and consequently no PVP was detected.

Example 2

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts polysulfone (Amoco, Udel-P1700), 3 parts polyvinyl pyrrolidone (ISP, K30) and 3 parts of polyvinyl pyrrolidone (ISP, K90) are dissolved in 77 parts of dimethylacetamide and 1 part of water with heating, to obtain a spinning solution for membrane formation. The viscosity of the spinning solution It was 18 Pa at 50 ° C. A module was manufactured in the same way as in Example 1 The water content in the hollow fiber membrane after expelling water from the membrane it was 330%. The side of the dialysate was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state where the membrane It was wet and the module was filled with inert gas. It was determined the permeation of water, the clearance of each solute and the albumin permeability. As a result, it was shown that the module had a clearance of urea, creatinine, uric acid, acid phosphoric and VB12 of 193 ml / min, 182 ml / min, 178 ml / min, 184 ml / min and 142 ml / min, respectively, a water permeation of 720 ml / h / m2 / mmHg and an albumin permeability of 1.8%. After drying, the water content in the membrane was 0%, the permeation of the hollow fiber water was 734 ml / h / m2 / mmHg, and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 4.0%. The content of insoluble material in the hollow fiber after irradiation with gamma rays it was determined at 7.8%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane in the aqueous layer, it is not detected PVP, as in the case of Example 1.

Example 3

4 parts of polysulfone (Amoco, Udel-P3500), 12 parts polysulfone (Amoco, Udel-P1700), 2 parts polyvinyl pyrrolidone (ISP, K30) and 4 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide and 1 part of water with heating, to obtain a spinning solution for the formation of the membrane. The viscosity of the spinning solution was 23 Pa.sa 50 ° C A module was manufactured in the same way as in the Example 1.

The water content in the fiber membrane Hollow after expelling water from the membrane was 400%. He dialyzed side was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state in which the membrane It was wet and the module had been filled with inert gas. He performed the determination of water permeation, clearance of each solute and the permeability of albumin. As a result, it was shown that the module had a water permeation of 702 ml / h / m2 / mmHg, a clearance of urea, creatinine, acid uric, phosphoric acid and VB12 of 191 ml / min, 180 ml / min, 175 ml / min, 181 ml / min and 140 ml / min, respectively and a permeability to 1.0% albumin. After drying the water content in the membrane was 0%, water permeation of the hollow fiber was 727 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 4.7%. The content of insoluble material in the hollow fiber after irradiation with gamma rays it was determined in 8.3%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane to the aqueous layer, no detection was detected PVP, as in Example 1.

Example 4

Four parts of polysulfone were dissolved (Amoco, Udel-P3500), 12 parts polysulfone (Amoco, Udel-P1700), 1 part polyvinyl pyrrolidone (ISP, K30) and 5 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide solution and one part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution it was 29 Pa.s at 50 ° C. A module was manufactured in the same way as in Example 1.

The water content in the fiber membrane Hollow after expelling water from the membrane was 380%. He dialyzed side was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state where the membrane It was wet and the module had been filled with inert gas. He determined the permeation of water, the clearance of each solute and the permeability of albumin. As a result, it was shown that the module had a water permeation of 675 ml / h / m2 / mmHg, a clearance of urea, creatinine, uric acid, phosphoric acid and VB12 of 190 ml / min, 179 ml / min, 173 ml / min, 179 ml / min and 138 ml / min respectively, and an albumin permeability of 0.9%. After drying, the water content in the membrane was 0%, the permeation of the hollow fiber water was 668 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elementary analysis was 5.1%. The content of the hollow fiber insoluble material after irradiation with Gamma rays were determined at 8.9%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane, no PVP was detected, as in the case of Example 1.

Example 5

Four parts of polysulfone were dissolved (Amoco, Udel-P3500), 12 parts polysulfone (Amoco, Udel-P1700), and 6 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide solution and a part of water with heating, to obtain a solution of spinning for membrane formation. The viscosity of the Spinning solution was 29 Pa.s at 50 ° C. A module was made of the same way as in Example 1.

The water content in the fiber membrane hollow after eject the water from the membrane was 350%. He dialyzed side was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state where the membrane It was wet and the module had been filled with inert gas. He determined the permeation of water, the clearance of each solute and the permeability of albumin. As a result, it was shown that the module had a water permeation of 620 ml / h / m2 / mmHg, a clearance of urea, creatinine, uric acid, phosphoric acid and VB12 of 189 ml / min, 177 ml / min, 169 ml / min, 178 ml / min and 137 ml / min respectively, and an albumin permeability of 0.8%. After drying, the water content in the membrane was 0%, the permeation of the hollow fiber water was 656 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 5.5%. The content of the hollow fiber insoluble material after irradiation with Gamma rays were determined in 9.2%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane, no PVP was detected, as in the case of Example 1.

Example 6

16 parts of polysulfone (Amoco, Udel-P3500), 4 parts polyvinyl pyrrolidone (ISP, K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide solution and a part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution was 14.0 Pa.s at 50 ° C. A module was manufactured in the same way as in Example 1

The water content in the fiber membrane hollow after expelling water from the membrane was 260%. He dialyzed side was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state where the membrane It was wet and the module had been filled with inert gas. He determined the permeation of water, the clearance of each solute and the permeability of albumin. As a result, it was shown that the module had a water permeation of 350 ml / h / m2 / mmHg, a clearance of urea, creatinine, uric acid, phosphoric acid and VB12 195 ml / min, 185 ml / min, 180 ml / min, 187 ml / min and 145 ml / min respectively, and an albumin permeability of 0.5%. After drying, the water content in the membrane was 0%, the permeation of the hollow fiber water was 330 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 3.1%. The content of the hollow fiber insoluble material after irradiation with Gamma rays were determined at 7.5%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane, no PVP was detected, as in the case of Example 1.

Comparative example 1

18 parts of polysulfone (Amoco, Udel-P3500), 6 parts polyvinyl pyrrolidone (BASF, K30) and 3 parts polyvinyl pyrrolidone (BASF, K90) in 72 parts of dimethylacetamide solution and a part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution was from 70 Pa.s to 50ºC. The spinning solution was introduced in a row at 50 ° C, and they were extruded, along with a core solution that it comprises 65 parts of dimethylacetamide and 35 parts of water, of the row through a tube with double slit and annular with a external diameter of 0.35 mm and an internal diameter of 0.25 mm, per which formed a hollow fiber membrane. The membrane was submitted at a humidity condition at 30 ° C and a dew point of 28 ° C The conditioned membrane was passed to a dry area of ​​a length of 250 mm, then to a coagulation bath at 40 ° C containing 20% ​​dimethylacetamide by weight and 80% water by weight. The resulting membrane was subjected to a water wash step at 80 ° C for 20s, and then at a stage of conditioning to the moisture with a glycerin solution. After removing the glycerin solution, the resulting membrane was packaged in a module cartridge and then it was isolated. The isolated beam was generated with the faces open at both ends to form a module of dialysis. Then the module was washed to remove the Free glycerin, filled with water, and then irradiated with rays gamma-25 (25 KGy). The permeation of the water, the clearance of each solute and the permeability of the albumin. As a result, it was shown that the module had a clearance of urea, ccreatinine, uric acid, phosphoric acid and VB12 of 194 ml / min, 185 ml / min, 176 ml / min, 183 ml / min and 135 ml / min, respectively, and a water permeation yield of 716 ml / h / m2 / mmHg and an albumin permeability of 0.7%.

The PVP content in the fiber membrane Gap determined by elemental analysis was 4.5%. The content of insoluble material in the hollow fiber after irradiation by gamma rays it was 8.0%. When the elution test was performed forced to determine the concentration of PVP transferred from the hollow fiber membrane to the aqueous layer, no PVP was detected, at same as in Example 1. Next, the filling liquid of the module was extracted. After drying the membrane with a dryer, water permeation was determined again, the clearance of each solute and albumin permeability. As result, it was shown that the module had a urea clearance, creatinine, uric acid and phosphoric acid and VB12 of 186 ml / min, 177 ml / min, 169 ml / min, 176 ml / min and 119 ml / min, respectively, a 0% permeability, a water permeation of 10 ml / h / m2 / mmHg, and an albumin permeability of 0.1%. In consequently, the membrane showed significant degradation after of drying. When a portion of the fiber was removed from the module hollow before drying and dried in the same manner as described previously, a similar degradation was also observed.

Comparative example two

17 parts of polysulfone (Amoco, Udel-P3500), 5 parts polyvinyl pyrrolidone (BASF, K30) and 4 parts of polyvinyl pyrrolidone (BASF, K90) in 73 parts of dimethylacetamide solution and 1 part of water with heating, to obtain a spinning solution for membrane formation. The viscosity of the spinning solution it was 40 Pa.s at 50 ° C. A module was manufactured in the same way as in Comparative Example 1. The module was irradiated with gamma rays in the state in which the module had been filled with water. It was determined the permeation of water, the clearance of each solute and the albumin permeability of the module. As a result it was demonstrated that the module had a clearance of urea, creatinine, acid uric, phosphoric acid and VB12 of 195 ml / min, 186 ml / min, 177 ml / min, 184 ml / min and 137 ml / min, respectively, and a permeation of water of 600 ml / h / m2 / mmHg, and a permeability to 1.2% albumin.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 4.8%. The content of insoluble material in the hollow fiber after irradiation by gamma rays it was 10.0%. When the elution test was performed forced to determine the concentration of PVP transferred from the hollow fiber membrane to the aqueous layer, no PVP was detected, at same as in Example 1. Next, the liquid was extracted from module filling. After drying the membrane with a dryer, water permeation was determined again, the clearance of each solute and albumin permeability. As result, it was shown that the module had a urea clearance, creatinine, uric acid and phosphoric acid and VB12 of 189 ml / min, 179 ml / min, 172 ml / min, 178 ml / min and 126 ml / min, respectively, a 0% permeability, a water permeation of 200 ml / h / m2 / mmHg, and an albumin permeability of 0.2%. In consequently, the membrane showed significant degradation after of drying. When a portion of the fiber was removed from the module hollow before drying and dried in the same manner as described previously, a similar degradation was also observed.

Comparative example 3

7 parts of polysulfone (Amoco, Udel-P3500), 5 parts polyvinyl pyrrolidone (BASF, K30) and 3 parts of polyvinyl pyrrolidone (BASF, K90) in 74 parts of dimethylacetamide solution and 1 part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution was from 33 Pa.s to 50ºC. A module was manufactured in the same way as in the Comparative Example 1. The module was irradiated with gamma rays in the state in which the module had been filled with water. It was determined the permeation of water, the clearance of each solute and the albumin permeability of the module. As a result it was demonstrated that the module had a clearance of urea, creatinine, acid uric, phosphoric acid and VB12 of 196 ml / min, 187 ml / min, 178 ml / min, 185 ml / min and 138 ml / min, respectively, and a permeation of 525 ml / h / m2 / mmHg water, and a permeability to 0.8% albumin.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 4.0%. The content of insoluble material in the hollow fiber after irradiation by gamma rays it was 93%. When the elution test was performed forced to determine the concentration of PVP transferred from the hollow fiber membrane to the aqueous layer, no PVP was detected, at same as in Example 1. Next, the liquid was extracted from module filling. After drying the membrane with a dryer, water permeation was determined again, the clearance of each solute and albumin permeability. As result, it was shown that the module had a urea clearance, creatinine, uric acid and phosphoric acid and VB12 of 191 ml / min, 181 ml / min, 173 ml / min, 180 ml / min and 126 ml / min, respectively, a 0% permeability, a water permeation of 340 ml / h / m2 / mmHg, and an albumin permeability of 0.5%. In consequently, the membrane showed significant degradation after of drying. When a portion of the fiber was removed from the module hollow before drying and dried in the same manner as described previously, a similar degradation was also observed.

Example 7

16 parts of polysulfone (Amoco, Udel-P3500), 4 parts polyvinyl pyrrolidone (ISP, K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide solution and 1 part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution was 14.0 Pa.s at 50 ° C. A module was manufactured in the same way as in the Example 1, except that the dry zone was not in a steam atmosphere dry.

The water content in the fiber membrane Hollow after expelling water from the membrane was 230%. He dialyzed side was also replaced with inert gas. The module is irradiated with gamma rays (25 KGy) in a state where the membrane It was wet and the module had been filled with inert gas. He determined the permeation of water, the clearance of each solute and the permeability of albumin. As a result, it was shown that the module had a water permeation of 350 ml / h / m2 / mmHg, a clearance of urea, creatinine, uric acid, phosphoric acid and VB12 of 190 ml / min, 180 ml / min, 175 ml / min, 182 ml / min and 138 ml / min respectively, and an albumin permeability of 0.6%. After drying, the water content in the membrane was 0%, the permeation of the hollow fiber water was 340 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 3.3%. The content of the hollow fiber insoluble material after irradiation with Gamma rays were determined at 7.8%. When the test was performed forced elution to determine the concentration of PVP transferred from the hollow fiber membrane, no PVP was detected, as in the case of Example 1.

Comparative example 4

16 parts of polysulfone (Amoco, Udel-P3500), 4 parts polyvinyl pyrrolidone (ISP, K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90) in 77 parts of dimethylacetamide solution and 1 part of water with heating, to obtain a spinning solution for membrane formation The viscosity of the spinning solution was 14.0 Pa.s at 50 ° C. A module was manufactured in the same way as in the Example 1, except that the filler water was extracted from the membrane with compressed air and the atmosphere was not replaced with inert gas. The water content in the hollow fiber membrane in this state It was 260%. The membrane was irradiated with gamma rays (25 KGy) in a state in which the module was filled with air and the membrane wet. Water permeation was determined, the clearance of each solute and albumin permeability of the module. As a result it was shown that the module had a water permeation of 350 ml / h / m2 / mmHg, a clearance of urea, creatinine, acid uric, phosphoric acid and VB12 of 195 ml / min, 185 ml / min, 180 ml / min, 187 ml / min and 145 ml / min, respectively, and, and a permeability to 0.5% albumin. After drying, the water content in the membrane was 0%, the water permeation of the hollow fiber of 340 ml / h / m2 / mmHg and no degradation was observed.

The content of PVP in the fiber membrane Gap determined by elemental analysis was 3.1%. The content of insoluble material in the hollow fiber after irradiation by gamma rays it was 7.8%. When the elution test was performed forced to determine the concentration of PVP transferred from the hollow fiber membrane to the aqueous layer, 1255 ppm of PVP in the aqueous phase.

Consequently, the realizations of the The present invention allows to provide: (1) a dialyzer for blood treatment that has incorporated a membrane semipermeable dry type, which suffers less changes in its yield before and after drying and presenting the advantages Lightweight, be free from the problem of freezing and have good water permeability and dialysis function; (2) a dialyzer for the treatment of blood that has a weight Lightweight, easy to handle and has a reduced elution of a hydrophilic polymer; and (3) a process for the production of a semipermeable membrane for the proper treatment of blood by the dialyzers

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