JPS6236705B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is suitable as a medical hydrophilic membrane material,
The present invention relates to an ascites treatment device using a membrane system using a polyvinyl alcohol-based permselective membrane as an ascites membrane. A considerable number of patients suffer from ascites due to liver cirrhosis, internal cancer, renal failure, etc., and the number is increasing in Japan. Conventionally, drainage of fluid through ascitic puncture has often been applied to such patients, but although this provides temporary relief to the patient, it tends to re-accumulate, and nutrients such as proteins in ascites are lost. At the same time, the patient's symptoms often worsen, which is a problem. In contrast, a treatment method of reinjecting autologous ascitic fluid intravenously has recently been clinically evaluated, and the development of a treatment device for this purpose has become desirable. Re-infusion of autologous ascites has been widely used by Gallup et al. (1911
(2012) attempted this, but it was based on repeated intravenous injection of autologous ascitic fluid without modification, and its effectiveness was uncertain, so it was not widely used. Afterwards E. Adlercreutz (Acta.
Med.Scand. 161 , 1, 1958), R.C. Britton
(Arch. Surg. 83.364.1961 ) attempted to solve the problem of excessive fluid load by performing concentrated re-infusion using an artificial kidney dialysis machine, but the operation was complicated and the machine's capacity was also problematic. However, it was not considered because it was uneconomical. Moreover, this method poses a problem in that if the ascites contains unnecessary substances such as bacteria and giant cells, these will also be concentrated and returned to the blood vessels. In contrast, a method has recently been attempted in which ascitic fluid is filtered in advance to remove cancer cells and bacteria, and then concentrated and re-injected intravenously, making it safer for this type of use.
It is also attracting attention as a widely used treatment method. For this purpose, for example, Japanese Patent Laid-Open No. 140387/1987 proposes an ascites treatment device equipped with a filter and a concentrator. In this invention, a cellulose acetate membrane is specifically shown as the membrane. Although this membrane has the ability to achieve its intended purpose as a membrane for ascites, it has insufficient biocompatibility, heat resistance, pressure resistance, etc., and various restrictions are required when using it. Here, biocompatibility is related to the presence or absence of denaturation of proteins in the ascites to be treated, and heat resistance is related to whether a membrane sterilized by high-pressure steam can be provided. Autoclaved membranes are desirable for this purpose in that they do not contain chemicals such as formalin or ethylene oxide gas. From this perspective, the present inventors discovered PVA as a material that is inherently hydrophilic and has excellent biocompatibility, and whose heat resistance can be improved through chemical treatment.
As a result of examining the system membranes, we found that highly hydrophilic substances such as PVA membranes have a high water content and excellent water permeability, but have poor strength (pressure resistance), but improving pressure resistance conversely reduces hydrophilicity. However, the present invention was completed after recognizing that a permeable membrane that can be sterilized by high-pressure steam could be obtained by imparting a specific structure to a PVA-based membrane. That is, the present invention has a uniform porous structure with an average pore diameter in the range of 0.01 to 2μ, a swelling degree ψ of 1.0≦ψ≦1.2, and a Young's modulus ratio T≧
0.3 (T here means the Young modulus ratio Y ₁₀₀ /Y ₄₀ in water at 100°C and 40°C)
The unit consists of a permselective membrane with a built-in PVA-based permselective membrane that can be autoclaved at 105 to 140°C, and a concentration unit with a permselectively membrane that concentrates the ascites filtered through the persunit. This is an ascites treatment device characterized by: The above-mentioned porous structure is a structure recognized by electron microscopic observation at a magnification of 10,000 times. Originally, removing cancer cells through ascites through a membrane is a difficult task that tends to cause clogging, but the porous structure of the membrane according to the present invention has an effective micropore average diameter of 0.01 to 2μ. We have unexpectedly discovered that by using a PVA-based permselective membrane, separation is possible at high flux without clogging. If the effective average pore diameter is 2 μ or more, it is unsuitable because there is a high possibility that blood cells or cancer cells will pass through. Further, if it is less than 0.01μ, the recovery rate of useful proteins is poor, and the separation ability, that is, the processing ability, decreases rapidly, which is not preferable. The membrane more preferably has an effective average pore diameter of 0.01 to
It has a porous structure of 0.2μ. According to this membrane, bacteria can be removed along with cells when treating patients with ascites with repeated intravenous injection of autologous ascites.
It can be expected to have a significant effect on improving symptoms. Such a structure can be achieved in the membrane of the present invention because the pore size can be easily adjusted. Effective average pore diameter is 0.2μ
If the amount exceeds that level, the inhibition rate against bacteria will decrease. The effective pore size here is evaluated by the rejection rate of latex, etc. containing white blood cells, proteins with a molecular weight of about 1 million, and particles of 0.2μ against the membrane. The porous structure described above is a structure that can be observed by electron microscopy using the method described below. However, the internal structure of the membrane is not expressed only by the structure observed by electron microscopy; for example, considering the particle size of the permeable component, it is thought that there is another micropore structure in addition to the structure observed by electron microscopy. is considered appropriate. In the film according to the present invention, 0.01~ observed by electron microscopy
Based on the permeability test of various solutions, it is thought that there are micropores of 0.01 to 2μ on the 2μ porous structure, so these micropores are considered as effective micropores. The effective micropores have a structure different from that seen through electron microscopy. The membrane of the present invention is characterized by having a specific degree of swelling in addition to the above-mentioned porous structure. It has been recognized that for the purposes of the present invention it is necessary for the membrane to have high pressure resistance as well as high permeability, and it is necessary for the membrane to have a certain degree of swelling for the pressure resistance.
Here, the degree of swelling ψ indicates the ratio (times) of wet to dry of the outer diameter of the cross section of the membrane (hollow fiber) or the length in the thickness direction (flat membrane). This degree of swelling is 1.0≦
It is necessary that ψ≦1.2. When ψ is larger than 1.2, pressure resistance and other mechanical properties are insufficient, and the membrane is likely to deform as pressure increases, resulting in wide fluctuations in permeability. Dry measurements are performed after being left at 25°C and RH 60% for 24 hours, and wet measurements are made after being left in water at 25°C for 24 hours. With conventional techniques, highly hydrophilic membranes such as PVA-based membranes inevitably have a high degree of swelling, and it has only been possible to obtain a swelling value of 1.2 times or more, usually 1.4 times or more. In other words, the shape of a large hydrophilic structure inevitably swells and deforms in a water-containing state, so the degree of swelling is
It had to be more than 1.4 times as large. Therefore, it was believed that in order to reduce the degree of swelling, the material must be selected from hydrophobic polymers.
However, the present inventors succeeded in obtaining a PVA-based membrane with high hydrophilicity and low degree of swelling, creating a new and unprecedented PVA-based membrane that has both the characteristics of hydrophilic and hydrophobic polymers. I was able to provide it. In addition, swelling degree is generally a measure of hydrophobicity, and polyacrylonitrile-based and cellulose acetate-based polymers are hydrophobic, so if we consider only swelling degree, they are about the same, but what does it mean? However, it should be noted that the PVA-based membrane of the present invention is clearly different. The degree of swelling of the membrane of the present invention is determined by adding monoaldehyde such as formaldehyde, acetaldehyde, or benzaldehyde, or glutaraldehyde, glyoxal, or PVA to periodate ion or cerium ion at any stage after the PVA membrane leaves the coagulation bath. It can be adjusted by acetalization with a dialdehyde such as PVA dialdehyde obtained by oxidative decomposition, or by PVA modification treatment such as esterification or etherification. In these chemical modification treatments,
Of course, it is possible to use two or more types of modifiers, and a heat treatment operation can also be used in combination. The PVA-based membrane of the present invention can have excellent heat resistance and high-temperature properties not found in other ultrafiltration membranes such as cellulose acetate and polyacrylonitrile. The medical membrane targeted by the present invention must be free of eluates and must be sterilized. The amount of eluted substances is evaluated by treating the membrane in water at 70°C for 1 hour and evaluating the amount of substances eluted, which is closely related to the heat resistance of the membrane material. The sterilization process can also be performed by known formalin water sterilization or ethylene oxide gas sterilization. However, there is a growing concern that sterilization using these drugs may have an adverse effect on patients due to the residual amount of the drugs. From this point of view, 105 is recommended for sterilization of medical membranes.
It is desirable to be able to perform high-pressure steam sterilization at ~140°C or high-pressure steaming at 105-140°C in the presence of water or physiological saline. Whether or not the membrane can maintain its performance as a semipermeable membrane under such high-temperature, moist heat treatment depends entirely on its heat resistance. The present inventors investigated whether such a high degree of heat resistance could be imparted to the membrane of the present invention described above, and as a result, the Young modulus ratio T was T. 0.3.
It has been found that, preferably, if T. Of course, such a membrane has a sufficiently satisfactory level of eluate at 70°C. T here means the ratio of Young's modulus (indicating the degree of crosslinking between molecules of PVA polymer) Y ₁₀₀ /Y ₄₀ in water at 100°C and 40°C, which is a measure of pressure resistance and heat resistance. It is. Even after steam treatment at 121°C for 20 minutes, the film with T≧0.3 did not show any change in shape that would pose a practical problem.
The film shows no change in shape due to the same treatment. The PVA membrane of the present invention, which satisfies T≧0.3, has the surprising property that no change in performance is observed even after repeated heat-and-moisture treatment up to 140°C several times. The Young's modulus ratio T can be achieved by using an intermolecular crosslinking reaction as at least a part of the chemical modification treatment for controlling the degree of swelling described above. As a crosslinking treatment, a substance that forms intermolecular crosslinks of PVA, such as glutaraldehyde,
Crosslinking using dialdehydes such as glyoxal and terephthalaldehyde, crosslinking using diisocyanates such as phenylene diisocyanate and tolylene diisocyanate, and ester crosslinking using thioglycolic acid esters are used. Among these, it is advantageous to use dialdehyde crosslinking from the viewpoint of ease of reaction, and glutaraldehyde is particularly preferred. As mentioned above, the PVA-based membrane used for the ascites membrane has a completely unique structure that exhibits the characteristics of a hydrophobic polymer in swelling degree while retaining the hydrophilic properties of PVA. It has excellent performance with high strength. Moreover, this membrane can be subjected to high-pressure steam sterilization at 105 to 140°C, and even in this case, there is no deterioration in performance as a membrane. This fact is unknown for any conventional membrane. Next, the concentration membrane according to the present invention will be explained. The concentration membrane according to the invention has a water permeability of at least 0.2
ml/hr.atm.cm ² (in vitro distilled water) and a permselective membrane with a molecular weight cut off of 45,000 or less, but it is generally used in artificial kidneys as described in JP-A-51-140387. A membrane that has been prepared can be used. Among these, it is preferable to use a membrane made of the same material as the overused PVA membrane mentioned above and an ethylene-vinyl alcohol copolymer (EVA) having an ethylene content of 10 to 50 mol%. The membrane preferably has constituent particles having an average particle diameter of 100 to 10,000 Å as determined by electron microscopic observation of a substantially dry membrane.
The particle diameter is in the range of 500 to 7000 Å and has a structure in which the particles are bonded to each other. A PVA-based membrane having such a structure has the above-mentioned water permeability and molecular weight cutoff, and can be used as a membrane for concentrating ascites. If the water permeability is less than 0.2 ml/hr.atm.cm ² , a large membrane area or a long time will be required, which is not practical, and if the molecular weight cut-off is more than 45,000, proteins, which are useful components, will be lost, which is not appropriate. The PVA-based overuse membrane and EVA concentration membrane mentioned above are disclosed in, for example, Japanese Patent Application Laid-Open No. 52-123385 and Japanese Patent Application No. 51-107089.
(Japanese Unexamined Patent Publication No. 53-31580) and No. 52-152877. In the present invention, the overflow membrane and the concentration membrane are used in the form of hollow fibers or flat membranes to constitute overflow units and concentration units of various structures. Each unit may be housed in separate housings or in a single housing. These structural units are integrated with a known pump infusion circuit, etc., and are used for actual treatment of ascites. The present invention will be explained below with reference to Examples. Examples 1 to 3 and Comparative Examples 1 and 2 PVA with saponification degree of 98.5%, DP2400, and molecular weight
1000 PEG was mixed with PVA at 100% and dissolved by heating at 100°C to prepare a homogeneous aqueous solution with a PVA concentration of 14.5%. This spinning stock solution is passed through an annular nozzle using NaOH/
Hollow fibers were obtained by precipitation in a coagulation bath containing Na ₂ SO ₄ =70/240g/. Next, the hollow fibers were heated at 70°C in a crosslinking treatment bath of glutaraldehyde/H ₂ SO ₄ /Na ₂ SO ₄ system.
It was immersed for 5 hours and then washed with running water at 25°C for 3 hours to completely remove PEG and form a microporous structure.
Thereafter, the fibers were air-dried at room temperature to obtain dry hollow fibers. Table 1 shows the degree of swelling ψ, Young's modulus ratio T, water permeability and pressure resistance of the hollow fibers after autoclaving at 120°C for 20 minutes. Note that water resistance is the bursting pressure when pressurizing the inside of the hollow fiber in a wet state.

[Table] As is clear from the examples and comparative examples shown in Table 1, the water permeability and pressure resistance after high-pressure steam sterilization of hollow fibers that satisfy the swelling degree ψ of 1.0≦ψ≦1.2 and the Young's modulus ratio T of T≧0.3. It had excellent characteristics. Example 4 Saponification degree 98.5%, PVA with DP2400 and molecular weight 1000
PEG (95%/PVA) was heated and dissolved at 100℃, and PVA
Apply the spinning stock solution with a concentration of 16% through the annular nozzle.
Hollow fibers were obtained under extrusion normal conditions. Next, the obtained hollow fibers were treated with glutaraldehyde/H ₂ SO ₄ /
Na ₂ SO ₄ =3/30/200g/70℃-5
After soaking for a time and crosslinking treatment, wash with water at room temperature and further at 85℃.
PEG was removed by washing for 1 hour to form a microporous structure. Thereafter, the fibers were air-dried at room temperature to obtain dry hollow fibers. The outer diameter of the obtained hollow fiber was 800μ, and the membrane thickness was 200μ. The young modulus of the obtained hollow fiber is
Y ₄₀ =7.0Kg, _Y100 =6.2Kg, and Young's modulus ratio T was 0.89. A filtration device with an effective membrane area of 0.5 m ² was fabricated using this hollow fiber, and high-pressure steam sterilization was repeated three times at 121°C for 20 minutes, and the performance fluctuations were observed, but the membrane performance was not impaired at all. When we observed the cross section of this dry hollow fiber using an electron microscope, we found that
It was observed that the particles had a uniform diameter and were evenly arranged in the cross section. The degree of swelling ψ was 1.04.
Using this hollow fiber, a filter device with an effective membrane area of 1.0 m ² was created. In addition, as a concentration membrane, the ethylene content is 33 mol%.
EVA hollow fiber membrane for artificial kidney was used. A concentrator with an effective membrane area of 1.0 m ² was fabricated using this hollow fiber. Ascites was treated using these devices. The total protein concentration in ascites of a cancerous patient was 2.4 g/dl. After paracentesis of the ascites, the total protein concentration was 2.4 g/dl, and the pressure was controlled at 60 ml/min.
The mixture was allowed to pass for 30 minutes with partial recirculation and then passed through a concentrator under pressure control to concentrate the total protein concentration by 2.5 times. As a result of analysis of the ascites after the procedure, no bacteria, cancer cells, etc. were detected and it was completely removed. The final protein concentration was also 6.0 g/d, as specified.

Claims (1)

[Claims] 1 It has a uniform porous structure in which micropores with an average pore diameter of 0.01 to 2μ are uniformly arranged in the cross section, and its degree of swelling ψ is 1.0≦ψ≦1.2, and the Young's modulus ratio T is T≧0.3 (where T means 100℃ and 40
Young modulus ratio in °C water Y ₁₀₀ / Y ₄₀
), which is equipped with a polyvinyl alcohol-based permselective membrane that can be autoclaved at 105 to 140°C, and a permselective membrane that concentrates the ascites passed through the perunit. An apparatus for treating ascites, characterized by comprising a concentration unit.