JPH0133228B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a precision filtration method for obtaining pyrogen-free ultrapure water used primarily for pharmaceutical and medical purposes. The pyrogen mentioned in the present invention is a general term for pyrogenic substances, and this pyrogen is a metabolite of living microorganisms, such as bacteria, mold, and yeast, or a dead microorganism itself, and is a substance that causes a fever reaction in living organisms when injected. Refers to what is defined as. Pyrodiene exists wherever microorganisms are allowed to grow, has similar properties regardless of the type of microorganism, and is chemically classified as a heat-resistant polymeric complex glycolipid containing nitrogen and phosphorus. It is thought to be water-soluble and have a size of 1 to 5 mμ. It is said that a trace amount of 0.01 μg/Kg causes a fever reaction in living organisms, and for example, in the case of blood, transfusions, medicines, and other injections mixed with pyrodiene, it also causes side effects such as fever and shock in living organisms. Therefore, water used particularly in the pharmaceutical and medical fields needs to be sterile water and so-called pyrogen-free water. However, this pyrogen cannot be destroyed or removed by conventional sterilization methods, such as steam sterilization under high pressure or bacterial filtration. Therefore, fairly advanced water treatment technology is required to obtain pyrogen-free water. Methods for obtaining pyrogen-free water include the conventionally used distillation method, ultrafiltration method, and reverse osmosis method, which have been studied relatively recently, but all of these methods require large-scale requires equipment,
Furthermore, it has the disadvantage of high operating costs, and at present it cannot be said that it is necessarily a suitable method for obtaining a large volume of pyrogen-free water. Furthermore, the micropore structure of conventional ultrafiltration membranes is close to spherical, and in order to remove pyrodiene, which is said to be several tens of angstroms thick, using a membrane with such a structure, the pore size of the membrane must be made extremely small. , the amount of water permeation inevitably decreases, resulting in poor productivity. Fields that require large volumes of pyrogen-free water include the pharmaceutical manufacturing field, including injection drugs, and the medical field, such as water for washing syringes and surgical instruments, water for washing hands before surgery, and water for patient's organs during surgery. and water for cleaning wounds. In particular, since the amount of water used for cleaning is extremely large, it is desirable to use low-cost pyrogen-free water, and the importance of producing low-cost pyrogen-free water is increasingly being recognized. This is the current situation. Under these circumstances, the present inventors conducted various studies on a rational method for producing pyrogen-free water, and as a result, they arrived at the present invention. That is, in the present invention, a large number of strip-shaped micropores formed by microfibrils arranged in the fiber length direction and nodules connected at almost right angles to the microfibrils are mutually connected from the inner wall surface of the hollow fiber to the outer wall surface. This is a method for removing pyrogen in water, which is characterized by using a separation membrane having a connected laminated structure as a pyrodiene separation membrane. The feature of the present invention is that by using a membrane having a special structure as described above, the average pore diameter of the membrane's pores is several times to several tens of times larger than the size of the pyrodiene to be passed through, yet it can effectively separate the particles. It lies in being done. Separation membranes with such special microstructures can be formed by melt-extruding and stretching crystalline polymers such as polyolefin, polyester, nylon, and polyoxymethylene. Desirable from the viewpoint of pore-forming properties. The form of the membrane may be either a flat membrane, a tube membrane, or the like, but a hollow fiber membrane is preferred since it can provide a large membrane area per unit volume. Porous hollow fibers with such a special microstructure are produced by, for example, highly oriented crystalline undrawn hollow fibers obtained by melt-spinning polymers such as polyethylene or polypropylene using a special nozzle for manufacturing hollow fibers. It is manufactured by controlling each process condition in a limited manner in the main process of cold stretching and then heating stretching.
The separation membrane obtained in this way has a special microstructure as described above, which is significantly different from other separation membranes such as cellulose acetate and polyacrylonitrile produced by wet or dry methods. It is thought that the structure greatly contributes to the removal of pyrodiene from water. Next, the special fine structure of the separation membrane used in the present invention will be explained in more detail with reference to the drawings.
FIG. 1 is an electron micrograph of the polyethylene porous hollow fiber obtained in Example 1 of the present invention (hollow fiber outer surface magnification: 10,000). Figure 2 is a schematic diagram of one plane of the stacked structure of strip-shaped micropores drawn to make the photograph in Figure 1 easier to understand. Nodules connected at right angles, 3 are strip-shaped micropores,
The strip-shaped micropores 3 made up of microfibrils and nodules have a laminated structure with each nodule interposed therebetween. Further, the laminated structure of the micropores means that the fibers are laminated in the longitudinal direction of the hollow fibers in one plane via the knots, and at the same time, the planes having such a structure are stacked in the thickness direction of the wall membrane of the hollow fibers. Although the separation membrane with such a microporous structure has a large micropore diameter measured with a mercury porosimeter as described below, it is true that extremely small pyrodiene, which is thought to have a diameter of 1 to 5 μm, is separately removed. This is a surprising fact that even the inventors had not expected at first.
Furthermore, although it cannot be said that the pyrodiene removal mechanism has been completely elucidated at this point, as shown in Figure 2, strip-shaped micropores composed of microfibrils and nodules are formed in the wall membrane of hollow fibers. It is presumed that the stacked structure in the thickness direction greatly contributes to pyrogen removal. This assumption can also be explained by the fact that, as will be described later, if the thickness (T) of the wall film is increased, even if the micropore diameter () is increased, pyrogenes tend to be removed. On the other hand, as long as pyrodiene is removed, the larger the diameter of the micropores and the larger the porosity of the separation membrane, the higher the water permeation rate, which is preferable. According to studies by the present inventors, as a result of measuring the average pore diameter and porosity of porous hollow fibers using a mercury porosimeter, it was found that in the case of hollow fibers having strip-shaped micropores as described above, pyrodiene is separated. It was found that the maximum pore diameter varies depending on the membrane thickness T (μ) of the hollow fiber membrane. That is, if the film thickness T is increased, even if the average pore diameter is large, the pyrogen is separated and not included in the liquid. This is thought to be because when the film thickness is large, the pyrodiene is caught by the microfibrils in the film and cannot pass through the film, even if the average pore diameter of the film is large. In the case of porous hollow fibers, the relationship between membrane thickness and pore diameter is expressed as D=0.002×T+0.3, and it has been found that a lower limit of 0.03μ or more is effective in terms of water permeation rate. In other words, the diameter of the micropores is 0.03μ or more,
It has been found that by using hollow fibers of (0.002 x T + 0.3) μ or less, water from which pyrodiene has been completely removed can be obtained while maintaining a high water permeation rate. Furthermore, the thickness of the hollow fiber is in the range of 10 to 100μ, preferably 20 to 80μ, and the porosity is in the range of 20 to 100μ.
A range of 90 Vol%, preferably 40 to 80 Vol% is preferable from the viewpoint of water permeation rate and physical strength of the membrane. Next, the method for removing pyrodiene in water according to the present invention will be explained in more detail. FIG. 3 is a schematic sectional view showing an embodiment of the present invention, showing that it is a cartridge type filter in which porous hollow fibers are housed in a housing. Reference numeral 4 indicates a porous wall membrane portion of the porous hollow fiber, 5 indicates a resin that focuses and fixes the porous hollow fiber, 6 indicates a hollow opening of the porous hollow fiber, and 7 indicates a housing.
8 indicates the inlet of the water to be treated, 9 indicates the outlet of the excess water,
Arrows indicate water flow. That is, for example, the porous wall membrane part 4 of the porous hollow fibers bent into a U-shape as shown in FIG. Pyrogen-free water can be obtained by flowing out from the outlet portion 9 of the housing 7 through the hollow opening 6 of the porous hollow fiber. Furthermore, when polyolefin porous hollow fibers are used as the pyrodiene separation membrane of the present invention, the hollow fibers are very flexible and can be stored in the housing in a freely bent or curved state, which reduces the internal volume of the housing. It is possible to significantly increase the effective separation membrane area ratio. In addition, the separation membrane has the characteristic that the rate of decrease in the amount of liquid permeable is small even after long-term use, but when the amount of liquid permeable decreases, the separation membrane should be removed and washed with ethanol etc., or the hollow opening 6 It is also possible to reuse it by flushing it with compressed air or liquid. As explained above, the present invention is a method that can efficiently remove pyrogens contained in well water, tap water, etc., and is superior in terms of equipment and operating costs compared to conventional methods, and is particularly low cost and As a way to obtain large amounts of pyrogen-free water,
Its practical value is considered to be extremely high. Next, the present invention will be explained in more detail with reference to Examples. The detection method of pyrodiene used in this example is
The Limulus lysate test was performed. The detection reagent is Teikoku Organ Pharmaceutical Co., Ltd.
Pregel reagent (trade name) manufactured by KK was used. The detection principle is based on the fact that blood cells in the hemolymph of horseshoe crabs react with extremely small amounts of pyrodiene and form a gel. Pregel is a reagent in which the above-mentioned freeze-dried blood cell components are sealed in an ampoule.A test solution is added to this ampoule, incubated in an incubator at 37°C for 1 hour, and then kept at room temperature for 5 minutes before opening the ampoule. A method was followed in which the degree of gelation was determined by tilting the plate at 45°. The judgment criteria are as follows. (++): Forms a hard gel and does not lose its shape even if the ampoule is tilted. (+): A gel is formed, but when the ampoule is tilted, it moves as a lump. (±): Formation of coarse granular gel and significant increase in viscosity. (-): Remains liquid with no change. The detection limit of pyrogen by this method is
10 ^-3 μg/ml. Example 1 It had a microstructure as shown in FIGS. 1 and 2, and the average pore diameter of the micropores measured using a mercury porosimeter model 221 manufactured by Carlo Erba was 0.23μ, and the porosity was
A porous hollow fiber made of polyethylene of 60 Vol%, a membrane thickness of 60 μm, and an inner diameter of the hollow fiber of 280 μm was used. The hollow fibers were bundled into a U-shape as shown in Fig. 3, and the hollow openings were kept unobstructed, and the tips were bundled and fixed using a polyurethane resin to form a cartridge-type filter, which was used as a pyrodiene separation membrane. The separation membrane is installed in the housing as shown in Figure 3, and connected to the well water pipe via a pressure regulator, with a back pressure of 2.5 kg/
The water was continuously passed through the well water for 2400 hours at ^cm2 , and the presence or absence of pyrogen was measured in the well water before and after the filtration. The results are shown in Table 1. In addition, the water permeability is 250/m ² hr at the initial stage.
After 480 hours of water permeation, the water permeation amount decreased to 170/m ² hr, but when the separation membrane was removed from the housing and washed with a 50% ethanol aqueous solution.
The water permeability rate recovered to 210/m ² , hr. As a result of further water flow, the water permeability after 2400 hours was 160/
It was ^m2 , hr.

[Table] As shown in Table 1, it was confirmed that pyrodiene in well water was removed by the method of the present invention. Example 2 A porous hollow fiber made of polypropylene with an average micropore diameter of 0.05 μm as measured by a mercury porosimeter, a porosity of 70 Vol%, a membrane thickness of 40 μm, and a pore diameter of 250 μm at the hollow opening was used as a separation membrane. Normal tap water was filtered under the same conditions as in Example 1, and the presence or absence of pyrogen was measured in the tap water before and after filtering. The results are shown in Table 2. The water permeation amount was 170/m ² , hr at the initial stage, and decreased to 125/m ² , hr after 480 hours of water permeation. When the separation membrane was washed in the same manner as in Example 1, the water permeation rate recovered to 145/m ² hr, and as a result of continuing the filtration experiment, the water permeation rate after 2400 hours was as follows.
It was 120/m ² , hr.

[Table] As shown in Table 2, it was confirmed that pyrodiene in tap water was removed by the method of the present invention. Comparative Example 1 A porous hollow fiber made of polyethylene with an average micropore diameter of 0.68μ as measured by a mercury porosimeter, a porosity of 80Vol%, a membrane thickness of 40μ, and a hollow fiber inner diameter of 250μ is used as a separation membrane.Other conditions are as in Example. Ordinary tap water was filtered under the same conditions as in Example 2, and the presence or absence of pyrogen was measured in the tap water before and after filtering. The results are shown in Table 3.

[Table] As shown in Table 3, in the separation membrane whose average pore diameter () does not satisfy the above-mentioned condition () = 0.002 The pyrodiene removal effect tends to deteriorate with water flowing for a long time, and as in the present invention, the average pore diameter () of the micropores is () = 0.002 ×
It has been found that (T)+0.3 or less is preferable.

[Brief explanation of drawings]

FIG. 1 is a surface electron micrograph of the separation membrane used in the present invention. FIG. 2 is a schematic diagram showing the laminated structure of strip-shaped micropores of the separation membrane used in the present invention. FIG. 3 is a schematic cross-sectional view of an apparatus for carrying out the method of the invention. 1... Microfibril, 2... Nodule, 3...
...Strip-shaped micropore, 4...Hollow fiber, 5...Hollow fiber focusing and fixing resin part, 6...Hollow fiber opening, 7...Housing, 8...Water to be treated inlet, 9...Treated water outlet.

Claims (1)

[Claims] 1. A large number of strip-shaped micropores formed by microfibrils arranged in the fiber length direction and nodules connected at almost right angles to the microfibrils extend from the inner wall surface of the hollow fiber to the outer wall surface. A method for removing pyrodiene in water, characterized in that a separation membrane made of a polyolefin polymer having an interconnected layered structure is used as a separation membrane for pyrodiene. 2. The method for removing pyrodiene according to claim 1, wherein the separation membrane is a porous hollow fiber membrane. 3 The thickness T (μ) of the wall membrane layer of the porous hollow fiber is 10~
100μ, the porosity measured with a mercury porosimeter is
20~90vol%, average pore diameter (μ) of micropores is 0.03μ
Above, and in relation to T, the value is =
The pyrogene removal method according to claim 2, characterized in that the value is 0.002×T+0.3 or less.