JPH119923A - Filter medium for removing white corpuscle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enhance white corpuscle-removing capacity and ensure good flow of a white corpuscle containing liquid by using a nonwoven cloth of a split cellulose containing cellulose-microfibril having a particular fiber diameter. SOLUTION: In order to prepare a white blood corpuscle removing filter medium for removing white blood corpuscles from a white blood corpuscle containing liquid, a split cellulose fiber containing cellulose-microfibril having a fiber diameter of not less than 0.03 μm and not more than 1.0 μm is used. As the most preferred split cellulose fiber, lyocell, superpolynosic and the like are listed. In order to prepare a nonwoven cloth of the split cellulose fiber containing cellulose-microfibril from a split cellulose fiber, a water flow interlacing method is employed, wherein first a fiber mat comprising the split cellulose fiber is prepared and then a high pressure liquid flow is sprayed onto the nonwoven cloth so as to fibrillate the slit cellulose fiber and interlace the fibers.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a leukocyte removal filter material for removing leukocytes from a leukocyte-containing liquid.

[0002]

2. Description of the Related Art In recent years, in the field of blood transfusion, in addition to so-called whole blood transfusion, a recipient of a whole blood product is required in addition to so-called whole blood transfusion, in which an anticoagulant is added to blood collected from a donor. What is called component blood transfusion is generally performed in which a blood component is separated and the blood component is transfused. Component transfusions include erythrocyte transfusions, platelet transfusions, plasma transfusions, etc., depending on the type of blood component required by the recipient.The blood component preparations used for these transfusions include erythrocyte preparations, platelet preparations, and plasma preparations. and so on. In recent years, so-called leukocyte-removal transfusion, in which a blood product is transfused after removing leukocytes mixed in the blood product, has become widespread.
This includes relatively minor side effects such as headache, nausea, chills, and non-hemolytic fever reactions associated with blood transfusion, alloantigen sensitization that has a serious effect on recipients, viral infection, and GVHD after blood transfusion.
It has been clarified that such serious side effects are caused mainly by leukocytes mixed in blood products used for blood transfusion. Headache, nausea, chills,
It is said that in order to prevent relatively minor side effects such as fever, leukocytes in blood products should be removed until the residual ratio becomes 10 ^-1 to 10 ^-2 or less. It is also said that leukocytes should be removed until the residual ratio becomes 10 ^-4 to 10 ^-6 or less in order to prevent alloantigen sensitization and virus infection, which are serious side effects.

[0003] Methods for removing leukocytes from blood products include:
It is roughly divided into a centrifugal separation method that separates and removes white blood cells using the difference in specific gravity of blood components using a centrifugal separator, and a filter material made of a porous material such as a fiber material or a porous material having continuous pores. There are two types of filter methods for removing leukocytes. The filter method has been widely used at present because of its advantages such as excellent leukocyte removing ability, simple operation, and low cost. Furthermore, among the filter methods, a method of removing leukocytes by adhesion or adsorption using a nonwoven fabric as a filter material,
It is most widely used at present because of its excellent leukocyte removal ability. The mechanism of the leukocyte removal by the filter device using the fiber material or the porous body is mainly based on the fact that the leukocytes in contact with the surface of the filter material adhere or adhere to the surface of the filter material. For example, EP-A
0155003 discloses a technique using a nonwoven fabric as a filter material. In addition, fiber diameter 0.01μm
Hereinafter, a lump composed of a large number of small fiber pieces having a length of about 1 to 50 μm and a spinnable short fiber having a fineness of about 0.05 to 0.75 d and an average length of 3 to 15 μm are dispersed in a dispersion medium. The leukocyte-removing filter material produced by dispersing in a dispersion medium and removing the dispersion medium from the obtained dispersion is WO93 / 018.
80.

[0004]

The current leukocyte removal filter has a leukocyte removal ability of a residual leukocyte count of 1 × 10 ⁵ or less. Under such circumstances, two major demands for leukocyte depletion filters have been raised in the market. The first requirement is to improve the recovery ratio of useful components and to eliminate the need to recover the useful components remaining in the filter and circuit due to the presence of physiological saline and air, thereby improving handling. It is. In particular, blood, which is a raw material of blood products, is often valuable blood provided by blood donation in good faith, and blood that remains in the leukocyte removal filter and cannot be collected is discarded together with the filter and is wasted. Because it becomes
Improving the recovery of useful components over current leukocyte removal filters is extremely significant. However, with the leukocyte removal filter using the conventional technique, it is difficult to significantly improve the recovery of useful components. A second need is to achieve higher leukocyte rejection rates than current leukocyte depletion filters and completely prevent the serious side effects caused by leukocytes infused into patients. However, it is difficult for a leukocyte removal filter using a conventional technique to achieve a leukocyte removal rate high enough to completely prevent such side effects. An object of the present invention is to provide a leukocyte-removing filter material having a leukocyte-removing ability per unit volume which is extremely higher than that of a conventional filter material, and in which the flow of a leukocyte-containing liquid is good, and furthermore, red blood cells, platelets, and the like. An object of the present invention is to provide a leukocyte-removing filter material having good blood compatibility and having little adverse effect on blood cells.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, the present inventors have found that a splittable cellulose containing cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm is obtained. Using a nonwoven fabric as a leukocyte-removing filter material, surprisingly high leukocyte-removing ability, good flow of leukocyte-containing liquid, and blood compatibility were found to be a good leukocyte-removing filter material, and completed the present invention. It is a thing. That is, the present invention
A leukocyte removal filter material comprising a splittable cellulose nonwoven fabric containing cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The term "divideable cellulose" as used in the present invention means that cellulose fibers themselves are divided by physical stimulation,
Refers to cellulose fibers that have the property of producing fibrils.
This refers to cellulose fibers that produce very fine, submicron-order microfibrils by high-pressure homogenizer treatment or the like. As the most preferred splittable cellulose fibers, cellulose fibers such as lyocell and superpolynosic can be exemplified. In the method of converting the splittable cellulose into a splittable cellulose nonwoven fabric containing cellulose microfibrils, a fibrous mat composed of splittable cellulose fibers is first prepared, and then a high-pressure liquid flow is jetted onto the nonwoven fabric to convert the splittable cellulose fibers into fibrils. A hydroentanglement method in which fibers are entangled and entangled with each other, and a method in which splittable cellulose fibers are first fibrillated using a mixer or a high-pressure homogenizer and then formed into a nonwoven fabric by a papermaking method. Dividable cellulose containing cellulose microfibrils is a mixture of cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm and cellulose fibers having a fiber diameter of 1.0 μm or more which are not completely microfibrillated. And has the form of a nonwoven fabric. The splittable cellulose fibers are divided into random diameters, and there are portions where the splittable cellulose fibers are used as trunks and cellulose microfibrils are branched in a branch shape. Cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm greatly contribute to capturing some lymphocytes having particularly low adhesion among leukocytes.

The term "fiber diameter" as used in the present invention refers to the diameter of each fiber when the nonwoven fabric is observed with a scanning electron microscope. Fiber having a fiber diameter of less than 0.03 μm has a low fiber strength,
The fibers are liable to be cut by leukocytes and other blood cell components that collide during processing of the leukocyte-containing liquid, which is not suitable for the purpose of the present invention. Further, fibers having a fiber diameter of 1.0 μm or more do not contribute to capturing some lymphocytes having particularly low adhesion among leukocytes. In order to efficiently capture low-viscosity lymphocytes and the like having relatively small diameters among leukocytes by contacting them with the filter material at multiple points, the fiber diameter of the cellulose microfibril is 0.03 μm or more and 0.8 μm or more.
It is preferable that the number of particles is smaller than μm. Fiber diameter is 0.03
The existence ratio between cellulose microfibrils having a diameter of 1.0 μm or more and cellulose fibers having a fiber diameter of 1.0 μm or more, when the leukocyte removal filter material of the present invention is observed with a scanning electron microscope, the fiber diameter is 0.03 μm or more. 1.0 μm
It is preferable that the total area of the cellulose microfibrils less than 1.0% occupies an area of 1.0% or more and 50% or less based on the area of all the cellulose fibers. If the content is less than 1.0%, the amount of cellulose microfibrils becomes insufficient in order to capture leukocytes in the leukocyte-containing liquid, and if it exceeds 50%, the amount of cellulose microfibrils increases. And the flow of the leukocyte-containing liquid is unfavorably deteriorated. A more preferred range is 5% to 45%.
Hereinafter, more preferably, it is 10% or more and 40% or less.
The fiber diameter of the cellulose fiber having a fiber diameter of 1.0 μm or more is preferably 1.0 μm or more and 20 μm or less, and more preferably 1.5 μm or more and 15 μm or less. In the leukocyte removal filter material of the present invention, the porosity is preferably 50% or more and less than 95%. The porosity of the filter material is 50%
If it is less than the above, the flow of the leukocyte-containing liquid becomes poor, and is not suitable for the purpose of the present invention. When the porosity is 95% or more,
Since the mechanical strength of the filter material is weakened and the filter material is easily crushed when the leukocyte-containing liquid is processed, the filter material is not suitable for the purpose of the present invention. The porosity is measured by measuring the dry weight (W ₁ ) of the filter material cut into a predetermined area,
Further, the thickness is measured to calculate the volume (V). This filter material is immersed in pure water, degassed, and the weight (W ₂ ) of the hydrated filter material is measured. From these values, the porosity is determined by the following calculation formula. Note that ρ in the following formula is the density of pure water. Porosity (%) = (W ₂ −W ₁ ) × ρ × 100 / V

In the leukocyte-removing filter material of the present invention, it is preferable that cellulose microfibrils having a very small fiber diameter form a network structure. It is preferable that the network-like cellulose microfibrils be present so as to cover pores formed by cellulose fibers having a fiber diameter of 1.0 μm or more and fixed to the cellulose fibers having a fiber diameter of 1.0 μm or more. The characteristics of the physical properties of the filter material of the present invention will be described below. In the filter material of the present invention, a plurality of cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm form a network structure, and are held by cellulose fibers having a fiber diameter of 1.0 μm or more. However, the cellulose microfibrils constituting the network structure are not bundled, and each fiber is in a spread state, that is, a so-called single fiber,
These single fibers are physically entangled to form a network structure. As the network structure, since the cellulose microfibrils have a curved structure, the formed network tends to have a curved structure. It is preferable that the reticulated cellulose microfibrils are uniformly held by cellulose fibers having a fiber diameter of 1.0 μm or more in a cross section perpendicular to the flow of the leukocyte-containing liquid, because leukocytes can be efficiently captured. . The fact that the cellulose microfibrils are uniformly held by cellulose fibers having a fiber diameter of 1.0 μm or more in a cross section perpendicular to the flow of the leukocyte-containing liquid means that the cellulose microfibrils are not uniformly held in the cross section perpendicular to the flow of the leukocyte-containing liquid. This means that the amount (density) of introduction of microfibrils in each part of the filter material that was randomly sampled is almost the same, and this amount actually exists in a certain amount of filter material in each part of the sampled filter material. It can be determined by measuring the variation in the amount of cellulose microfibrils to be formed. In addition, in the cross section perpendicular to the flow of the leukocyte-containing liquid, the amount of cellulose microfibrils introduced into each part of the randomly sampled filter material is almost equal, and the distribution of the mesh size in each part is It is particularly preferable that substantially the same and substantially the same network structure is formed. In this specification, such a state is expressed as “a uniform mesh structure is formed”. More specifically, a uniform network structure is formed when the network structure in each part of the filter material sampled at random is a distribution of a network having a size similar to that observed by an electron microscope. And a similar mesh pattern, and are considered to be substantially the same. When a uniform network structure is not formed, the distribution of the mesh size in each part differs greatly when observing the network structure in each part of the filter material sampled at random, and the form is also clear. State that can be determined to be different.

[0009] The leukocyte-removing filter material of the present invention is characterized by being a nonwoven fabric made of splittable cellulose containing cellulose microfibrils having a fiber diameter of 0.03 µm or more and less than 1.0 µm. It is suitable for taking a preferred structure of the leukocyte removal filter material described above, and the above-mentioned network structure is also formed in a preferred form. Cellulose microfibrils forming a network-like structure are difficult to cut in spite of their thinness and have moderate softness, so erythrocytes can pass through without excessive deformation, allowing liquid to pass through. Low resistance and less damage to red blood cells. Further, it is considered that cellulose microfibrils have strong affinity for leukocytes because of their thinness, and can be firmly captured. Further, since the leukocyte-removing filter material of the present invention is made of cellulose, all the fibers are made of cellulose, the affinity for blood cells such as red blood cells and platelets is originally low, and it is difficult to stimulate these cells. It's perfect about gender. The preferred thickness of the leukocyte removal filter material of the present invention is 0.1 mm or more in the flow direction of the leukocyte-containing liquid.
Preferably it is less than 0 mm. If the thickness is less than 0.1 mm, the frequency of collision between the leukocytes in the leukocyte-containing liquid and the filter material decreases, and it is difficult to achieve high leukocyte removal ability, which is not preferable. When the thickness is 30 mm or more, the passage resistance of the leukocyte-containing liquid is increased, which is not preferable because the treatment time is prolonged and hemolysis is caused by destruction of the erythrocyte membrane. More preferably, the thickness of the filter material in the flow direction is 0.1 mm or more and less than 15 mm. When the leukocyte-removing filter material of the present invention is treated with a binder such as a non-water-soluble polymer solution as a post-processing, generally, fibers constituting the fibrous structure are bundled together, or a plurality of fibers are formed. It is preferable not to treat with such a binder, since there is a possibility of breaking the network structure such as formation of a film between fibers. On the other hand, when the physical confounding of the fibers is insufficient, if the leukocyte removal filter material of the present invention is treated with a binder such as a relatively dilute water-insoluble polymer solution as a post-processing, Is effectively fixed, and the falling off of the fiber can be prevented.

Next, a leukocyte removal filter device using the leukocyte removal filter of the present invention will be exemplified. The leukocyte removal filter device is a device in which a filter including the filter material of the present invention is appropriately filled in at least a container having an inlet and an outlet. One or more filter materials may be stacked in the flow direction of the leukocyte-containing liquid and filled in the container. The leukocyte removal filter device may further include another filter material upstream and / or downstream of the filter material. Generally, the leukocyte-containing liquid often contains microaggregates. A prefilter can also be used to remove leukocytes from a leukocyte-containing liquid containing a large amount of such microaggregates. As the pre-filter, the average fiber diameter is 8 μm to 5 μm.
Aggregate of 0 μm fibers and average pore size 20 μm to 200 μm
A continuous porous body having the above pores is preferably used. The cross-sectional area of the filter material of the leukocyte removal filter device perpendicular to the flow direction of the leukocyte-containing liquid is 3 cm ² or more and 100 or more.
It is preferably less than cm ² . If the cross-sectional area is less than 3 cm ² , the flow of the leukocyte-containing liquid becomes extremely poor, which is not preferable. If the cross-sectional area is 100 cm ² or more, the thickness of the filter must be reduced, and a high leukocyte removal ability cannot be achieved, and the filter device is undesirably increased in size.

Hereinafter, a method for removing leukocytes from a leukocyte-containing liquid using a leukocyte removal filter device including the leukocyte removal filter material of the present invention will be described. The leukocyte removal method comprises treating a leukocyte-containing liquid with a leukocyte removal filter device and collecting the filtered liquid. More specifically, using a device including 1) an inlet, 2) a filter including the filter material of the present invention, and 3) an outlet, a leukocyte-containing liquid is injected through the inlet, and filtered through the filter through the outlet. This is a method for removing leukocytes from a leukocyte-containing liquid, which comprises recovering the liquid that has cleaved. Examples of the leukocyte-containing liquid to be filtered by the leukocyte removal filter device include a whole blood product, a concentrated red blood cell product, a concentrated platelet product, and a body fluid.
When the leukocyte-containing liquid is a whole blood product or a concentrated erythrocyte product, it is preferable to treat the leukocyte-containing liquid with a leukocyte removal filter device having a unit volume of 3 mL or more and less than 20 mL. Here, one unit is about 300 mL
Refers to whole blood products or concentrated red blood cell products in an amount of from .about.550 mL. If the device capacity per unit is less than 3 mL, a high leukocyte removal rate may not be achieved, which is not preferable. If the unit capacity per unit is 20 mL or more, the loss of useful components in the unrecoverable leukocyte-containing liquid remaining inside the device, in other words, the amount of useful components, is not preferable. By filtering the whole blood product or the concentrated erythrocyte product with a leukocyte removal filter device, leukocytes in the collected liquid can be removed to a residual white blood cell count of less than 1 × 10 ³ cells / unit. When the leukocyte-containing liquid is a concentrated platelet preparation, it is preferable to treat the leukocyte-containing liquid with a leukocyte removal filter device having a device capacity per unit of 1 mL or more and less than 10 mL. Here, 5 units means
Refers to a concentrated platelet product in an amount of about 170 mL to about 200 mL. If the device capacity per 5 units is less than 1 mL,
It is not preferable because it is highly likely that a high leukocyte removal rate cannot be achieved. If the device capacity per 5 units is 10 mL or more, unrecoverable useful components remaining inside the device increase, which is not preferable. By filtering the platelet concentrate preparation in the leukocyte removal filter apparatus of the present invention, the white blood cells in recovered liquid can be removed to less than the residual leukocyte number 1 × 10 ³ cells / 5 units. When using a leukocyte removal filter device to perform transfusion at the hospital bedside and simultaneously remove leukocytes, it is preferable to filter the leukocyte-containing liquid at a rate of 1 g / min or more and less than 20 g / min.
On the other hand, when leukocytes are removed from a blood product for transfusion at a blood center using a leukocyte removal filter device,
It is preferable to filter the leukocyte-containing liquid at a rate of 0 g / min or more and less than 100 g / min. The leukocyte removal filter device can be used not only for removing leukocytes, which cause various side effects after blood transfusion, from blood products for transfusion, but also for removing leukocytes in extracorporeal circulation therapy for autoimmune diseases. Extracorporeal circulation therapy for autoimmune diseases
It consists of removing leukocytes from the body fluid by continuously filtering the body fluid of the patient, which is a leukocyte-containing fluid, with a leukocyte removal filter device and returning the collected fluid to the body. As described above, the leukocyte removal filter material of the present invention,
Since the affinity with leukocytes is extremely high, the leukocyte-containing liquid can be efficiently processed without lowering the processing speed. In addition, it has excellent blood compatibility and has little damage to red blood cells and platelets.

[0012]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples.

Example 1 A splittable cellulose nonwoven fabric containing cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm was produced by the following procedure. As the splittable cellulose fiber, lyocell yarn having a monofilament fiber diameter of about 12 μm (Tencel, manufactured by Coatles) was used. This splittable cellulose fiber was immersed in a 1 wt% aqueous solution of sodium hydroxide and subjected to an alkali treatment at 0 ° C. to 5 ° C. for 60 minutes. After washing with water, it was immersed in a 3 wt% sulfuric acid aqueous solution and subjected to an acid treatment at 70 ° C. for 30 minutes. After washing with water, the fiber was spread and spread on a net to form a mat. Subsequently, the obtained mat was subjected to a high-pressure liquid treatment. That is, a columnar flow having a nozzle diameter of 0.2 mm, a nozzle pitch of 5 mm, and a pressure of 30 kg / cm ^{2 was} applied for 30 cm.
Was sprayed onto this mat for 10 seconds on each side for a total of 20 seconds. The obtained nonwoven fabric was dried, and physical properties were examined. The thickness was 0.2 mm, the porosity was 82%, and the ratio of the total cellulose area to the total area of the cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm as measured by scanning electron microscopy was 28%. Cellulose fibers of 1.0 μm or more were distributed between 1.0 μm and 13 μm. Further, cellulose microfibrils of 0.03 μm or more and less than 1.0 μm have a network structure close to a circle,
It was well entangled with cellulose fibers of 1.0 μm or more.
The obtained nonwoven fabric was used as a leukocyte removal filter material of the present invention and subjected to the following experiments. The leukocyte-removing filter device is produced by filling a laminate of eight leukocyte-removing filter materials produced as described above into a container having an effective filtration section of 9.0 cm ² (3.0 cm × 3.0 cm). did. The total volume of the leukocyte removal filter material was 1.44 cm ³ . 56 mL of CPD solution (composition: sodium citrate 26.3 g / L, citric acid 3.27 g) in 400 mL of blood
/ L, glucose 23.20 g / L, sodium dihydrogen phosphate dihydrate 2.51 g / L), and centrifuged, 456 mL of whole blood was prepared.
5 mL of MAP solution (composition: sodium citrate 1.50)
g / L, citric acid 0.20 g / L, glucose 7.21
g / L, sodium dihydrogen phosphate dihydrate 0.94 g /
L, sodium chloride 4.97 g / L, adenine 0.14
g / L, mannitol 14.57 g / L) to prepare concentrated red blood cells (RC-MAP). 7 at 4 ° C
50 g of concentrated erythrocytes (RC-MAP: hematocrit value: 58%, leukocyte count: 5,200 / μL) stored for one day were filtered by the above leukocyte removal filter device. The temperature of the concentrated red blood cells immediately before the start of the filtration was 10 ° C. Filtration of the concentrated red blood cells by the leukocyte removal filter device was performed at a head of 1.0 m, filtration was performed until the concentrated red blood cells disappeared in the blood bag, and the filtered blood was collected (hereinafter, the collected concentrated red blood cells were collected). Liquid). The average processing speed when filtering the concentrated red blood cells was 10.8 g / min. The volume of the concentrated erythrocytes before filtration (hereinafter, referred to as a pre-filtration solution), the volume of the recovered solution, and the number of leukocytes were measured, and the leukocyte remaining rate was determined. Leukocyte residual ratio = (the number of leukocytes in the recovered liquid) / (the number of leukocytes in the pre-filtration liquid) The volumes of the pre-filtration liquid and the collected liquid were each divided by the specific gravity of the blood product (1.075). Value. The leukocyte concentration of the pre-filtration solution was measured by injecting the pre-filtration solution diluted 10-fold with the Turk solution into a Bürker-Turk type hemocytometer and counting the number of leukocytes using an optical microscope. The measurement of the leukocyte concentration of the recovered solution was performed by the following method. The recovered solution is diluted to 5 times with a leuco plate solution (manufactured by SOBIODA). After mixing well, the mixture was left at room temperature for 6 to 10 minutes. This was centrifuged at 2,750 × g for 6 minutes, and the supernatant was removed to adjust the liquid amount to 1.02 g. After the sample solution was mixed well, the mixture was poured into a nadget type hemocytometer, and the number of leukocytes was counted using an optical microscope to measure the leukocyte concentration. As a result, the leukocyte residual rate was 10 ^−3.11 . When the free hemoglobin before and after filtration was compared, no difference was found between the two.

[0013]

Industrial Applicability The leukocyte-removing filter material of the present invention can remove leukocytes, which cause side effects of blood transfusion, from a leukocyte-containing liquid with high efficiency, and can obtain a high recovery rate of useful blood components. It is very useful as a filter material for a leukocyte removal filter used at the time of blood transfusion because it receives less damage.

Claims (1)

[Claims] 1. A leukocyte removal filter material comprising a splittable cellulose nonwoven fabric containing cellulose microfibrils having a fiber diameter of 0.03 μm or more and less than 1.0 μm.