JP2001204816A - Body fluid treatment device for direct blood perfusion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a body fluid treatment device capable of directly supplying total blood to be stably sent without choking because there is no useless space in space where body fluid treatment granules are filled in extracorporeal circulation treatment conducted as cause substance is adsorbed from blood taken from a patient. SOLUTION: The body fluid treatment granules are filled by 100% or more and less than 110% in this body fluid treatment apparatus.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an extracorporeal circulation treatment in which blood taken out of a patient is passed through a body fluid processor, the causative substance present in the blood is adsorbed, the blood is processed, and the processed blood is returned to the patient. The present invention relates to a body fluid processor that can stably flow without clogging even when whole blood is directly flowed.

[0002]

2. Description of the Related Art Blood purification by extracorporeal circulation is used as an effective treatment for diseases in which a causative substance is present in the blood and sufficient improvement cannot be achieved with drugs.
The blood purification method by extracorporeal circulation is a method in which blood is taken out of the body, disease-related substances such as causative substances are removed from the blood, and the blood is returned to the patient. Conventionally, when the molecular weight of the causative substance is large, many plasma perfusion methods have been developed in which plasma is separated from blood in advance using a plasma separation membrane or the like and the separated plasma is processed. There are several methods for removing the causative substance, such as adsorption, membrane separation, and sedimentation separation.If there is a selective adsorbent for the causative substance, the caustic substance can be removed simply by contacting the adsorbent Therefore, the adsorption method is the simplest, and many adsorbents have been developed. However, in recent years, due to the simplicity of operation, a method of directly contacting blood with an adsorbent without separating blood has attracted attention.

[0003] As a method of bringing the body fluid-treated particles into direct contact with blood, there are a method of filling the body fluid-treating particles into a container or the like and allowing blood to pass through the container (also called an online system), or a method of treating the body fluid into a blood bag or the like. There is a method (batch method) in which particles for body fluid treatment are sparsely mixed, mixed with blood and subjected to a predetermined treatment, and then the particles for body fluid treatment are filtered and blood is returned to the patient.
The on-line method is preferably used because of its simplicity of operation, and this method is generally called a direct blood perfusion method.

[0004] In the treatment of extracorporeal circulation, blood taken out of the patient from the body is returned to the patient after a predetermined treatment. In the case of plasma perfusion in which only plasma components having low viscosity and containing no blood cells are processed, or in the case where blood is separated from the body fluid processing particles by mixing the blood in a batch system, the blood can be separated without much difficulty. However, in the case of the on-line system, it is necessary to allow blood containing blood cells to pass stably and reliably between particles for treating body fluid, which is difficult.

[0005] One of the main factors (factors) regarding the stable flow of blood is the particle size. As an adsorption-type body fluid treatment device that can directly perfuse blood, first, it has an average particle diameter of 500.
Those using activated carbon of μm or more have been put to practical use. Generally, in order to increase the efficiency of adsorption and activation, it is sufficient to reduce the average particle size of the body fluid treatment particles and increase the effective surface area. However, when blood is directly perfused by the online method as described above, clogging or the like must be avoided, which is technically more difficult than the plasma perfusion method or the batch method.

On the other hand, studies have been made on an adsorbent suitable for a direct blood perfusion method in view of the physical and chemical properties of the adsorbent. Japanese Patent Application Laid-Open No. 63-115572 focuses on the average particle size and the particle size distribution.
Wherein 80% by volume or more of the particles have a volume average particle size of ± 2%.
It is described that particles distributed within 0% and having a particle size of less than 74 μm are at least 5% by volume and particles having a particle size of less than 25 μm are at most 0.1% by volume can be directly used as spherical particles for blood perfusion. I have. Also, JP-A-8-00532
No. 9 describes that "sulfated polysaccharide and / or a salt thereof bind to a water-insoluble carrier" improves blood permeability and can reduce the average particle size as compared with the original water-insoluble carrier.

[0007] In any of these cases, the usefulness as an adsorbent has been studied, but no detailed study has been made on a practical body fluid processor or blood flow rate. In practical use, it is needless to say that it is excellent as an adsorbent, but it also needs to have excellent characteristics as a body fluid treatment device filled with the adsorbent.

[0008] As an adsorber for direct blood perfusion, Japanese Patent No. 2660470 describes a container for filling an adsorbent for direct blood perfusion and a filled adsorber. According to the specification, the patent is characterized in that in an adsorber filled with an adsorbent, there is a space (referred to as a subspace in the specification) in which the adsorbent does not exist above a portion filled with the adsorbent. And The subspace has several useful functions, including facilitating the removal of air bubbles between the dried adsorbents, and is an essential requirement in the patent.

[0009] Extracorporeal circulatory therapy, as described above, requires the removal of blood from the patient to bring the blood into contact with the bodily fluid treatment particles. However, removing blood from the patient outside the body during treatment reduces the amount of blood in the patient and places a burden on the patient's body. Therefore, it is preferable that the amount of blood to be removed (extracorporeally circulating blood) is small. Since the volume of a portion through which blood passes, such as a body fluid processor and a circuit for connecting the patient to the body fluid processor and circulating blood, corresponds to the extracorporeal blood volume, it is desirable to minimize this volume. From such a viewpoint, a space in which the body fluid processing particles are not present in the space in which the body fluid processing particles are to be filled is not necessarily preferable because the space extracorporeally circulating blood is unnecessarily increased.

Further, when subjected to vibrations such as transportation, if there is a space where the body fluid processing particles do not exist, the body fluid processing particles easily move and contact between the particles occurs.
There is a concern that the particles may be broken or fine particles may be generated. If the particulates are returned with the blood into the patient's blood vessels, there is a risk of clogging the capillaries. For this reason, there is a standard for fine particles as a water-insoluble foreign substance in an infusion solution or the like. For example, according to the Japanese Pharmacopoeia, for an infusion with an internal volume of 100 ml or more, 5 μm
The standard of 0 or less and 5 or less of 25 μm or more is Brit.
In ish Pharmacopeia (1993),
For large volume injections of 100 ml or more, 5 μm or more and 100 or less, 10 μm
The above shows 50 or less standards.

In the case of extracorporeal circulation treatment, blood is returned to the patient, so the same concept can be applied to fine particles flowing out of the adsorber. Therefore, it is important to suppress the generation of fine particles in the blood processor from the viewpoint of reducing concerns about the outflow of fine particles, and it is necessary to eliminate the space where the particles can freely move in the blood processor and fix the particles firmly. preferable. However, if the body fluid treatment device is filled with particles for body fluid treatment in order to firmly fix the particles, then if you try to compress and fix it strongly, the space between the particles will be narrowed, making it difficult for blood to flow, or the particles will be destroyed by compression. There is a concern that fine particles may be generated. In particular, in practical use, it is necessary to consider how much the particles for body fluid treatment should be filled, taking into account the accuracy of the filling.

In order to fix particles in a container firmly and minimize wasteful space to make contact with liquid,
HPLC column (High performance liquid chromatography column; Hi
ghPerformance Liquid chlo
matographic Column) is widely used. The particles are firmly fixed by the mesh and used to prevent air bubbles from entering. In this case, in order to run a liquid without solid content and perform efficient analysis,
The average particle size is around 10μm and the column pressure drop is also 10kg / cm
It is common to operate in ^two or more. In the case of direct blood perfusion in which blood containing a solid content is flowed and the operation is performed at about several hundred mmHg or less in consideration of pressure loss and blood cell destruction as in the present invention, there are many technical differences from HPLC. That is, in the case of direct blood perfusion, there is a technical difficulty in handling blood, and it is difficult to analogize a preferable body fluid processor from the technique of the HPLC column.

As described above, there is no useless space which conventionally increases the amount of extracorporeal blood, the particles for body fluid treatment are held firmly, and the blood, which is the original purpose, can be stably flowed. The body fluid treatment device has not been sufficiently studied.

[0014]

SUMMARY OF THE INVENTION In accordance with the present invention, the space for holding the bodily fluid treatment particles has no useless space, the body fluid treatment particles are firmly fixed, and blood is reliably passed. It is intended to provide a body fluid processor for direct blood perfusion that can be performed.

[0015]

Means for Solving the Problems The present inventors have conducted intensive studies on the relationship between the state of filling, blood permeability, and outflow of fine particles. As a result, the filling rate of the body fluid processing particles in the space holding the body fluid processing particles has been found. By setting to a predetermined value, blood circulation is excellent,
The present inventors have found that a bodily fluid treatment device which can be put to practical use with almost no risk of outflow of fine particles can be obtained, and the present invention has been completed. That is, the present invention provides a container having an inflow port and an outflow port, in which a mesh is provided on each of the inflow port side and the outflow port side, and the space in the container formed between the meshes is filled with the bodily fluid treatment particles. A body fluid processor for direct blood perfusion, wherein the filling rate is 100% or more and less than 110%. "

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The particles for treating body fluid used in the present invention have a substantially spherical shape. Regarding the particle size distribution, either case where all the particles have the same particle size or a case where there is a so-called particle size distribution in which various types of particles are mixed may be used. In the case of a uniform particle size, the particle size of each particle is the same as the average particle size.

If there is a particle size distribution, the particle size of each particle is determined, and the average particle size can be determined based on the value. The average particle size has various definitions such as volume average, area average, number average, and log average. For example, in the case of the number average,
The average particle diameter can be determined by measuring the particle diameters di of the N individual particles and dividing the sum of the particle diameters di of the individual particles by the number N. Hereinafter, this number average particle size is simply referred to as an average particle size. In addition, as the particle size distribution becomes smaller,
The difference between the average particle size and other definitions is small, and in the case of a uniform particle size, the same value is obtained in any definition.

As a method of measuring the particle size of each particle, a photograph is taken by enlarging using an optical microscope, the particle size on the photograph is obtained, and the actual particle size is obtained by dividing by the enlarged ratio. it can. The average particle size can also be measured using a commercially available apparatus for measuring the particle size of a powder or the like. For example, when using a Coulter counter (manufactured by Beckman Coulter Co., Ltd.) that measures the change in electric resistance in an aqueous solution, the measured value of the target particles with the same device and the actual particle size are used. Can be obtained in advance, the average particle diameter is measured by the same apparatus, and the actual average particle diameter can be obtained from the conversion coefficient.

The particles used in the body fluid treatment device of the present invention must have an average particle size of 80 μm or more. If the average particle size is too small, the gap between the particles will be narrowed, making it difficult for blood to pass through. Although there is no critical value for the upper limit of the average particle diameter, as the average particle diameter increases, the surface area of the body fluid treatment particles decreases and the adsorption rate decreases.
Desirably, it is smaller than 0 μm. Preferably 150μ
m or more and less than 300 μm.

The particle size distribution does not need to be uniform, but if the particle size distribution is too wide, many small particles are present even if the average particle size is the same. Become.

Regarding the strength of the body fluid treating particles, it is not preferable that the particles are too soft or easily broken. When blood is passed, if consolidation occurs, sufficient blood flow cannot be obtained, and treatment time may be prolonged and treatment may not be continued.Therefore, in order to prevent consolidation of the adsorbent, the adsorbent must have sufficient mechanical strength. (Hard). The term “hard” as used herein refers to a carrier that swells less with a solvent and is less likely to be deformed by pressure, as compared to a soft carrier such as dextran or agarose. Hard carriers and soft carriers can be distinguished by the following method.
That is, the relationship between the pressure loss and the flow rate when the carrier is uniformly packed in a cylindrical column and the aqueous solution flows is almost linear for a hard carrier, while the pressure is exceeded for a soft carrier when the pressure exceeds a certain point. Deformation and consolidation prevent the flow rate from increasing.
In the present invention, a material having the above linear relationship up to at least 0.3 kg / cm ² is referred to as hard.

Examples of body fluid treatment used in the present invention will be described. First, examples of causative substances removed from blood include bilirubin, creatinine, amino acids, other medium-molecular-weight substances, drugs, toxicants, low-density lipoproteins, and immune complexes.

Next, examples of ligands immobilized on the body fluid treatment particle carrier and adsorbing the causative substance in blood include, for example, dextran sulfate and polyacrylic acid for low-density lipoprotein, and β- For 2-microglobulin, hydrophobic alkyl compounds, polyamino acids and κ-
Carrageenan and the like can be mentioned as examples.

Examples of the carrier for immobilizing the ligand include polysaccharides such as cellulose and dextran, and synthetic polymers such as polystyrene and polyvinyl alcohol. Generally, hydrophilic ones are preferable in that non-specific adsorption of proteins is small, but hydrophobic carriers may be used for non-specific adsorption of whole proteins, such as when a drug bound to a protein is adsorbed. is there.

It is preferable that the carrier of the body fluid treatment particles has a so-called porous structure having pores into which a target substance or the like can be removed. With this structure, not only the outer surface of the particles but also the inside of the particles can participate in the adsorption, and the amount of adsorption can be increased.

After the ligand is immobilized on the carrier, further modifications such as immobilization of various substances may be performed. For example, chemical modification for suppressing the adsorption of a substance other than the target, and surface coating for reducing the generation of fine particles from the adsorbent may be mentioned.

In some cases, the adsorbent used for plasma perfusion can be directly improved and used for blood perfusion by, for example, increasing the average particle size.

The container of the body fluid treatment device used in the present invention has an inlet and an outlet, and the inlet and the outlet have meshes. The mesh needs to be able to hold the body fluid treatment particles so as not to leak from the body fluid treatment device and to allow blood to pass through. The mesh may be in any form such as a crossed or knitted yarn, a flat plate having a large number of holes, or a line of linear wires. The opening of the mesh through which blood flows is called an aperture, and the value of the aperture can be a diameter when the shape of the opening is circular. In the case of a square diameter, a diameter of an equivalent circle having the same area can be used. In the case where the openings are interdigital, for example, in a case where linear wires are arranged, the length of the side with a shorter interval can be used.

In order to allow blood to pass through, the mesh must have an opening of 20 μm or more. If the opening is less than 20 μm, blood cells are easily trapped in the mesh. Further, in order to retain the particles, the mesh opening is preferably less than 50% of the average particle size. In particular, when there is a particle size distribution, it is necessary to consider the existence of particles having a particle size smaller than the average particle size, and to make the openings such that the particles having a small particle size do not leak.

The body fluid processor of the present invention is a body fluid processor for direct blood perfusion in which the filling rate of the particles for body fluid treatment is 100% or more and less than 110%. The filling rate of the body fluid treatment particles used in the present invention is defined by the ratio of the volume of the filled body fluid treatment particles to the volume of the body fluid treatment device, and is represented by the following equation.

Filling rate [%] = 100 × volume of particles for treating body fluid in filling solution / volume of body fluid treatment device In the filled state, the container is filled with an aqueous solution. The filling liquid can be selected according to the characteristics of the body fluid treatment particles, such as water, physiological saline, a buffer for keeping the pH constant, and a solution in which an antioxidant is dissolved. However, the volume of the body fluid processing particles may be measured using water, physiological saline, or the like instead of the filling liquid in a range where the volume of the body fluid processing particles does not change.

The volume of the body fluid treatment device in the present invention is the volume of the space filled with the body fluid treatment particles surrounded by the meshes on the inlet and outlet sides of the body fluid treatment device filled with the body fluid treatment particles. Point to. This volume can be obtained by calculation from the drawings, or can be obtained by actual measurement.

The volume of the body fluid treating particles in the present invention is:
A slurry solution in which the body fluid treatment particles are dispersed in an aqueous solution is placed in a container such as a graduated cylinder that does not apply a load to the body fluid treatment particles at the upper portion, and the body fluid treatment particles are settled, subjected to a moderate impact, and settled. It can be obtained at the stage when the volume occupied by the body fluid treatment particle portion does not change. If the measurement is performed without applying an appropriate impact, that is, in a very sparse sedimentation state, the volume occupied by the body fluid treatment particle portion changes easily due to the impact, and reliable measurement cannot be performed. Here, the moderate impact is an impact received during storage, transportation, treatment, and other handling. If the body fluid treatment device is filled in a very sparse state, the volume occupied by the body fluid treatment particles will easily change due to the impact received during storage, transportation, treatment, and other handling, and it will not be as easy as during manufacturing. The state of filling changes during use, which is not preferable. In addition,
The amount of the bodily fluid treatment particles may be measured by another method having reproducibility, and the measured amount may be converted into a value obtained by the above-described method for measuring the volume of the bodily fluid treatment particles. When the volume of the body fluid treatment particles is determined by this method, the body fluid treatment particles may be in a dry state or a wet state when measuring the amount of the body fluid treatment particles.

When the filling rate of the body fluid treatment particles is less than 100%, it means that the volume of the filled body fluid treatment particles is smaller than the volume of the body fluid treatment device. In the state, a space not filled with the body fluid treatment particles exists in the container. In this case, since there is a space that is not filled with the bodily fluid treatment particles, the extracorporeal circulation amount is increased unnecessarily, and the particles move inside the bodily fluid treatment device due to an impact during transportation or the like, and the particles are broken, It is not preferable because of concern about occurrence.

[0035] The filling rate of 100% or more means that the body fluid processing particles are filled to a volume larger than the volume of the body fluid processor, and the body fluid processing particles are necessarily deformed and compressed to the volume of the body fluid processor. become. In this case, the particles for body fluid treatment are deformed and compressed in the filled state as compared to the state before filling, but if excessively deformed and compressed, the gap between the particles becomes narrow and blood cell permeability is reduced. In addition, large deformation may cause breakage of particles and generation of fine particles, which is considered to be undesirable.

The state where the filling rate is 100% is a state in which particles for body fluid treatment equal to the volume of the body fluid treatment device are filled, and there is no space in which particles for body fluid treatment are not filled.
At the same time, it is an ideal state without deformation and compression of the body fluid treatment particles.

However, when actually manufacturing a body fluid treatment device, it is impossible to always adjust the filling rate to 100%, and it is inevitable that the filling rate of the manufactured body fluid treatment device has a wide range.

The inventors of the present invention have conducted intensive studies and found that if the filling rate is less than 110%, practical blood flow can be performed directly as a body fluid processor for blood perfusion. In the study, the effect of clogging of solids was not known simply by flowing the solution, and even if a slurry in which polymer particles were dispersed was used, adhesion of blood components such as proteins and blood cells to Based on the fact that the effects of activation and the like could not be grasped, the propriety was determined using bovine blood under blood transit conditions close to realistic extracorporeal circulation treatment. When the filling rate was 110% or more, the pressure loss gradually increased when blood was flowed into the body fluid treatment device, and finally blood could not flow.

On the other hand, when the filling rate was less than 100%, it was found that the increase in the number of fine particles in the body fluid treating device when the body fluid treating device was vibrated was significantly larger than when the filling rate was 100% or more.

Increase rate [%] of the number of fine particles in the body fluid treatment device =
100 × (the number of particles in the body fluid processor after vibration / the number of particles in the body fluid processor without vibration-1) The increase in the number of particles in the body fluid processor is considered to be due to the collision of particles due to vibration. Can be Therefore, when the filling rate is less than 100%, there is a space in the body fluid treatment device where the body fluid treatment particles do not exist, and the body fluid treatment particles are likely to move, so that the number of fine particles tends to increase.

It is considered that the fine particles in the body fluid treatment device are dispersed in the filling solution or adhered to the body fluid treatment particles, and in order to reduce the possibility of the fine particles flowing out of the body fluid treatment device during treatment, it is necessary to use the body fluid. It is preferable that the number of fine particles in the processor is small. From the viewpoint of suppressing the increase in the number of fine particles in the body fluid processor due to vibration during storage or transportation of the body fluid processor,
Filling rate is 100% in the sense of suppressing the increase of unnecessary extracorporeal circulation
The above is preferred.

Further, in a body fluid treatment device having a filling rate of the body fluid treatment particles of 100% or more and less than 110% as an adsorbent, the number of fine particles flowing out of the body fluid treatment device was measured under normal operating conditions. The outflowing particulates were very low. Also in this respect, it was found that the body fluid treatment device was very useful.

When filling the container of the body fluid processor with particles,
There are two main methods. One method is to remove one of the meshes on the inlet side or the outlet side, fill the particles, set the removed mesh, and fix it. Another method is to fix the mesh on the inlet side and the outlet side in advance in a container having a particle introduction port in the body part, put the particles through the particle introduction port, and then seal the particle introduction port. It is. Either filling method may be used, but in the former case, after filling the particles for body fluid treatment, the mesh is moved according to the volume of the particles for body fluid treatment, the space for that is secured, and the operation for fixing the mesh is performed. On the other hand, in the latter case, the mesh is fixed in advance to determine the volume of the body fluid treatment device, and the particle introduction port can be sealed after filling the particles, which is advantageous in production.

In the body fluid treatment device of the present invention, the filling liquid is sealed together with the body fluid treatment particles, and bubbles are generally removed.
When storing for a long period of time, gas molecules may be generated in the body fluid treatment device through the container wall or gap of the body fluid treatment device, but there is no problem if the amount is small.

The body fluid treatment device of the present invention can be subjected to a treatment after being subjected to a sterilization treatment such as steam sterilization or gamma ray sterilization. Sterilization of the body fluid treatment device can be performed by a commonly used method.

Appropriate conditions may be selected for the volume of the body fluid processor, the blood flow rate, and the like according to the purpose of treatment and the condition of the patient. Generally, the volume of the body fluid processor is 100 ml to 10 ml.
The blood flow rate is set at 200 ml / min or less. If the patient's weight is large, the patient's blood volume will be large, and the volume of the body fluid processor that can be used can be large. In addition, when the amount of the causative substance to be removed increases, a body fluid treatment device having a large volume is required. In some cases, after absorbing and removing the causative substance in the body fluid processor, replace the used body fluid processor with an unused body fluid processor, or activate the used body fluid processor to restore the adsorption capacity The extracorporeal circulation treatment can be performed again. The blood flow rate is usually about 200 ml / min for hemodialysis, hemofiltration dialysis, etc., and about 100 ml / min for plasma perfusion blood purification, but is set depending on the condition of the patient and the like. It can be changed during treatment. Of course, if there is no problem in the treatment, the condition may be out of the above range depending on the purpose of treatment or the condition of the patient.

FIG. 1 shows an example of an extracorporeal circuit using the body fluid treatment device according to the present invention. A blood collection circuit that leads the blood drawn from the patient to the body fluid processor is connected to the body fluid processor inlet, a blood return circuit that returns the blood from which the causative substance has been adsorbed and removed to the patient is connected to the body fluid processor outlet, and further, blood collection A pump for flowing blood is set in the circuit. The air chamber is connected to a pressure gauge, and can measure the pressure loss of the body fluid processor by measuring the inflow pressure and the outflow pressure of the body fluid processor.

Since the body fluid processor contains a filling liquid and contains almost no air bubbles, care must be taken to prevent the introduction of new air bubbles, and the cleaning and priming solution is simply passed through the body fluid processor. Ready to use.

The treatment involves removing blood from the patient and returning the processed blood to the patient by passing it through a body fluid processor.

The air chamber installed in the blood collection circuit and the blood return circuit has a larger cross-sectional area than that of a normal circuit (tube portion) and usually has a volume of about 10 ml, which slightly increases the extracorporeal blood volume. Even if air bubbles enter the circuit due to the cause, they have a very important function to trap the air bubbles and prevent them from flowing to the body fluid processor and the patient behind.

However, the cross-sectional area of the air chamber installed in the circuit is smaller than the cross-sectional area of a commonly used body fluid treatment device, and the body fluid is placed above the body fluid treatment device like the adsorber disclosed in Japanese Patent No. 2660470. This is a proper method from the viewpoint of reducing the amount of extracorporeal circulating blood because the volume can be reduced compared to the case where a space is also used as an air chamber by using the cross section of the processor. In addition,
The usage described here is for explaining the minimum necessary parts, and in addition, an anticoagulant and its circuit, a washing / priming circuit, a recovery circuit, and the like are additionally provided as necessary. In addition, a case where it is used in combination with another body fluid treatment device or the like is also conceivable, and can be changed as needed.

[0052]

The method of the present invention will be specifically described below with reference to examples.

(Preparation Example 1) [Preparation of adsorbent] Porous cellulose beads having an average particle diameter of 195 μm (manufactured by Chisso Corporation): 2000 ml, water: 2000 ml, 2N-
NaOH: 1060 ml and epichlorohydrin: 3
60 ml was added, and the mixture was stirred at 40 ° C. for 2 hours to react.
After the reaction, the beads were sufficiently washed with water to obtain epoxidized cellulose beads.

Dextran sulfate (sulfur content about 18%):
A solution of dextran sulfate in which 930 g was dissolved in 630 ml of water was prepared, and epoxidized cellulose beads: 200
0 ml and water: 100 ml were added. Furthermore, NaOH
After adjusting the pH to 9.5 with an aqueous solution, the mixture was reacted at 45 ° C. for 22 hours. After the reaction, the beads were sufficiently washed with water and NaCl water, monoethanolamine: 19.6 ml was added, and the mixture was allowed to stand at 45 ° C for 2 hours to seal unreacted epoxy groups. Thereafter, the resultant was sufficiently washed with water to obtain dextran sulfate-immobilized cellulose beads (adsorbent).

(Preparation Example 2) [Preparation of adsorbent] Dextran sulfate fixed cellulose beads (adsorbent) were obtained by the same process as Preparation Example 1 using porous cellulose beads having an average particle size of 195 µm to 227 µm.

(Example 1) [Blood-flow experiment] The adsorbent of Preparation Example 1 (152 ml) was filled into a cylindrical container having a volume of 142 ml (cross-sectional area: 7.6 cm ² , length: 18.8 cm), and the body fluid was filled therein. A processor was obtained. Ringer's solution, Japanese Pharmacopoeia, was used as the filling solution. The filling factor was 107%. 1
Bovine blood (ionized Ca concentration: 0.35 mM) anticoagulated with 300 ml of citric acid was used as a blood pool, and circulated through a body fluid processor at a superficial linear velocity of about 2.5 cm / min.
Blood was able to flow stably for 90 minutes. Finally, the pressure loss (= inlet pressure-outlet pressure) of the body fluid treatment device was 125 mmHg.

(Examples 2, 3, 4, Comparative Example 1 and Reference Example 1) [Blood Passing Experiment] The adsorbents of Preparation Example 1 and Preparation Example 2 were prepared by using a length of 18.8 c.
m in a cylindrical container at a filling ratio of 97% to 110% to obtain a body fluid treatment device. Ringer's solution, Japanese Pharmacopoeia, was used as the filling solution. Bovine blood anticoagulated with citric acid was passed through the body fluid treatment device at a superficial linear velocity of about 2.5 cm / min in the same manner as in Example 1 in a circulating manner. The results are shown in Table 1.

Both the filling rate of 100% (Example 2) and the filling rate of 97% (Reference Example 1) were able to flow stably for 90 minutes. At a filling rate of 110% (Comparative Example 1), the pressure increase was remarkably interrupted within 90 minutes. At a filling rate of 103% (Example 3), blood pressure was increased over time, but blood could be passed up to 90 minutes. At a filling rate of 107% (Example 4), the blood flow was able to be performed stably for 90 minutes at one time, and blood pressure could be passed up to 90 minutes at one time, although the pressure increased with time.

[0059]

[Table 1] (Example 5) [Measurement of the number of fine particles in the body fluid treatment device] The adsorbent of Preparation Example 2 was filled in a 730 ml container at a filling rate of 10%.
It was filled with 3% to obtain two body fluid treatment devices. A citrate buffer (pH about 6) was used as the filling solution.

While the adsorbent was washed away from the first body fluid processor with a liquid containing no fine particles, the entire amount together with the filling liquid was taken out in a slurry state into a collection container. The slurry solution is transferred to an empty collection container five times to separate the fine particles from the bodily fluid treatment particles, and allowed to stand for 3 minutes. Then, 2 ml of the supernatant is collected and the fine particle concentration in the supernatant is reduced. It was measured. The number of fine particles in the body fluid treatment device was determined by multiplying the fine particle concentration by the volume of the liquid in the slurry.

For the second bodily fluid processor, the bodily fluid processor is placed in a box, and vibrated in the horizontal and vertical directions for 1 hour each in accordance with JIS Z0232 “Vibration test method for packaged cargo and containers”. The number of fine particles in the body fluid treatment device was determined in the same procedure as in the body fluid treatment device.

The results are as shown in Table 2. The rate of increase in the number of fine particles in the body fluid treatment device due to vibration was 14 μm or more.
%, And 18% at 25 μm or more.

For the measurement of the fine particle concentration, a Coulter counter by an electric resistance method was used.

In this measurement, the size of the fine particles was 10 μm.
m and 80 μm or less. When filling a column used for treatment with a carrier of about 200 μm used for direct blood perfusion, etc., the carrier does not leak from the column,
In addition, assuming that the mesh used to allow the passage of blood cell components is about 50 μm, the size of the insoluble fine particles in the above range is sufficient.

(Comparative Example 2) [Number of Fine Particles in Body Fluid Processor] The adsorbent prepared in Preparation Example 2 was filled into a 730 ml capacity container at a filling rate of 90% to obtain two body fluid processors.

With respect to the two body fluid processors, one was not subjected to vibration and the other was subjected to vibration, and the number of particles in the body fluid processor was determined in the same manner as in Example 5.

Table 2 shows the results. The increase rate of the number of fine particles in the body fluid treatment device due to vibration is 75% and 25 μm for 10 μm or more.
m and 98%.

[0068]

[Table 2] (Example 6) [Number of outflow foreign substances] The adsorbent of Production Example 2: 754 ml was filled in a container having a volume of 730 ml to obtain a body fluid treatment device. The filling factor is 103%. A citrate buffer (pH about 6) was used as the filling solution.

This body fluid treatment device was subjected to high-pressure steam sterilization to produce a body fluid treatment device ready for practical use. The body fluid treatment device after sterilization was vibrated in the same manner as in Example 5 assuming transportation and storage. Using the body fluid processor after vibration, by the following method,
After cleaning assuming actual use, the number of fine particles flowing out of the body fluid treatment device was measured.

100 ml of physiological saline for injection was placed in the body fluid processor.
1 / min for 2 hours
The test solution flowing out of the body fluid treatment device for 1.5 hours, 1.5 hours, and 2 hours was collected. At the same time, physiological saline for injection was collected as a blank test solution. The number of particles in the test solution and the blank test solution was measured using a Coulter counter, and the difference in the number of particles between the test solution and the blank test solution was defined as the number of generated particles, and the total number of generated particles in 0 to 2 hours was determined by the integration method. Was. The average particle number (particles / ml) was determined by dividing by the total amount of the effluent.

The number of particles flowing out of the body fluid treatment device was 5 μm
More than 0.0 / ml, more than 25μm 0.0 / ml
Met.

[0072]

The bodily fluid processor for direct blood perfusion of the present invention comprises:
Blood can flow stably, there is no useless space in the space filled with the bodily fluid treatment particles, and an increase in particles in the column due to vibration can be suppressed.

[Brief description of the drawings]

FIG. 1 shows an example of an extracorporeal circulation circuit

[Explanation of symbols]

 REFERENCE SIGNS LIST 1 body fluid processor 2 mesh 3 body fluid processor inlet 4 body fluid processor outlet 5 body fluid processing particles 6 blood collection circuit 7 blood return circuit 8 blood collection port 9 blood return port 10 air chamber 11 pressure gauge 12 pump

Continued on the front page (72) Inventor Shigeo Furuyoshi 3-28-33 F-term (reference) 4C077 AA09 BB02 BB03 CC04 EE01 KK11 KK15 KK30 MM04 MM06 MM07 MM10 NN07 NN18 PP02 PP08 PP09 4D017 AA11 BA03 CA14 CB01 DA01 EA03 EB02

Claims (7)

[Claims] 1. A container having an inflow port and an outflow port, wherein meshes are installed on the inflow side and the outflow side, respectively, wherein the container space formed between the two meshes is filled with the bodily fluid treatment particles. Fluid treatment device, wherein the filling rate is 1
A bodily fluid processor for direct blood perfusion that is at least 00% and less than 110%. 2. The body fluid treatment device for direct blood perfusion according to claim 1, wherein the body fluid treatment particles have an average particle size of 80 μm or more and less than 500 μm. 3. The body fluid treatment device for direct blood perfusion according to claim 1, wherein the body fluid treatment particles are hard carriers. 4. The body fluid treatment device for direct blood perfusion according to claim 1, wherein the mesh has an opening of 20 μm or more and less than half the average particle size of the body fluid treatment particles. 5. The body fluid treatment device for direct blood perfusion according to claim 1, wherein the body fluid treatment particles are an adsorbent obtained by immobilizing dextran sulfate on porous cellulose. 6. The body fluid treatment device has a volume of 100 ml or more,
6. The body fluid processor for direct blood perfusion according to claim 5, wherein the volume is not more than 000 ml. 7. The body fluid processor for direct blood perfusion according to claim 6, wherein the apparatus is operated at a blood flow rate of 200 ml / min or less.