JPS5861753A - Blood treating apparatus - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood processing device for the purpose of treating immune-related diseases, cancer diseases, familial hypercholesterolemia, liver diseases, kidney diseases, and the like.

Recently, plasma exchange has attracted attention due to its remarkable effectiveness in treating autoimmune diseases, immune-related diseases such as rejection after organ transplantation, cancer diseases, familial hypercholesterolemia, liver diseases, and kidney diseases. has been done. This includes antibodies in the blood, immunosuppressive factors secreted by cancer cells, low-density lipoproteins,
Alternatively, this may be because disease-causing substances such as proteins bound to metabolic products, liver and nephrotoxic substances were removed together with plasma. However, in plasmapheresis, it is necessary to discard the patient's plasma or replace it with normal human plasma or macroserum albumin, making it difficult to treat many patients. Furthermore, it is a wasteful method because it removes other useful components along with unnecessary disease-causing substances.

On the other hand, blood purification methods that use adsorbents have the advantage of almost no need for replenishment fluids because they remove unnecessary components, but when activated carbon or porous resins are used as adsorbents, low-molecular-weight substances such as creatinine and uric acid can be removed. Substances are adsorbed, but
Disease-causing substances with large molecular weights are hardly removed and sufficient therapeutic effects for the above-mentioned diseases cannot be obtained. In addition, some porous resins (for example, the porous resin Amberlite XAD-7 manufactured by Rohm & Baas) can adsorb proteins with a medium molecular weight or higher, but at the same time they absorb proteins such as vitamins and sugars. It has disadvantages such as adsorption of useful components, elution of impurities mixed in during manufacturing, and generation of fine particles, and is therefore of poor practical use.

As a result of various studies to solve these problems, the present inventors found that at least 0.1 μneo Ieint2 was added to the surface.
However, porous materials with silanol groups are usually amorphous, and when amorphous materials are used for blood treatment, they absorb white blood cells and platelets. It has been found that there is a problem in which a decrease in As a result of further investigation, the inventors discovered that these problems could be solved by separating blood into blood cells and plasma in advance and treating only the separated plasma with an adsorbent, thereby completing the present invention.

That is, the present invention provides a blood processing apparatus mainly composed of a mechanism for separating blood into blood cells and plasma, a mechanism for treating the separated plasma with an adsorbent, and a mechanism for mixing the adsorbed plasma and blood cells. There is at least 0 of the agent on the surface.
．． This blood processing device is characterized by being a porous body having silanol groups of 1 μHIOI e/7722.

The porous body conveniently used in the present invention has a surface with at least 0
．． 1 prnole/7722, preferably 0.5
μm01677722 or more, particularly preferably 0.5 μm
It is necessary to have silanol groups of ole/m2 or more. When the number of silanol groups is less than 0.1 μmole77722, the protein adsorption ability is low and it is not suitable for the purpose of the present invention. Note that the silanol group referred to here is (=S
It is a group represented by i-01(,), and its surface concentration is a value measured by methyl red absorption method. Also,
The surface includes not only the outer surface but also the inner surface of the pores. As a porous body having such a silanol group on the surface.

Porous glass, porous silica, porous silica-alumina, and other porous bodies treated with water glass treatment, polymer coating, chemical bonding, etc. to introduce silanol groups onto the surface. can be given. .

Porous glass is produced by melt-molding alkali borosilicate glass, then heat-treating it in a transition temperature range, and then acid-treating fine phase-separated glass. Usually, the amorphous crushed product is sieved and used. Porous silica is obtained by acid treatment of an aqueous solution of sodium silicate, and porous silica-alumina is obtained by firing a hydrated silica-alumina molded body. The introduction of silanol groups by water glass treatment can be carried out, for example, by immersing the porous body in water glass, drying it after washing, and then immersing it in a hydrochloric acid solution or the like, followed by heating and drying. Introduction of silanol groups by polymer coating involves coating the porous body with a polymer having silanol groups (for example, a trimethoxysilylpropyl methacrylate polymer or an acrylic or methacrylic polymer containing trimethoxysilylpropyl methacrylate as a copolymerization component). This can be done by As a coating method, a method can be used in which a monomer is coated with a solution containing a polymerization initiator if necessary, and then polymerized by heating polymerization or the like. Introduction of silanol groups through chemical bonding can be carried out by directly reacting a silane coupling agent with the porous body.

Among the above-mentioned porous materials having silanol groups, porous glass is preferably used because it has high physical strength and a high concentration of silanol groups. The diameter is preferably within the range of 0.1mm to 5H, and 0.2ff to 2mm.
More preferably, it is within the range of HIM. If the particle size is smaller than 0.1 MM, problems such as increased pressure loss in the adsorbent layer and reduced throughput per unit time will occur. If the particle size is larger than 5M, the voids between the particles will be large and the adsorption performance will deteriorate, which is not preferable.

In addition, the pore volume of the porous body is 0.3cc//II~20c
It is preferably within the range of c//y. 0.3cc/
If it is less than 7, the protein adsorption capacity will be low and it will not be suitable for the purpose of the present invention. 2. If Ocr-/(7 or more), the skeleton becomes weak and fine fragments are likely to occur.Furthermore, the pore diameter of the porous material is preferably within the range of 20^ to 3000λ.If it is smaller than 2OA, the protein becomes Since it cannot enter the inside, it is not effectively adsorbed.If the pores are larger than 3000A, the surface area becomes small and the skeleton becomes brittle, which is not preferable.

Furthermore, if the pore size distribution of the porous body is wide, the selective adsorption depending on the protein size will be reduced, so it is preferable that the pore size distribution is uniform. That is, when the average pore diameter is D, it is preferable that the volume of pores having a pore diameter in the range of 0.8D to 1.2D accounts for 80% or more of the total pore volume. If a material with such a sharp pore size distribution is used, the target protein can be absorbed by using a porous material with an appropriate pore diameter depending on the molecular weight of the protein to be adsorbed, as described below. can be selectively adsorbed and removed.

There is a close relationship between the average pore diameter and the type of protein adsorbed.
tA (immuno-ragulatory a)
TOGF (T cell), an immune-related soluble factor secreted by T lymphocytes
growth factor), G8F (growth factor)
k+ 5olable factor),
88F (5uppressor 5olublef
actor), TRF (1' cell replac
ing factor), UJ1i' (killer
cell help factor), thymic humoral factor LSF (I ymphocyme-sti)
mulating factor) Ya0IF(com
(inducing factor)
, vri077- TDF (thy
rnocyte-mountainferentiation f
The average pore diameter for immunoglobulin G with a molecular weight of 160,000 is 550.
The average pore diameter ranges from 900 to 160 OA for low-density lipoproteins with a molecular weight of several hundred blades, and the average pore diameter ranges from 1000 to 1000 for immune complexes with a molecular weight of 200,000 to 1 million OA. 2500i range is suitable for each.

These porous bodies are used by filling columns.

The column has a main body having an inlet and an outlet shaped to be easily connected to a blood circuit on both sides of a porous layer, and a gap between the adsorbent layer and the inlet and outlet through which plasma passes but the porous body does not pass.
A column having a filter having a mesh size of 0 to 180 is preferable, but any column having a substantially similar function may be used for this purpose. As the material of the column, glass, polyethylene, polypropylene, polycarbonate, polystyrene, polymethyl methacrylate, etc. can be used, but polypropylene, polycarbonate, etc., which can be sterilized by autoclaving, are particularly preferred. Any filter may be used as long as it is physiologically inert and strong, but filters made of polyester are particularly preferably used.

As a mechanism for separating blood into blood cells and plasma used in the present invention, a filtration separation device using a selectively permeable membrane or a separation device using a centrifugation method can be used. A filtration/separation device that does this is preferable because it causes less damage to blood cell components. As a permselective membrane, 0.01 to 2.0μ, more preferably 0.04 to 1
．． Membranes with an average pore size of 2μ are suitable, homogeneously porous membranes being preferred. The material for such a membrane is ethylene.

Propylene, vinyl chloride, vinylidene chloride, fluorinated ethylene, 4-methyl-1-pentene.

1.3- Phtadiene, isoprene, isobutylene.

Chloroprene, styrene, chlorostyrene, dichlorostyrene, carbomethoxystyrene, hinyltoluene, vinylbenzoin W, hinylnaphthalene.

Hinylcarbazole, vinylpyrrolidone, methyl methacrylate-1-, ethyl methacrylate, 2-hydroquine ethyl methacrylate, dimethylaminoethyl methacrylate, 2-ethylhexyl methacrylate, benzyl methacrylate-1-, methyl acrylate-1-, ethyl acrylate , acrylonitrile, methacrylonitrile, 1
Homopolymers or copolymers such as 1tlt vinyl, vinyl alcohol, vinyl formal, vinyl butyral, ethylene carbonate I., methyl hinyl ether, maleic anhydride, and polyamides, polyesters, polycarbonate I-. Polyurethane, polysulfone.

Silicone resins, cellulose derivatives such as nitrocellulose, ethylcellulose, and cellulose acetate-1- are used. Among these, polyvinyl alcohol, polysulfone and cellulose acetate are preferably used. These membranes can be used either in the form of a flat membrane or in the form of a hollow fibrous membrane, but hollow fibrous membranes are preferred in that they can efficiently separate plasma.

The mechanism for mixing plasma and blood cells used in the present invention preferably has a stirring mechanism, but it may also be a Y-shaped connector that simply brings plasma and blood cells together.

The present invention will be explained in more detail below using the drawings. FIG. 2 is a cross-sectional view of an example of a column filled with an adsorbent. Plasma is introduced from a plasma population 2, treated with an adsorbent 5, and then discharged from a plasma outlet 6. The adsorbent is retained within the column by a filter 4. FIG. 6 is a sectional view of an example of a plasma separation device using a permselective membrane. Blood is introduced from the inlet lower, and the hollow fibrous membrane 1
0, it is separated into blood cell components and plasma components. Naco plasma components pass through the pores of the membrane and are led out from the plasma outlet 9, and blood cell components are led out from the blood cell outlet 8. FIG. 1 is a schematic diagram showing an example of a blood processing apparatus of the present invention.

Blood is introduced into the device through the blood inlet 11, and the pump 1
2, the blood is supplied to a plasma separator 6, where it is separated into blood cells and plasma. The separated plasma is supplied through a pump 13 to a column 1 filled with an adsorbent, and after being subjected to adsorption treatment, it is mixed with blood cells in a plasma/blood cell mixing device 14 and led out from a blood outlet 15.

In addition to the above-mentioned mechanism, the device of the present invention may be provided with a heparin supply mechanism, a heparin antagonist supply mechanism, etc., which are normally used in artificial kidneys and the like.

Diseases that can be treated by the blood processing device of the present invention include systemic lupus erythematosus, chronic rheumatoid arthritis, chronic glomerulitis 1 myasthenia gravis, multiple sclerosis, polymyositis, and Bartchet's disease.

SjOgrcn syndrome 1 scleroderma syndrome soft tissue eosinophil granulomatosis.

I (ecrfordt syndrome, Wegner's granulomatosis, bronchial asthma.

Hypersensitivity pneumonitis, acid pneumonitis, chronic active hepatitis.

Primary biliary cirrhosis, idiopathic inflammatory bowel disease 2 ankylosing spondylitis, diabetes, polyarteritis, aplastic anemia, autoimmune hemolytic anemia, Fe1ty syndrome, idiopathic thrombocytopenic purpura, organ Examples include immune-related diseases such as post-transplant rejection, cancer diseases, familial hypercholesterolemia, liver diseases, and kidney diseases.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to such embodiments.

(Example) Porous glass with an average pore diameter of 56 OA (surface silanol group concentration - 0.47 μtl) Ie/m2, particle diameter range = 0.5 m to 1.011711, pore volume = 0.7)
6α/y, and when the average pore diameter is D, the percentage of the volume of pores whose pore diameter is within the range of 0.8D to 1.2D - 91%) is the internal volume shown in Figure 2. After filling a 200 cc cylindrical column (made of polypropylene, with 135 mesh polyester filters on both ends of the column), sterilization was performed in an autoclave to prepare a column filled with the adsorbent.

Overflow type plasma separation device using hollow W4 fiber membrane made of polyvinyl alcohol (Surface area: Q, 5 m2. Average pore diameter 0.0
Blood was introduced into the carotid artery of an anesthetized dog (17.0 ml+, male) at a flow rate of 96,117 m1n, and filtered plasma was introduced into the adsorbent column at a flow rate of about 24 M1/mn. The plasma processed by the adsorbent column was combined with blood cell components in the plasma separator and returned to the body via the jugular vein.

After 6 hours of blood processing, blood cell components were extracted.

The effect on plasma protein components was investigated.

As shown in the table, there was almost no change in blood cell components before and after the treatment, demonstrating that the blood processing apparatus of the present invention has high safety for blood cell components.

In addition, when plasma components were analyzed by liquid chromatography, the removal rate of γ-globulin was 2.6 times that of albumin, and this blood processing table device selectively adsorbed the γ-globulin fraction. I found out that it can be removed.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing an example of the apparatus of the present invention. Second
The figure is a sectional view showing an example of a column filled with an adsorbent used in the device of the present invention, and FIG. 6 is a sectional view showing an example of a device for separating blood into blood cells and plasma. 1. Adsorbent packed column 2. Plasma inlet 3, plasma outlet
4. Filter 5, adsorbent 6
．． Plasma separator 7, blood population 8, blood cell outlet 9 plasma outlet 10. Hollow fibrous membrane 11
Blood inlet 12. Pump■13, pump■
14. Plasma/blood cell mixing device 15, blood outlet port Patent applicant RiRa Co., Ltd. Agent Patent attorney Kendai Honda 1 f @ 2nd giant 3rd figure

Claims (1)

[Scope of Claims] 1. A blood processing device mainly consisting of a mechanism for separating blood into blood cells and plasma, a mechanism for treating the separated plasma with an adsorbent, and a mechanism for mixing the adsorbed plasma and blood cells. , the adsorbent is present on the surface at least 0.1 μmol
A blood processing device characterized in that it is a porous body having silanol groups of e/7n2. 2. The blood processing device according to claim 1, wherein the particle size of most of the porous body is within the range of 0.1 fl to 5 fl. 3. The blood processing device according to claim 1, wherein the particle size of most of the porous body is within the range of 0.2ff to 2W. 4. The pore volume of the porous body is 0.5cc//f~2.0cc/
Blood processing device 5 according to any one of claims 1 to 3, which falls within the range of The blood processing device according to any one of the ranges 1 to 4. 6. The porous body has pores in which the volume of pores with a pore diameter in the range of 0.8D to 1.2D accounts for 80% or more of the total pore volume, where the average pore diameter is D. The blood processing device according to any one of claims 1 to 5, which is a blood processing device. 7. The blood processing device according to any one of claims 1 to 6, wherein the porous body is selected from the group consisting of porous glass, porous silica, and porous silica-alumina. 8. The blood processing device according to any one of claims 1 to 6, wherein the porous body is porous glass.