JP2005110832A - Module for blood purification and blood purification method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a module for blood purification and a blood purification method for efficiently reducing a plurality of harmful substances such as bilirubin, ammonia, endotoxin, bile acids, hepatitis B viruses and hepatitis C viruses in blood or plasma by improving the harmful substance absorbing and removing ability of titanium oxide. <P>SOLUTION: In the module for the blood purification, each two or more kinds of the titanium oxide of different properties among the titanium oxide exhibiting photocatalytic activity, the titanium oxide not exhibiting the photocatalytic activity and the titanium oxide in which a part of oxygen is replaced with a substance other than the oxygen is individually housed in a container 10 by the kind, the plurality of containers 10 are serially connected and housed inside one module, and the blood or the plasma is distributed inside the containers. By using the module, the titanium oxide inside the module is irradiated with light and the plurality of harmful substances in the blood or the plasma discharged from the module are reduced. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention is for blood purification using titanium oxide for efficiently reducing various harmful substances such as bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, hepatitis C virus and the like present in blood or plasma. The present invention relates to a module and a blood purification method.

  Conventionally, in a blood purification method in which a blood or plasma of a patient is brought into contact with an adsorbent and a harmful substance which is a pathogenic substance is removed using a physicochemical phenomenon or an immune reaction, a coconut shell adsorbent or an oil pitch type is used. , Peat-based, charcoal-based activated carbon, styrene / divinylbenzene copolymer anionic ion-exchange resin with amino groups, quaternary ammonium groups, etc. as active sites, polystyrene derivative fibers with antibiotics Immobilized fibers and the like were used as the adsorbent.

  Among these, the adsorption of blood by activated carbon has been a major problem with the outflow of coal dust and platelet adhesion from activated carbon. However, these problems have been improved by microencapsulation of activated carbon and blood purification using activated carbon. The law was widespread.

  The anionic ion exchange resin having an amino group, a quaternary ammonium group or the like as an active site in the styrene / divinylbenzene copolymer is an adsorbent for bilirubin produced by decomposing hemoglobin when aged erythrocytes break down As clinical use.

  Furthermore, the fiber in which an antibiotic is immobilized on the polystyrene derivative fiber is used for adsorption and removal of endotoxin, which is a cell wall component of Gram-negative bacteria, which is considered to be a central etiological agent of various pathologies that develop from sepsis and sepsis. ing.

  Recently, for example, an adsorbent composed of titanium oxide particles suitable for plasma compatibility has been proposed as an adsorbent for bilirubin (see, for example, Patent Document 1).

JP 2001-245973 A

However, each of the above conventional adsorbents has some drawbacks and cannot be said to be sufficiently satisfactory from a practical viewpoint.
Specifically, the activated carbon is excellent in removing low to medium molecular weight substances having a molecular weight of 5000 or less, but its ability to remove protein binding substances such as bilirubin and bile acids is insufficient. It was.

  In addition, since the anionic ion exchange resin has insufficient compatibility with plasma, it is necessary to improve the surface by using a blood compatible polymer substance such as polyhydroxyethyl methacrylate, Inconveniences such as a decrease in volume and surface area occurred.

  Fibers with antibiotics immobilized on polystyrene derivative fibers can be used to remove endotoxins. To stabilize the immobilized antibiotics, it is necessary to make the filling solution in the module acidic (about pH 2). There is. For this reason, there were inconveniences, such as having to use 4 liters or more of physiological saline for washing.

  In addition, the conventional commercially available modules containing the above adsorbents have specified harmful substances that can be adsorbed, and multiple modules are used to remove multiple harmful substances. A single module could not adsorb and remove a plurality of harmful substances such as bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, and hepatitis C virus.

  Thus, as a result of repeated studies on adsorbents that adsorb and remove harmful substances in blood or plasma, the present inventors have found that various titanium oxides are bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, C type. It has the ability to adsorb and remove multiple harmful substances such as hepatitis virus. Furthermore, depending on the type of harmful substance, it has been found that a better removal effect can be obtained by expressing photocatalytic activity in titanium oxide. .

  Accordingly, the present invention aims to improve the ability of adsorption and removal of harmful substances of titanium oxide, and a plurality of harmful substances such as bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus and hepatitis C virus in blood or plasma. It is an object of the present invention to provide a blood purification module and a blood purification method capable of efficiently reducing the blood pressure.

The blood purification module according to the present invention includes physical properties of titanium oxide exhibiting photocatalytic activity, titanium oxide not exhibiting photocatalytic activity, and titanium oxide obtained by substituting a part of oxygen with a substance other than oxygen. Contain two or more types of titanium oxides, and reduce any two or more harmful substances in total bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, hepatitis C virus in blood or plasma It is characterized by.
By using a plurality of types of titanium oxide having different physical properties as described above as an adsorbent for blood purification and incorporating them into one module, a single module can be used to remove a plurality of harmful substances in blood or plasma. It can be reduced at once.

In addition, preferable embodiments of the blood purification module according to the present invention include physical properties of titanium oxide exhibiting photocatalytic activity, titanium oxide not exhibiting photocatalytic activity, and titanium oxide in which a part of oxygen is substituted with a substance other than oxygen. Different types of different titanium oxides are individually stored in containers for each type, and a plurality of the containers are connected in series in one module, and blood or plasma circulates in the container It is comprised so that it may do.
By using the blood purification module configured as described above, one module can appropriately select and apply titanium oxide corresponding to the harmful substance to be reduced according to the symptoms of each patient. Also, convenience is excellent.

In the blood purification module, the titanium oxide is preferably in the form of granules having a particle size of 0.05 mm or more and 2 mm or less.
From the viewpoint of the amount of liquid passing through the module and the amount of harmful substances adsorbed, the titanium oxide used in the present invention is preferably within the above particle size range.

In addition, the blood purification method according to the present invention includes a plurality of types of oxidized materials having different physical properties among titanium oxide exhibiting photocatalytic activity, titanium oxide not exhibiting photocatalytic activity, and titanium oxide in which a part of oxygen is substituted with a substance other than oxygen. Distributing blood or plasma containing harmful substances in a module containing titanium and irradiating the titanium oxide with light to reduce harmful substances in blood or plasma discharged from the module To do.
Using a plurality of types of titanium oxide as described above, blood or plasma containing a high concentration of harmful substances is distributed outside the body so as to come into contact with the titanium oxide, and against titanium oxide exhibiting photocatalytic activity. Thus, by irradiating light and improving the ability to remove harmful substances, a plurality of types of harmful substances can be efficiently reduced.

As described above, if the blood purification module according to the present invention is used, harmful substances present in blood or plasma can be efficiently reduced.
In addition, the blood purification module according to the present invention can be appropriately selected and incorporated with a single type of titanium oxide corresponding to the harmful substance to be reduced in one module according to the symptoms of each patient. Also excellent in properties. Furthermore, since a plurality of types of harmful substances can be reduced with a single module without using a plurality of blood purification devices, the blood purification device can have a simple configuration.
Therefore, the blood purification method according to the present invention using the above-described blood purification module can be suitably used for blood purification treatment by extracorporeal circulation such as hemodialysis, plasma exchange, adsorption therapy and the like.

Hereinafter, the present invention will be described in more detail.
The blood purification module according to the present invention includes a plurality of types of titanium oxide having different physical properties among titanium oxide exhibiting photocatalytic activity, titanium oxide not exhibiting photocatalytic activity, and titanium oxide obtained by substituting a part of oxygen with a substance other than oxygen. Are used in combination.
As described above, titanium oxide has different physical properties, that is, substances exhibiting adsorption ability, depending on the mode, and a plurality of types of titanium oxide having different physical properties are appropriately combined as an adsorbent for blood purification. By incorporating in one module, it is possible to reduce a plurality of harmful substances in blood or plasma at once by one module.
As a result, blood or plasma containing a high concentration of harmful substances can be circulated outside the body so as to be in contact with a plurality of types of titanium oxide in the module. Become.
Therefore, the blood purification module according to the present invention can be suitably used for blood purification treatment by extracorporeal circulation such as hemodialysis, plasma exchange, adsorption therapy and the like.

Specific examples of the harmful substance include pathogenic substances such as total bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, and hepatitis C virus.
As described above, the conventional blood purification module has been identified to be able to adsorb among these harmful substances, and in order to adsorb and remove multiple harmful substances, a plurality of modules are used in combination. Had to do.
On the other hand, according to the blood purification module according to the present invention, it is possible to effectively adsorb and remove these plural harmful substances with one module.

In addition, titanium oxide in which a part of oxygen is substituted with a substance other than oxygen is a substance in which a part of oxygen which is a constituent atom of titanium oxide is substituted by doping, for example, nitrogen, carbon, sulfur, etc. And is represented by the chemical formula TiO _2-x A _x . Here, A is nitrogen, carbon, sulfur or the like.
Such titanium oxide is particularly excellent in the ability to adsorb and remove bilirubin due to photocatalytic activity under visible light irradiation, and can sufficiently adsorb, decompose and remove bilirubin even under the light of a fluorescent lamp. .

Further, in the blood purification module according to the present invention, a plurality of types of titanium oxide having different physical properties are individually stored in containers for each type, and a plurality of the containers are serially connected in one module. It is preferably configured to be connected and housed so that blood or plasma flows through the container.
By adopting such a configuration inside the module, even a single module can be used in various ways according to the blood state of each patient, and can be excellent in convenience.

FIG. 1 shows an example of a container for individually storing a plurality of titanium oxides having different physical properties.
A titanium oxide container 10 shown in FIG. 1 contains a titanium oxide 20 inside a translucent tubular main body 11, and plate-like porous bodies 13 are arranged at both ends of the main body 11, The body 13 is firmly fixed by the end cap 12 through the sealing material 14.

The porous body 13 is for preventing the titanium oxide 20 accommodated in the main body from flowing out. The porous body 13 is made of a material such as glass or ceramics and has pores having a pore diameter of about 10 to 100 μm.
The sealing material 14 is made of a material generally used for a biocolumn, such as silicon, nitrile, Teflon (registered trademark) coating Viton (registered trademark), or fluorosilicone.
The end cap 12 is formed with an O-ring groove 15.

FIG. 2 shows an example of a blood purification module in which the titanium oxide container 10 is housed.
In the module shown in FIG. 2, a plurality of containers 10 in which a plurality of titanium oxides having different physical properties are individually stored for each type are closely connected in series via an O-ring 30 and one module is connected. Built in.
Therefore, a plurality of harmful substances can be efficiently removed by circulating blood or plasma containing a plurality of harmful substances in one module housing a plurality of containers 10.

  For example, for patients with high levels of bilirubin in blood or plasma, store more containers containing titanium oxide with high bilirubin adsorption capacity in the module, or for patients with high levels of ammonia in blood or plasma. Is an adsorbent for blood purification consisting of titanium oxide corresponding to harmful substances to be reduced according to the symptoms of each patient, such as storing a large number of containers containing titanium oxide with high ammonia adsorption capacity in the module Can be appropriately selected and applied.

  Further, by configuring the module so as to transmit light, titanium oxide having photocatalytic activity can exhibit photocatalytic activity during circulation of blood or plasma in vitro. The removal effect can be improved with respect to the harmful substances in the part.

Here, to exhibit photocatalytic activity means to exhibit an action as a catalyst by irradiating with ultraviolet and / or visible light.
Examples of titanium oxide exhibiting such photocatalytic activity include those in which oxygen deficiency defects are formed in titanium oxide fine particles, those in which platinum is supported, and those in which nitrogen is doped, which are already commercially available. Has been.

  Titanium oxide exhibiting photocatalytic activity as described above not only exhibits an excellent bilirubin removal effect, but also suppresses the adsorption of useful albumin in plasma components. Due to its photocatalytic activity, such as hepatitis B virus and hepatitis C virus. The removal effect of harmful substances is also recognized.

The titanium oxide used in the blood purification module according to the present invention is granular and preferably has a particle size of 0.05 mm to 2 mm, more preferably 0.1 mm to 0.5 mm.
When the particle size is less than 0.05 mm, the pressure loss when housed in the module is high, and a desired liquid flow rate cannot be obtained.
On the other hand, if the particle size exceeds 2 mm, the surface area of the titanium oxide granules becomes too small, and the amount of harmful substances adsorbed decreases.

In the present invention, titanium oxide particles having a specific surface area of 35 m ² / g or more are preferably used in order to exhibit the effect of adsorbing and removing ammonia.
In addition, there is a kind of titanium oxide that exhibits the effect of removing ammonia without irradiating light, but in order to enhance the effect, it should exhibit photocatalytic activity under ultraviolet light and visible light irradiation. Therefore, the composition ratio of the crystal structure of titanium oxide is preferably (anatase type / rutile type)> 90/10.

The crystal structure of titanium oxide has a high ratio of brookite type and anatase type in the low temperature region, and transitions to the rutile type as the temperature increases.
Therefore, from the viewpoint of ammonia adsorption ability, it is particularly preferable that the fine particles have a large anatase type ratio and a large specific surface area. For this purpose, the titanium oxide heat treated at a relatively low temperature of 705 ° C. or lower is preferable. Particles are preferably used.

As a method for producing titanium oxide itself (raw material titanium oxide) as described above, there are generally a sulfuric acid method in which titanium sulfate is hydrolyzed and fired, a chlorine method in which titanium tetrachloride is oxidized at a high temperature, and the like.
In addition, since the said titanium oxide is used for the medical purpose which removes the some harmful | toxic substance in blood or plasma, it is preferable that content of chlorine is as low as possible.

  In addition, when the concentration of the doped nitrogen is high, the titanium oxide that has developed photocatalytic activity by doping nitrogen into the raw material titanium oxide as described above is caused by a reaction between the nitrogen and plasma water. Since ammonia may be generated, high concentration nitrogen-doped titanium oxide is not preferable in the present invention even if it exhibits high photocatalytic activity.

Further, as titanium oxide for adsorbing and removing endotoxin, it is preferable to use a product obtained by drying and baking a precipitate obtained by stirring a titanium alkoxide compound in water containing a volatile acidic or alkaline compound. .
The effect of titanium oxide used to remove endotoxin as described above is recognized regardless of the presence or absence of light irradiation, but the effect is greater when the photocatalytic activity is not exhibited.
In addition, from the viewpoint of endotoxin adsorption ability, fine particles having a large specific surface area are preferable. For this purpose, titanium oxide particles that have been heat-treated at a relatively low temperature of 800 ° C. or lower are preferably used.

  In the present invention, a plurality of types of titanium oxides each having different adsorption ability as described above are incorporated into one blood purification module, and blood or plasma containing a high concentration of harmful substances outside the body, A plurality of types of harmful substances can be efficiently reduced by irradiating light to titanium oxide that circulates in contact with titanium oxide in the module and exhibits photocatalytic activity.

EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not restrict | limited by the following Example.
[Examples 1 to 5]
Titanium oxide powders exhibiting photocatalytic activity for ultraviolet rays obtained by a production method (sulfuric acid method) in which titanium sulfate is hydrolyzed and calcined are heat-treated at 105 ° C., 245 ° C., 485 ° C., 550 ° C., and 705 ° C. for 3 hours, respectively. Titanium oxide powder samples having physical properties as shown in Examples 1 to 5 in Table 1 were prepared.

[Examples 6 and 7]
Tetraethyl orthotitanate was added to water added with hydrochloric acid as a catalyst, and the resulting precipitate was collected and sieved to produce a titanium oxide powder having a particle size of 150 to 212 μm and not showing photocatalytic activity.
This titanium oxide powder was heat-treated at 485 ° C. and 705 ° C. for 3 hours, respectively, to prepare titanium oxide powder samples having physical properties as shown in Examples 6 and 7 in Table 1.

Note that the titanium dioxide powder samples of Example 4, was subjected to impurity _{analysis, Fe: 0.0213wt%, NH 4} : <0.005wt%, Na: 0.13wt%, SO 4: 0.23wt%, Cl: <0.01 wt%.

[Example 8]
50 g of substantially spherical titanium oxide fine particles having an average particle diameter of 6 nm were placed on a refractory tray, and heat-treated at 630 ° C. for 2 hours in a mixed gas atmosphere of ammonia gas and propane gas (5% with respect to ammonia gas) A titanium oxide powder sample showing photocatalytic activity for visible light was prepared.

(Toxic substance removal test)
100 mg of the titanium oxide powder sample prepared in Examples 1 to 8 above was added to 1 ml of plasma (total bilirubin amount 8.7 mg / dl, ammonia amount 3.25 mg / dl, endotoxin amount 21.2 ng / ml). The mixture was stirred at 37 ° C. for 5 hours or 24 hours under light irradiation.
At this time, the total amount of bilirubin, the amount of ammonia, and the amount of endotoxin were measured.
These results are shown in Table 2.
In addition, the measured value when not adding a titanium oxide powder sample as a reference value (blank) is also shown.

As shown in Table 2, titanium oxide exhibiting photocatalytic activity can reduce the total amount of bilirubin more than that not exhibiting photocatalytic activity. It has been observed that it exhibits an excellent effect.
As for ammonia, titanium oxide that does not exhibit photocatalytic activity can be removed to some extent, but it has been recognized that titanium oxide that exhibits photocatalytic activity by ultraviolet irradiation is more effective.
In addition, titanium oxide that does not exhibit photocatalytic activity has been found to be particularly effective for removing endotoxin.
Therefore, in the present invention, it is effective to use a combination of a plurality of types of titanium oxides with different substances exhibiting the adsorption ability as shown in the above-mentioned examples.

It is sectional drawing which showed an example of the container which accommodates a titanium oxide. It is sectional drawing which showed an example of the module for blood purification which accommodates the container shown in FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Container 11 Main body 12 End cap 13 Porous body 14 Sealing material 15 O ring groove 20 Titanium oxide 30 O ring

Claims (4)

  A single module contains a plurality of types of titanium oxides having different physical properties among titanium oxide exhibiting photocatalytic activity, titanium oxide not exhibiting photocatalytic activity, and titanium oxide obtained by substituting a part of oxygen with a substance other than oxygen. A blood purification module characterized by reducing any two or more harmful substances of total bilirubin, ammonia, endotoxin, bile acid, hepatitis B virus, and hepatitis C virus in blood or plasma.   Titanium oxide that exhibits photocatalytic activity, titanium oxide that does not exhibit photocatalytic activity, and multiple types of titanium oxide with different physical properties among titanium oxides in which part of the oxygen is replaced with substances other than oxygen A blood purification module, wherein a plurality of the containers are housed in a single module and connected in series, and blood or plasma flows in the container. .   The blood purification module according to claim 1 or 2, wherein the titanium oxide is in a granular form having a particle size of 0.05 mm or more and 2 mm or less.   Hazardous substances in a module containing multiple types of titanium oxide with different physical properties among titanium oxide showing photocatalytic activity, titanium oxide not showing photocatalytic activity, and titanium oxide in which part of oxygen is replaced with a substance other than oxygen A blood purification method comprising: circulating blood or plasma containing benzene, irradiating the titanium oxide with light, and reducing harmful substances in the blood or plasma discharged from the module.

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