JPS606662B2 - Adsorption type artificial organ - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 1. Background Technical Field of the Invention The present invention relates to an adsorption type artificial organ and a pretreatment method thereof.

Here, an adsorption type artificial organ is one that contains an adsorbent and is used in an extracorporeal circulation circuit, and by bringing the adsorbent into direct contact with blood, it removes toxic substances or waste substances from blood or dish bags. It removes it by adsorption.

PRIOR ART When such an adsorption-type artificial organ is used, and blood or blood vessels are allowed to flow in and out of the artificial organ, and the blood or the like is brought into direct contact with the adsorbent, the blood or the like tends to coagulate in the artificial organ.

When blood or the like coagulates, pressure loss within the artificial organ increases and smooth blood flow is obstructed. In addition, thrombus occurs within the artificial organ, enters the body together with blood, and causes adverse effects such as causing clots in the capillaries within the body. Furthermore, contact between the blood and the adsorbent causes problems such as destruction of platelets. By the way, when performing extracorporeal circulation, heparin is generally used as an anticoagulant to prevent blood from coagulating.

Even when an adsorption type artificial organ is used, heparin is administered by intravenous injection or continuous injection into the circulation circuit to prevent blood coagulation.
However, such administration, so to speak, heparinizes the whole body, and requires administration of a large amount of heparin. Large doses of heparin can lead to overdosing of heparin, leading to leakage from capillaries after surgery and bleeding from esophageal veins, and especially in patients with liver failure, coagulation produced in the liver. Since the factor is reduced, patient safety is an issue. On the other hand, in order to prevent blood coagulation, the surface of the adsorbent used is coated with a coating-forming substance that is insoluble in water and has an anti-coagulant effect, dissolved in an organic solvent. Formation is taking place.

In this case, the coating-forming substances include collodion, polyhydroxyethyl methacrylate, acetylulose,
Cellulose derivatives etc. are used. The anticoagulant effect of the coating made of such a coating-forming substance reduces blood coagulation, prevents excessive administration of heparin, and also reduces the destruction of platelets. However, the adsorbent whose surface is coated and subjected to anti-blood coagulation treatment has a reduced adsorption capacity, particularly in the medium molecular region.

Therefore, the amount of adsorbent used increases, the size of the artificial organ increases, the amount of priming increases, and the burden on the patient increases. In addition, some organic solvent used during coating may remain in the coating, and this solvent and coating-forming substance may
It elutes during autoclave sterilization or during long-term storage, which poses a safety problem for living organisms. Furthermore, since a coating process must be performed on the adsorbent, the manufacturing method becomes complicated and costs increase. On the other hand, research is being conducted to locally exert the anticoagulant effect of heparin in areas where blood clots are likely to occur, thereby preventing the adverse effects of excessive heparin administration as described above.

For example, an ionic surfactant such as penzalkonium is adsorbed onto the surface of an anionically charged material such as graphite, and anionically charged heparin is immobilized thereon. There are two methods: ionic bonding of heparin, which releases heparin slowly into a dish, and membrane impregnation, which confines heparin in a polymer lattice and releases it slowly from the surface. However, when trying to apply such a method to locally exert an anticoagulant effect within an adsorbent artificial organ, if heparin is ionically bonded or impregnated into the adsorbent coating, Exactly the same inconvenience as above will occur.

Furthermore, if heparin is ionically bonded or membrane-impregnated into a material separate from the adsorbent, an increase in the number of materials and production steps will be required, resulting in higher costs. D. Purpose of the Invention The invention of this application was made in view of the above circumstances, and the first purpose of the invention of this application is to provide an adsorption type artificial organ in which the occurrence of blood coagulation is prevented. be.

The second objective is to achieve this goal by creating an adsorption system that does not require coating the adsorbent, does not cause a decrease in adsorption capacity, does not degrade its clearance performance, and requires a small device. The aim is to provide type artificial organs. The third objective is to provide an adsorption type artificial organ in which destruction of platelets is reduced. The fourth objective is to achieve these objectives by eliminating the need for complex structures such as ionically bonding heparin or immersing it in membranes, and in addition, localizing the anticoagulant effect of heparin within an adsorption-type artificial organ. be able to demonstrate
As a result, it is an object of the present invention to provide an adsorption type artificial organ that can perform extracorporeal circulation without separately administering a large amount and excessive amount of heparin.
Other objects of the inventions of these applications will become apparent from the following description. The inventors of the present invention have conducted extensive research in order to realize such an objective.

As a result, we used an uncoated adsorbent to
A predetermined amount of heparin is dissolved and contained in an adsorption type artificial organ which is filled and sealed with water or an aqueous solution, and before use, according to a normal pretreatment method,
When the artificial organ was washed with physiological saline, a small amount of heparin remained in the artificial organ after washing, and due to this residual heparin, blood coagulation hardly occurred during the subsequent extracorporeal circulation.Also, platelet destruction occurred. Furthermore, the adsorption capacity of the adsorbent does not deteriorate as it does when anticoagulant coating is applied, and the clearance also shows a high value. Based on these findings, the invention of this application was made. It is something.

That is, the invention of this application provides an adsorption type artificial organ in which an adsorbent is filled and sealed in a container together with water or an aqueous solution, in which 50 to 5,000 μg of the adsorbent is added to the water or aqueous solution per night. The adsorption type artificial organ is characterized by containing dissolved units of heparin.

Note that it has not been known to date that a predetermined amount of heparin is dissolved and contained in an adsorption-type artificial organ in this way.

m. Specific Structure of the Invention The specific structure of the invention of this application will be explained in detail below.

The adsorptive artificial organ in this petition contains an adsorbent.

Adsorbents used include activated carbon, zeolite, activated clay,
Ion exchange resin, non-ion exchange resin, dextran gel, etc. may be used. However, among these, activated carbon is preferred.

Of the activated carbons, the most preferred is petroleum pitch-based granular activated carbon made from petroleum pitch. Petroleum pitch-based granular activated carbon is usually obtained by melt molding, so it is almost spherical particles, and exhibits high adsorption capacity for not only low molecular weight substances but also medium and high molecular weight substances. It is preferable because it has high hardness, a smooth surface, and less release of coal dust particles when it comes into contact with blood.

In addition, the petroleum pitch activated carbon used is usually 0.1 to 1
It is sufficient to use particles with a particle size similar to that of willow. Note that the surface of such an adsorbent must not be coated with the above-mentioned anticoagulant coating-forming substance over its entire surface.

When such a coating is formed, almost no heparin remains in the container after the pre-cleaning described below, and the anti-coagulant effect and anti-platelet destruction effect of the remaining heparin in this application cannot be expected, and the above-mentioned This is because, as the adsorption capacity of the adsorbent deteriorates, inconveniences such as a decrease in clearance performance occur. In this case, if the coating-forming substance is partially formed as a coating on the surface of the adsorbent, this effect can be achieved to some extent. However, in such a case, the effect is insufficient and the number of manufacturing steps increases, so it is preferable to use the film without any coating treatment. Although there is no limit to the amount of adsorbent used, approximately 30 to 500 ta of such adsorbent is usually incorporated into an artificial organ.

Such an adsorbent is filled and sealed in a container together with water or an aqueous solution.

In this case, water or physiological saline is preferably used as the water or aqueous solution. On the other hand, the container used is
Various known adsorption type artificial organs may be used.

In this case, the container usually has a main body, an inlet and an outlet for blood or blood, which are suitable for the main body, and furthermore, in order to prevent the adsorbent filled inside the container from flowing out, the container should be arranged near the outlet, preferably at the outlet and the inlet. A mesh having a predetermined hole diameter is provided nearby and has a structure that can be sealed. Under such a premise, heparin is contained in the above water or aqueous solution. The heparin used may be various types of Q-heparin having D-glucosamine residues, D-glucuronic acid residues, and sulfate groups, but it is used as an anticoagulant. Average molecular weight 5,000-25
,00 degrees Fahrenheit is suitable. Such heparin is dissolved in water or an aqueous solution, and is contained in an amount of 50 to 5,00 international units, more preferably 200 to 2,00 units, per evening of the above-mentioned adsorbent.
If the amount is less than the pen level, no heparin will remain after the pretreatment described below, and the amount will be too small, making it impossible to sufficiently prevent the occurrence of blood clots and platelet destruction, which are the effects of the present invention.

Moreover, if it exceeds 5000 units, the amount of heparin remaining after the pretreatment is too large, resulting in excessive administration of heparin, which poses a safety problem. The suction type artificial organ in this application has the above-mentioned configuration.

In this case, most of the heparin dissolved and contained in the water or aqueous solution is dissolved in the aqueous solution, but some of it is present on the surface of the adsorbent or in its micropores. Those who are still alive will be sacrificed. The artificial organ constructed in this manner is manufactured by mixing a predetermined amount of adsorbent into water or an aqueous solution containing a predetermined amount of heparin dissolved therein, and filling and sealing the mixture into a container.

In this case, as the adsorbent used, a commercially available adsorbent may be used as is, or it may be used after being mechanically classified as required.

Further, particularly when petroleum pitch activated carbon is used, it may be previously subjected to heat treatment in a predetermined atmosphere or treatment with acid, alkali, or the like. When petroleum or pitch-based granular activated carbon is used, it is preferable to perform a predetermined cleaning process in advance to remove particulate coal dust present on its surface or in its micropores. Note that, as described above, it is preferable that the surface of such an adsorbent is not substantially coated with a coating-forming substance. Such adsorption-type artificial organs include DHP, which is used as an artificial kidney, an artificial liver, and a DHP for removing antigen complexes, to adsorb and remove toxic substances or waste substances in blood or dish bags in an extracorporeal circulation circuit. It is used as a column (direct blood groove flow column), etc.

In this case, such an adsorption type artificial organ is usually subjected to the following preliminary treatment according to a conventional method before being connected to an extracorporeal circulation circuit.

First, it is preferable to sterilize the sealed adsorption type artificial organ.

In this case, if a sterilized adsorbent and water or an aqueous solution containing heparin are used and then filled and sealed, there is no need to carry out such sterilization, but usually after both are filled and sealed, sterilization is performed. It is preferable to carry out treatment. As the sterilization treatment, known autoclave sterilization, Y-ray sterilization, or the like may be performed. When performing autoclave sterilization, mix the two before filling them into a container.
It is preferable to perform defoaming treatment in advance, such as by cooling after boiling. The adsorptive artificial organ is then washed with an isotonic salt solution having an osmotic pressure equal to the osmotic pressure of the body fluid according to a conventional method.

As the isotonic salt solution to be used, it is usually preferable to use physiological saline. In this case, irrigation is performed by flowing an isotonic salt solution into and out of the artificial organ container. The amount of isotonic salt solution to be used may be 0.5 to 5 kg, more preferably 1 to 2 kg, as is the case with the commonly used conditions, and when calculated per night of adsorbent, the amount is:
The flow rate of the isotonic salt solution during washing should be about 10 to 100'/night, preferably about 10 to 30'.
It may be approximately 200 minutes. When cleaning is performed in this way, most of the heparin that was present dissolved in water or an aqueous solution in the container or on the surface of the adsorbent is removed from the system, and only a portion of it is removed. Only the department
A small amount remains on the adsorbent surface and within the micropores.

Then, when the adsorbed artificial organ that has been pretreated in this way is connected to an extracorporeal circulation circuit and circulated, the small amount of remaining heparin has a local anticoagulant effect within the artificial organ. demonstrate. In this case, the anticoagulant effect is exerted within the organ where the adsorbent and blood or blood vessels come into contact.
The various inconveniences mentioned above are eliminated, and in particular, increases in pressure loss and occurrence of emboli are effectively prevented. and,
When the circulation time is several hours or less, such as in adsorption-type artificial organs, the effect lasts long enough. Furthermore, heparin is a substance that has both a surfactant effect and a protective colloid effect, and by washing it after filling it as described above, the particles that were present on the adsorbent surface and in the micropores can also be removed. The microparticles are washed away, and therefore, problems such as destruction of platelets or introduction of the microparticles into the living body due to the migration of the microparticles into the blood are eliminated. In addition, the heparin content after washing is small, and the adsorption capacity of the adsorbent does not deteriorate.
W. Specific Effects of the Invention As detailed above, according to the invention of this application, the occurrence of blood clots and destruction of blood 4 and plates in organs is extremely low.

In this case, the amount generated is comparable to the case where an anticoagulant coating is formed on the surface of the adsorbent as described above. Therefore, an adsorption type artificial organ with extremely high biocompatibility will be realized. Moreover, there is little pressure loss, and there is little burden on the patient. Moreover, “
As described above, there is no deterioration in the adsorption capacity of the adsorbent unlike when forming an anticoagulant coating, there is no decrease in clearance value, and there are various advantages such as miniaturization of the device. Furthermore,
Heparin can be supplied into the circulation circuit or into the body according to the conventional method for extracorporeal circulation, and the adverse effects of excessive heparin administration will not occur. In addition, ``Since we use an extremely simple structure in which heparin is dissolved and contained in water or an aqueous solution, there is no need to ionically bond heparin or immerse it in the waist, and the inconveniences of doing so are eliminated.Next, Examples, comparative examples, and experimental examples of the invention of this application will be shown, and the invention of this application will be explained in more detail.

Example 1 Thoroughly washed petroleum pitch-based activated carbon [B made by Kureha Chemical Co., Ltd.]
The AC-AO fluoride was mixed with 200 g of physiological saline containing 25 units/desktop heparin (average molecular weight 15,000) (heparin/activated charcoal = 500 units/polymer).

Thereafter, these were packed into a cylindrical column container with a diameter of 56 ribs and a height of 81 sides, and the container was sealed to prepare a DHP column. In this case, a mesh with a pore diameter of 200 mm was provided near the column inlet and outlet to prevent the adsorbent from flowing out. Example 1 The DHP column in Example 1 was autoclaved and then washed and pretreated by passing two saline solutions through the column at a flow rate of 100'/min.

After this, after leaving it for 30 minutes, the physiological saline solution was again flowed at a flow rate of 200/min. The results are shown in Figure 1. From the results shown in Figure 1, it can be seen that by washing as the first pretreatment, most of the heparin in the column container flows out and is removed, but some of it is absorbed by the activated carbon. It is thought that this residual heparin, which remains on the surface and within the micropores, exerts an anticoagulant effect locally within the column, resulting in the excellent effects shown in the experimental examples below. .

Example 2 The container size in Example 1 was changed to 2 mm in diameter and 30 mm in height, and the container was filled with 5 units of activated carbon and 10 units of heparinized saline solution (heparin/10 units/unit). Activated carbon = 50 units/night) Other than that, DHP was used as in Example 1.
A column was created.

Example 3 The same procedure as in Example 2 was carried out, except that the amount of heparin in the heparin caro-physiological saline solution was 100 units/day, and the amount of heparin per night of activated carbon was 200 units/night. A DHP column was produced.

Comparative Example 1 The petroleum pitch-based activated carbon in Example 1 was mixed with 2 parts of physiological saline solution per night of activated carbon, and the mixture was filled and sealed in the containers of Example 1 and Example 2, respectively.

In this case, the amount of activated carbon and the amount of physiological saline in each container were the same as above. Comparative Example 2 Thoroughly Washed Example 1
The petroleum pitch-based activated carbon LK9 was placed in a 12,000 oven and left to dry for about 24 hours.

Next, 2 nights of absolute ethanol was heated to 8,000 ℃, and 15 hours of polyhydroxyethyl methacrylate was added and dissolved. This was transferred to a drying vat, dried activated carbon lk9 was put therein, and ethanol was quickly evaporated under hot air. Furthermore, this was allowed to stand for 7 days at 90 oo in an open air condition to obtain activated carbon with an anticoagulant coating of about 1 mm on its surface. Using the thus obtained coated activated carbon, two types of DHP columns were produced in exactly the same manner as in Comparative Example 2.

In this case as well, the amount of activated carbon and the amount of physiological saline are the same as above. Example 2 In order to compare the anticoagulability and occurrence of platelet destruction of the DHP column of Example 2 and the small DHP columns of Comparative Examples 1 and 2, extracorporeal circulation was performed using a home test.

That is, blood was collected from the carotid artery of the patient and was sequentially connected to a DHP column and an air chamber placed in a 37° C. constant temperature bath via a pump, and allowed to flow into the jugular vein.

In this case, each DHP column was pre-sterilized by autoclaving, then 1 unit/100 mL of heparinized saline was added.
The top of the tube was washed at 20'/min, pre-treated, and extracorporeally circulated. Circulation was performed for 2 hours at a blood flow rate of 20'/min. Also, before circulation, under normal conditions,
150 units/k9 of heparin was administered intravenously, and no further heparin administration was performed. In this way, extracorporeal circulation is performed, and the pressure difference (△P) between the DHP column inlet and outlet is
The changes over time in the amount of in-vivo platelets per unit amount (% value relative to the initial value) were measured.

The results are shown in Figures 2 and 3, respectively. In both figures, curves a, b, c and d represent Example 2,
These are the results for Example 3, Comparative Example 1, and Comparative Example 2. From the results in Figure 2, in the case of Comparative Example 1 (curve c), △
It can be seen that P increases with time, blood clots occur within the column, and smooth dish flow is obstructed.

In fact, when the column after the circulation port was examined, a large amount of blood clots were found and removed. On the other hand, in Examples 2 and 3 (curves a and b), similar to Comparative Example 2 (curve d), ΔP
There was almost no increase in blood clots, and no blood clots were detected.

Furthermore, from the results shown in Fig. 3, Examples 2 and 3 (curves a and b) and Comparative Example 2 (curve d) are at the same level in terms of biological fluctuations in the amount of platelets, but Comparative Example 1 (c) It can be seen that after circulation, it has decreased to about 60%. Example
3. In order to compare the adsorption capacities of the DHP column of Example 1 and the large DHP columns produced in Comparative Examples 1 and 2, changes in clearance over time were measured using creatinine, vitamin B, 2, and inulin as indicator substances.

That is, a physiological saline solution containing creatinine, vitamin B, 2, and inulin, each containing 10 9/d, was filled into a storage tank, and a heat exchanger, a blood pump, a bubble trap, and a DHP column were connected to this tank in this order. , a single-pass flow path was formed.

In this case, each DHP column, after autoclave sterilization,
It was used after pretreatment by washing with physiological saline at a rate of 100 m/min for 2 days. In this manner, the clearance value CL of each solute indicator substance was measured. In addition,
The clearance value CL was calculated from the following formula. CL:C
B KIYUMI BOXQB Here, C6 and CBo indicate the column inlet and outlet concentrations (9/dso), and Q8 is the flow rate (bar/min).

These results are shown in FIG.

In the figure, a. , a2, a3 are Example 17c,,c
2, c3 is Comparative Example 1, d,, et al., d3 is D of Comparative Example 2
Changes in the HP columns and the subscript 1 in these
indicates the result when creatinine is used, subscript 2 is vitamin B, and subscript 3 is inulin. From the results shown in FIG. 4, it can be seen that the DHP column belonging to the present invention has a high clearance and no deterioration of adsorption capacity occurs.

In addition, such an effect is due to heparin/activated carbon of 50 to 5
,000 units/evening.

In the examples, comparative examples, and experimental examples detailed above,
Although we have shown a typical example of using petroleum pitch-based activated carbon as an adsorbent, it has been confirmed that similar effects can be achieved when using non-ionic or ion-exchanged resin, for example. has been done.

[Brief explanation of the drawing]

FIG. 1 shows the results when the adsorption type artificial organ of the present invention is washed.
FIG. 3 is a diagram showing the time change of the concentration of hebalin in the effluent. Figure 2 shows the pressure difference (△P) between the inlet and outlet of the artificial organ when extracorporeal circulation is performed using the adsorption type artificial organ of the present invention.
FIG. 3 is a graph showing the time change in the amount of platelets in the living body, and FIG. FIG. 4 is a diagram showing the change over time in the clearance of the adsorption type artificial organ of the present invention in comparison with the conventional one. Figure T Figure 2 Figure 3 Figure 4

Claims (1)

[Scope of Claims] 1. In an adsorption type artificial organ formed by filling and sealing an adsorbent together with water or an aqueous solution in a container, 50 to 5,000 units of heparin are added per gram of the adsorbent in the water or aqueous solution. An adsorption type artificial organ characterized by containing dissolved. 2. The adsorption type artificial organ according to claim 1, wherein the adsorbent is petroleum pittuce-based granular activated carbon. 3. The adsorptive artificial organ according to claim 1 or 2, wherein the surface of the adsorbent is not substantially coated with a coating-forming substance.