JPS6243696B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel artificial organ characterized by encapsulating a granular adsorbent whose surface is coated with ethyl cellulose. More specifically, a granular adsorbent treated with ethyl cellulose, which is intended to remove waste products or toxic substances from extracorporeally circulating blood using the adsorption principle, is sealed in a high-pressure steam sterilized state. It concerns artificial organs. The present invention is particularly advantageously applied to artificial organs in which spherical adsorbents surface-treated with ethyl cellulose are encapsulated, particularly spherical activated carbon derived from pitch. In recent years, artificial organs based on the adsorption principle are being used to treat various diseases, such as artificial kidneys or artificial livers. However, removing waste products and toxic substances from the blood by bringing an adsorbent such as activated carbon into direct contact with the blood can cause fine solid foreign matter to be released from the adsorbent, mix in the blood in the body, and damage tissues. Deposit or
This causes loss of useful components in the blood and causes problems such as blood coagulation, making it unsuitable for clinical use. As a measure to prevent such drawbacks, a method has been proposed in which the surface of the adsorbent is coated with a film of a polymeric material such as nitrocellulose. Generally, when using an adsorbent surface-treated with a polymeric material as an adsorbent that can be enclosed in an artificial organ that is brought into contact with blood to remove waste products and toxic substances from the blood, the following requirements must be met: There is. That is, (1) the adsorption performance for waste products and toxic substances in blood does not substantially impair the original performance of the adsorbent;
(Maintaining adsorption performance) (2) Adsorption of useful components in blood must be suppressed. (Imparting selective adsorption properties) (3) Being able to suppress the release of fine solid foreign matter from the adsorbent. (Suppression of dust release) (4) Blood coagulation should not occur. (Improving blood compatibility) (5) The polymer materials, solvents, cross-linking agents, and other chemicals used to process the adsorbent must be clinically safe. (Maintaining safety) (6) The above requirements (1) to (5) must be met for sterilization. (Maintaining sterilization resistance) Among these requirements, suppression of dust release is particularly important for artificial organs in which the adsorbent is brought into direct contact with blood, but this is the most technically difficult requirement to solve. Although methods have been proposed in which the surface of the agent is coated with, for example, nitrocellulose or polyhydroxyethyl methacrylate, these methods are still insufficient. There is also an example of an animal experiment in which waste products from blood were removed using ethyl cellulose microcapsules on the surface of an adsorbent. Research Coordination Bureau, Science and Technology Agency, “Comprehensive research on the development of artificial kidney devices using new methods”, page 77 (December 1972) and “Collection of Abstracts of the 6th Medical Polymer Symposium”, page 13 (1971)
(November 2012) stated that the adsorption performance of powdered activated carbon microencapsulated with ethylcellulose was significantly reduced compared to raw charcoal powder, and that ethylcellulose was unsuitable as an encapsulating material for direct blood perfusion. ing. When examining the blood compatibility of cellulose derivatives, the present invention found that ethylcellulose is stable to high-pressure steam sterilization (121°C, 20 minutes or more) and clinically acceptable. It was found that no growth of decomposition products that could be toxic was observed, and that it had a high ability to suppress the release of fine solid matter such as dust. Therefore, as a result of intensive research to improve the above-mentioned drawbacks, the inventor of the present invention found that by treating the surface of the granular adsorbent with a thin film of ethyl cellulose, it was possible to improve the adsorption performance without substantially impairing the original adsorption performance of the adsorbent. We were able to obtain an adsorbent that was excellent in suppressing dust release and had improved blood compatibility, and we were able to obtain an artificial organ using this adsorbent. That is, the present invention provides that the average ratio of ethoxy substituents per glucose unit is
2.0-3.0, toluene 80 vol% ethanol 20
25 when dissolved at 5.0% by weight in a mixed solvent of vol%
Ethylcellulose having a viscosity of 5 to 250 centipoise at °C is added from 0.01 to 1 per weight of the activated carbon particles.
The artificial organ is characterized in that the activated carbon particles coated at a ratio of % by weight are encapsulated in a high-pressure steam sterilized state. The untreated adsorbent used as the raw material for the adsorbent encapsulated in the artificial organ of the present invention is essentially spherical activated carbon that has the ability to adsorb part or all of waste products and/or toxic substances in the blood. It is a particle. This is preferably a spherical adsorbent such as spherical activated carbon derived from petroleum pit (for example, BAC series manufactured by Taiyo Kaken). The average particle size of the raw material adsorbent is from 0.05 mm to 10 mm, preferably 0.1 mm.
It is 3mm from The ethylcellulose used to treat the surface of the adsorbent has an average proportion of ethoxy substituents of 2.0 to 3.0, preferably 2.2 to 2.6 per glucose unit. The degree of polymerization of the ethylcellulose used in the present invention is determined by using a mixed solvent of 80% by volume of toluene and 20% by volume of ethanol, or 60% by volume of toluene,
A solution obtained by dissolving 5.0% by weight of the ethyl cellulose in a mixed solvent of 40% by volume of ethanol at 25°C.
The viscosity thereof is from 5 centipoise to 250 centipoise, preferably from 80 centipoise to 120 centipoise. These ethylcelluloses can be used alone or in combination. The solvent used when treating the surface of the adsorbent with ethyl cellulose may be virtually any solvent as long as it is clinically safe and can dissolve ethyl cellulose, but ethanol or an aqueous ethanol solution is preferred. Examples of methods for treating the surface of the adsorbent with ethylcellulose include immersing the adsorbent in a solution of ethylcellulose dissolved in a solvent, then drying the adsorbent separately, and/or spraying the solution onto the surface of the adsorbent. Then, a method of drying, etc. can be advantageously applied. The ethylcellulose concentration of the ethylcellulose solution ranges from 0.01% to 1.0% by weight, preferably from 0.02% to 0.5% by weight. The amount of ethylcellulose coated on the surface of the adsorbent ranges from 0.01% to 1.0% by weight per adsorbent.
% by weight, preferably from 0.05% to 0.5% by weight
It is. Even after high-pressure steam sterilization, the thus obtained adsorbent does not substantially impair the adsorption performance inherent to the raw material adsorbent, the release of dust is suppressed, and blood compatibility is further improved. Therefore, the adsorption type artificial organ of the present invention is clinically safe. In order to further improve the performance of the adsorbent, the surface-treated adsorbent is
Further treatment can also be carried out, for example with anticoagulants. The artificial organ of the present invention is manufactured by storing the granular adsorbent treated with ethyl cellulose obtained by the method described above in a chamber, sterilizing it with high-pressure steam, and then enclosing it. The artificial organ of the present invention uses an adsorbent coated with an extremely thin film of the specific ethyl cellulose described above, unlike the conventional technology in which the organ is microencapsulated with ethyl cellulose, so it has excellent performance as an adsorption type artificial organ. For example, it can be used as an artificial kidney or an artificial liver. Embodiment (1) of the present invention provides that (a ₁ ) the number of ethoxy substituents is 2 to 3 on average per glucose unit, and 5% by weight using a toluene-ethanol mixed solvent.
A solution in which ethyl cellulose having a degree of polymerization with a viscosity of 5 to 250 centipoise is dissolved in ethanol or an aqueous ethanol solution, and (a ₂ ) a spherical adsorbent of spherical activated carbon with a particle size of 0.05 to 10 mm are brought into contact (b). This is a method for producing an artificial organ, in which a 0.01 to 1% by weight ethyl cellulose thin film is formed on the surface of the adsorbent, and (c) the adsorbent coated with the ethyl cellulose thin film is filled into a chamber and then heat sterilized. Embodiment (2) of the present invention is an artificial organ obtained according to embodiment (1). The present invention will be further explained below with reference to Examples. Example 1 Spherical activated carbon with a diameter of approximately 0.7 mm (manufactured by Taiyo Kaken Co., Ltd., BAC-MU) derived from petroleum pit was classified using a 32-mesh sieve, and then treated with dilute hydrochloric acid, boiling with distilled water, and dilute alkali treatment. After repeating each process several times, ultrasonication was performed in water. Next, this spherical charcoal was washed with water, dried, and then coated with ethyl cellulose in an amount equivalent to 0.3% by weight based on the spherical charcoal. As a coating method, spherical charcoal is placed in a coating pan used for manufacturing sugar-coated tablets, and while the pan is rotated, ethylcellulose dissolved in ethyl alcohol (Dow Chemical Co., Ltd.'s Ethcel Medium,
The average proportion of ethoxy substituents was 2.5 per glucose unit, toluene 80% by volume, ethanol
The viscosity at 25°C is 106 centipoise when dissolved at 5% by weight in a 20% by volume mixed solvent)
A method was used in which the surface of spherical charcoal was coated with ethyl cellulose by gradually spraying ethyl cellulose and evaporating the solvent with hot air. The coated spherical carbon thus obtained is covered with a tough coating that completely fixes even the microscopically visible fine coal dust that is still attached to the surface of the spherical activated carbon.
After drying, this coated spherical charcoal was washed with water, and about 100 g of it was filled with physiological saline into a silicone-treated plastic container with an internal volume of 185 ml, and subjected to high-pressure steam brood cultivation (121°C, 20 minutes). This was sealed aseptically. Using the artificial organs thus created, the following experiments were conducted. First, about 10mg of creatinine/
dl, vitamin B ₁₂ about 10 mg/dl aqueous solution, about 4 each
The flow rate in the artificial organ was approximately 200 at 37°C.
Circulate at ml/min, creatinine and vitamins
The situation in which B ₁₂ is adsorbed was measured. The results are shown in Table 1. Next, the artificial organ was repeatedly dropped from a height of 30 cm above the floor to the floor 5 times, and distilled water filtered through 0.45 μ paper was injected into the artificial organ at a flow rate of about 200 ml/min. About 500 ml of the liquid was collected four times in a row. Each fraction of the effluent was filtered through 3μ paper to collect floating foreign matter in the effluent, which was counted using a microscope with a magnification of 100. The results are shown in Table 2. Next, a blood perfusion experiment using the artificial organ was conducted using a Pegle dog with kidney ligation, and changes in components in the circulating blood were examined for about 2 hours. An example of the results is shown in Table 3, which shows that significant adsorption of creatinine and uric acid occurred. During this experiment, blood was perfused smoothly and no phenomena suggesting blood coagulation were observed. Furthermore, after the experiment was completed, the blood in the artificial organ used was replaced with physiological saline, the artificial organ was disassembled, and the presence or absence of blood coagulation was examined, but no blood coagulation was observed. Comparative Example 1 A collodion-coated spherical charcoal containing 0.5% by weight of nitrocellulose was obtained by spraying topical collodion diluted with ethyl alcohol onto spherical charcoal obtained using the same raw materials and method as in Example 1 in the same manner as in Example 1. I got it. This coated spherical charcoal was dried, washed with water, and sterilized with high-pressure steam, then filled into the same plastic container as in Example 1, and then perfused with an albumin solution to produce an artificial organ in which collodion/albumin double-coated activated carbon was encapsulated. Experiments similar to those in Example 1 were conducted using this artificial organ. The results are shown in the Comparative Examples column of Tables 1 to 3.

【table】

【table】

【table】

[Table] Comparative Example 2 An experiment was conducted in the same manner as in Example 1 except that the conditions in Example 1 were changed as shown in Table 4.
The results obtained are also shown in Table 4. It should be noted that a product with an average ratio of ethoxy substituents exceeding 3 was not obtained, and toluene/ethanol (80/
20) It was difficult to obtain ethyl cellulose whose viscosity at 25°C exceeds 250 centipoise when dissolved at 5 wt% in a mixed solvent.

【table】

Claims (1)

[Claims] 1. On the surface of petroleum pitch-based spherical activated carbon particles having an average particle size of 0.05 mm to 10 mm, the average ratio of ethoxy substituents is 2.0 to 3.0 per glucose unit,
The activated carbon is coated with ethyl cellulose having a viscosity of 5 to 250 centipoise at 25°C when dissolved in a mixed solvent of 80 volume% toluene and 20 volume% ethanol at a rate of 0.01 to 1% by weight based on the weight of the activated carbon particles. An artificial organ characterized by encapsulating particles in a high-pressure steam sterilized state.