JPH08101189A - Manufacture of blood segregating agent - Google Patents

Abstract

PURPOSE: To provide a blood segregating agent excellent in the practical applicability by dispersing a viscosity adjusting material and/or specific gravity adjusting material in a high concentration previously within a segregated layer forming material, and diluting the resultant dispersed object to a specified concentration. CONSTITUTION: The specific gravity of the segregation forming material should lie in the intermediate region between a serum component and blood clot component or between the plasma component and corpuscle component, and a viscosity adjusting material and specific gravity adjusting material are included in the segregated layer forming material so as to generate a specific gravity and thixotropy required to perform the blood segregating operations. The standard adding amount of these materials should be 0.1-5 parts by wt. to 100 parts by wt. segregated layer forming material. The dispersing method for the viscosity adjusting material and specific gravity adjusting material in a high concentration is not restricted any specifically if it ensures uniformity of the composition. Appropriate concentration of these materials when dispersed is 10-20 parts by wt. to 100 parts by wt. segregated layer forming material.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a blood separating agent. More specifically, when separating a serum component and a blood clot component coexisting in blood or a plasma component and a blood cell component by the difference in their specific gravities, an intermediate specific gravity of both components is applied to form a partition wall between the two components. And a method for producing a blood separating agent which can be used for the purpose of facilitating the separation operation of these two components.

[0002]

2. Description of the Related Art Heretofore, as a method for producing this type of blood separating agent, polymer oils such as silicone oil, chlorinated polyolefin, polyisobutene, acrylic polymer, α-olefin / maleic acid diester copolymer and the like have been used. It is used as a material for forming the separation layer. Inorganic particles such as silica and clay, and organic particles such as polyethylene wax and polystyrene are charged as a viscosity adjusting material and a specific gravity adjusting material in a predetermined amount, and they are mixed together by a roll mill, Banbury mixer, etc. The method of dispersion was used. However, in the above production method, the viscosity adjusting material and the specific gravity adjusting material are generally in a small amount relative to the separation layer forming material, and it is difficult to make the particles fine and uniform in this state. In some cases, sufficient wettability cannot be obtained with a certain separation layer forming material. If sufficient wettability is not obtained, the specific gravity adjusting material and the separation layer forming material are separated by the centrifugal force during the centrifugal separation operation after blood collection, and the specific gravity as the blood separating agent changes, and the blood clot component in the lower layer is separated. There has been a problem that a barrier is not formed in the intermediate layer between the serum component or the blood cell component and the plasma component in the upper layer. Generally, a blood separating agent exhibits fluidity during a blood separating operation, but in other cases, such as when it is stored as a vacuum blood collection tube before separation or when it exists as a partition wall between components having different specific gravities after blood separation. It is necessary to have sufficient structural viscosity, and it is important to obtain appropriate thixotropy with good reproducibility. With regard to lipophilic layered inorganic compounds such as bentonite, which is effective as a material for adjusting the specific gravity and viscosity at the same time, the flakes are often present in the state of agglomeration, and they are not sufficiently miniaturized, and a separation layer is formed. If the affinity with the material is insufficient, the expected thixotropy may not be expressed in some cases. Further, in order to obtain a uniform dispersion with such a composition, a long time dispersion was required, and the productivity was very poor.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to obtain a blood separating agent which is free from these drawbacks and is excellent in practicality. The inventors of the present invention have conducted extensive studies to achieve such an object, and as a result, in the method for producing a blood separating agent, the viscosity adjusting material and / or the specific gravity adjusting material are dispersed in the separation layer forming material in a high concentration in advance. By diluting the obtained dispersion to a specified concentration, it has high productivity, and the viscosity adjusting material and / or the specific gravity adjusting material do not separate during the centrifugation operation, and the required thixotropy is obtained. The inventors of the present invention have found that they can be obtained with good reproducibility and have reached the present invention.

[0004]

That is, the present invention provides a blood separating agent containing a separation layer forming material, a viscosity adjusting material and / or a specific gravity adjusting material.
A viscosity separating material and / or a specific gravity adjusting material are dispersed in a high concentration of 10 to 200 parts by weight with respect to 0 parts by weight, and the obtained dispersion is diluted to a predetermined concentration. It is a manufacturing method.

The present invention will be described in detail below. As the separation layer forming material used for the blood separating agent of the present invention, as long as its specific gravity is in the intermediate region between the serum component and the blood clot component, or the plasma component and the blood cell component, various low-viscosity organic solvents and plasticizers are used. From agents to highly viscous polymeric oils can be used.

Practically, the viscosity at a temperature of 25 ° C. is 200 to 600,000 c in that it provides stable and appropriate fluidity and gelation property.
Polymeric oils in the ps range are suitable. Examples of such polymer oils include silicone, chlorinated polybutene, chlorinated polybutadiene, chlorinated polyolefin, poly (meth) acrylic acid ester, polyisobutene, α-
Examples thereof include an olefin polymer, polystyrene, α-olefin or a copolymer of styrene and maleic acid diester.

The viscosity adjusting material and the specific gravity adjusting material used in the blood separating agent of the present invention may be those which give specific gravity and thixotropy required for the blood separating operation by mixing with the above separating layer forming material. If there is no particular limitation, it is practically inert and does not affect the test value after separation,
Those having a specific gravity such that they are not separated from the material for forming the separation layer during the centrifugation operation are suitable. Such viscosity adjusting material,
Specific gravity adjusting materials include silica, alumina, titanium oxide,
Zinc oxide, iron oxide, calcium carbonate, barium sulfate, lithopone, magnesium carbonate, talc, diatomaceous earth, carbon black, ultramarine blue, lipophilic layered inorganic compound or polyethylene, polypropylene, polystyrene, polyurethane, polyacrylate and their modified products Organic compounds are mentioned. Among them, lipophilic layered inorganic compounds, for example, those in which metal ions between clay minerals such as natural mica, synthetic mica, mica, bentonite, and smectite are replaced with onium salts having a lipophilic group such as alkylammonium salt Used usefully.

The addition amount of these viscosity adjusting material and / or specific gravity adjusting material must be blended in consideration of the viscosity and specific gravity of the blood separating agent, but normally, the separating layer forming material 10 is used.
It is desirable to add 0.1 to 5 parts by weight to 0 parts by weight. If the amount of the lipophilic layered compound added is too small, sufficient thixotropy and specific gravity cannot be imparted, which causes the shape of the partition wall layer not to be retained during storage or after separation. Moreover, if the amount added is too large, the viscosity and specific gravity increase, which is not suitable for practical use.

The preferred specific gravity of the composition constituting the blood separating agent of the present invention is such that, when used as a serum or plasma separating agent, the specific gravity at a temperature of 25 ° C. is between that of blood clots or blood cells, that is, 1. 030 to 1.060 and a viscosity of 15
10,000-2,000,000 cps, yield value 100-2000dyn
A range of e / cm ² is suitable.

The method for dispersing the viscosity adjusting material and the specific gravity adjusting material at a high concentration in the present invention is not particularly limited as long as the composition can be made uniform, and a general mixing and kneading device can be used. . Specific examples include equipment such as a ball mill, a kneader, a Banbury mixer, and a three-roll mill.

The concentration of the viscosity adjusting material and / or the specific gravity adjusting material at the time of dispersion is 100% for the separation layer forming material.
10 to 200 parts by weight is suitable for the parts by weight. The optimum ratio needs to be appropriately adjusted depending on the viscosity adjusting material, the specific surface area of the specific gravity adjusting material, the particle size, etc., and preferably 15 to 150 parts by weight.
If the concentration during dispersion is low, it is difficult to disperse uniformly, and sufficient wettability with the separation layer forming material cannot be obtained. Further, in order to obtain a uniform dispersion, it is necessary to disperse for a long time, resulting in poor productivity. On the other hand, if the concentration at the time of dispersion is too high, sufficient dispersion stability cannot be obtained, or handling property becomes poor.

EXAMPLES The present invention will be described based on examples. In the examples, "part" and "%" are "part by weight" and "% by weight", respectively.

Example 1 100 parts of a mixed α-olefin having 12 and 14 carbon atoms and a maleic acid diester copolymer as a material for forming a separation layer, and maleic anhydride-introduced modified polyethylene (hereinafter abbreviated as modified polyethylene) as a viscosity and specific gravity adjusting material. ) 50 parts were mixed with a gate mixer to obtain a uniform mixture. Roll this with a three-roll mill manufactured by Buhler and set the roll cooling water temperature to 60.
High-concentration dispersion A was obtained by making two passes with a roll pressure of 20 bar while controlling the temperature to be ° C. Next, the separation layer forming material 100
Parts, 20 parts of Benton 38 (alkylammonium-modified natural smectite; manufactured by NL Industrie Co.) as a material for adjusting viscosity and specific gravity are mixed in the same manner, and the roll cooling water temperature is controlled at 60 ° C. by a three-roll roller manufactured by Buehler. Meanwhile, a high-concentration dispersion B was obtained by making 3 passes at a roll pressure of 30 bar. Next, 87 parts of the separation layer forming material, 12 parts of the high-concentration dispersion A, and 6 parts of the high-concentration dispersion were stirred for 30 minutes with a gate mixer, and then the roll drainage temperature was controlled to 40 ° C. with three rolls manufactured by Buehler. After one pass at a roll pressure of 30 bar to obtain a dispersion, this was defoamed in vacuum to obtain a blood separating agent. The obtained blood separating agent has a viscosity of 300,000 cps,
The yield value was 500 dyne / cm ² , and the specific gravity was 1.032. 1.5 g of the obtained separating agent was put into a 10 cc test tube having a total length of 100 mm to obtain a blood collection tube. When the blood collection tube was laid down and left in a dryer at 60 ° C for 4 days, the flow was 2
mm or less. When 7 cc of whole blood sample was placed in the blood collection tube and centrifuged at 1700 G for 10 minutes, the separating agent was located in the intermediate layer between the blood cell component and the plasma component, and no separation of bentonite or modified polyethylene from the separating agent was observed. It was

Example 2 Propylene / 1-butene (70 /
(30 mol ratio) 100 parts of a chlorinated product of the copolymer (chlorine content 26% by weight) and 20 parts of Benton 38 (alkylammonium-modified natural smectite; manufactured by NL Industrie Co., Ltd.) were mixed, and the mixture was mixed with a three-roll roller manufactured by Buehler. , While controlling the roll cooling water temperature to 60 ℃, roll pressure is 3 bar at 3 bar
After passing, a high-concentration dispersion C was obtained. Next, 90 parts of the separation layer forming material, 12 parts of the high-concentration dispersion C, and 1 part of Aerosil R-972 (silica powder: manufactured by Nippon Aerosil Co., Ltd.) as a material for adjusting the specific gravity were charged, and the mixture was stirred for 30 minutes with a gate mixer. Rolled water temperature 4 with 3 rolls
While controlling the temperature to 0 ° C, make one pass with a roll pressure of 30 bar,
After obtaining a dispersion, this was defoamed in vacuum to obtain a blood separating agent. The obtained blood separating agent had a viscosity of 150,000 cps, a yield value of 380 dyne / cm ² , and a specific gravity of 1.042.
1.5 g of the obtained separating agent was put into a 10 cc test tube having a total length of 100 mm to obtain a blood collection tube. When the blood collection tube was laid down and left in a dryer at 60 ° C for 4 days, the flow was 10
mm or less. When 7 cc of whole blood sample was placed in the blood collection tube and centrifuged at 1700 G for 10 minutes, the separating agent was located in the intermediate layer between the serum component and the blood clot component, and the separation of bentonite and silica from the separating agent was not observed. It was

Example 3 100 parts of a mixed α-olefin having 12 and 14 carbon atoms and a maleic acid diester copolymer as a material for forming a separation layer, and 100 parts of homocal D (calcium carbonate; manufactured by Shiraishi Calcium Co.) as a material for adjusting specific gravity were charged. 30 with a gate mixer
The mixture was stirred for a minute, and the temperature of the roll cooling water was controlled to 60 ° C. with three rolls manufactured by Buehler Co., and three passes were performed at a roll pressure of 20 bar to obtain a high concentration dispersion D. Next, 86 parts of the separation layer forming material, the high concentration dispersion A18 used in Example 1
Part and the above-mentioned high-concentration dispersion D4 part were stirred with a gate mixer for 30 minutes, and then with a three-roll mill manufactured by Buehler.
Roll pressure 30b while controlling the roll drain temperature to 40 ℃
After one pass with ar to obtain a dispersion, this was defoamed in vacuum to obtain a blood separating agent. The blood separating agent obtained has a viscosity of 3
50,000 cps, yield value 460 dyne / cm ² , specific gravity 1.
It was 034. The obtained separating agent is 100 mm in total length.
1.5 g was put into a 0 cc test tube to obtain a blood collection tube. When the blood collection tube was laid down and left in a dryer at 60 ° C. for 4 days, the flow was 3 mm or less. When 7 cc of whole blood sample was put into the blood collection tube and centrifuged at 1700 G for 10 minutes, the separating agent was located in the intermediate layer between the blood cell component and the plasma component, and separation of calcium carbonate and modified polyethylene from the separating agent was observed. There wasn't.

Comparative Example 1 100 parts of the material for forming the separation layer used in Example 1, 4 parts of modified polyethylene and 1 part of Benton 38 were charged, and the mixture was stirred for 1 hour with a gate mixer. After that, while controlling the roll drainage temperature to 40 ° C. with a three roll manufactured by Buehler, 6 passes was performed at a roll pressure of 30 bar to obtain a dispersion, which was then defoamed in vacuum to obtain a blood separating agent. . The obtained blood separating agent has a viscosity of 100,000 cps, a yield value of 45 dyne / cm ² ,
The specific gravity was 1.032. The total length of the obtained separating agent is 100
1.5 g was put into a 10 cc mm test tube to obtain a blood collection tube.
When the blood collection tube was laid down and left in a dryer at 60 ° C. for 4 days, the contents reached the tube mouth. When 7 cc of whole blood sample was put into the blood collection tube and centrifuged at 1700 G for 10 minutes, smectite and denatured polyethylene were separated from the separating agent, and the separating agent was not located in the intermediate layer between the blood cell component and the plasma component. Further, while controlling the blood separating agent at a roll drainage temperature of 40 ° C., the pressure was further passed 4 times at a roll pressure of 30 bar, and defoaming was performed in the same process as above to obtain a separating agent.
A blood collection tube using the separating agent was obtained in the same manner as described above, and a whole blood sample was centrifuged, whereby smectites from the separating agent,
Although no separation of the denatured polyethylene was observed, the blood collection tube was laid sideways and left in a dryer at 60 ° C. for 4 days, and the flow was 30 mm.

Comparative Example 2 100 parts of the separation layer forming material used in Example 2, 2 parts of Benton 38 and 1 part of Aerosil R-972 were charged, and the mixture was stirred for 1 hour with a gate mixer. After that, while controlling the roll cooling water temperature at 40 ° C. with a three roll manufactured by Buehler, 4 passes at a roll pressure of 30 bar to obtain a dispersion, which is then defoamed in vacuum to obtain a blood separating agent. Obtained. The obtained blood separating agent has a viscosity of 100,000 cps and a yield value of 80 dyn.
The specific gravity was e / cm ² and the specific gravity was 1.042. 1.5 g of the obtained separating agent was put into a 10 cc test tube to obtain a blood collection tube. When the blood collection tube was laid down and left in a dryer at 60 ° C. for 4 days, the contents reached the tube mouth. When 7 cc of whole blood sample was put into the blood collection tube and centrifuged at 1700 G for 10 minutes, smectite and silica were separated from the separating agent,
The separating agent was not located in the middle layer between the blood cell component and the plasma component.

Comparative Example 3 100 parts of the separation layer forming material used in Example 3, 6 parts of modified polyethylene, and 2 parts of homocal D were charged, and the mixture was stirred for 1 hour with a gate mixer. Roll pressure 30ba while controlling the temperature to 40 ℃
After 4 passes with r to obtain a dispersion, this was defoamed in vacuum to obtain a blood separating agent. The blood separating agent obtained has a viscosity of 10
10,000 cps, yield value 80 dyne / cm ² , specific gravity 1.04
It was 2. 1.5 parts of the obtained separating agent in a 10 cc test tube.
Then, a blood collection tube was obtained. The blood collection tube is laid down at 60 ° C.
When left for 4 days in the dryer, the contents reached the tube mouth. Also, put 7 cc of whole blood sample into the blood collection tube, and
After centrifugation at 700 G for 10 minutes, smectite and silica were separated from the separating agent, and the separating agent was not located in the intermediate layer between the blood cell component and the plasma component.

[0019]

INDUSTRIAL APPLICABILITY In the method for producing a blood separating agent, the viscosity adjusting material and / or the specific gravity adjusting material are dispersed in the separating layer forming material in a high concentration in advance, and the obtained dispersion is diluted to a predetermined concentration. , It has high productivity, and the viscosity adjusting material and / or the specific gravity adjusting material do not separate during the centrifugation operation, and the required thixotropy can be obtained with good reproducibility.

Claims (2)

[Claims] 1. A separation layer forming material, a viscosity adjusting material, and / or
Alternatively, a blood separating agent containing a specific gravity adjusting material was obtained by dispersing a viscosity adjusting agent and / or a specific gravity adjusting material at a high concentration of 10 to 200 parts by weight with respect to 100 parts by weight of a separation layer forming material. A method for producing a blood separating agent, which comprises diluting a dispersion to a predetermined concentration. 2. The method according to claim 1, wherein the viscosity adjusting material and / or the specific gravity adjusting material is a lipophilic layered inorganic compound.