WO2007029525A1

WO2007029525A1 - Polymer for blood separating media and blood separating medium compositions

Info

Publication number: WO2007029525A1
Application number: PCT/JP2006/316736
Authority: WO
Inventors: Michihiro Kaai; Ryusuke Okamoto
Original assignee: Toagosei Co., Ltd.; Sekisui Chemical Co., Ltd.
Priority date: 2005-09-09
Filing date: 2006-08-25
Publication date: 2007-03-15
Also published as: JP4510893B2; JPWO2007029525A1

Abstract

A polymer for blood separating media consisting of a (meth)acrylic ester polymer made from a raw material comprising one or more (meth)acrylic ester monomers, which polymer has a specific gravity of 1.025 to 1.060, a weight-average molecular weight of 3000 to 50000, a viscosity of 10 to 300Pa·S at 25ºC, and an oxygen content of 10 to 22%. It is preferable that a (meth)acrylic ester having C6-10 cyclic alkyl be contained as part of the (meth)acrylic ester monomers still preferably in an amount of 5 to 50% by mass based on the ester monomers. The cyclic alkyl is preferably cyclohexyl or isobonyl.

Description

Specification

Polymer for blood separating agent and blood separating agent composition

Technical field

[0001] The present invention provides a method of centrifuging a blood sample by utilizing a difference in specific gravity of the blood sample to obtain a serum layer or plasma layer, a blood cell layer or a blood clot layer (hereinafter simply referred to as a serum layer and a blood cell layer). The present invention relates to a polymer for blood separating agent and a blood separating agent composition capable of easily separating both components by forming a partition between them.

Background art

[0002] A blood separating agent composition has separability and thixotropy between a serum layer and a blood cell layer. That is, the blood separating agent composition does not have fluidity when allowed to stand, and flows when centrifugally separated to form a partition between the serum layer and the blood cell layer. Keep separation of blood layer and blood cell layer. Examples of the polymer as a main component of such a blood separating agent composition include a copolymer of aolein and maleic diester having a predetermined viscosity and specific gravity (see, for example, Patent Document 1), and Copolyesters having a certain range of kinematic viscosity, density and average molecular weight (for example, see Patent Document 2) are known. Furthermore, an acrylic copolymer having a specific gravity and viscosity (see, for example, Patent Document 3), and a hydrogenated cyclopentadiene petroleum resin having a specific gravity and melt viscosity within a predetermined range (for example, patents) (Ref. 4) is known.

[0003] In recent years, this type of blood separating agent composition has been used to increase the concentration of drugs in blood (for example, antiepileptic drugs such as phenobarbital, carbamazepine, and fetoin) in addition to normal clinical tests. It is also being used for monitoring purposes. In this case, when such a drug is adsorbed to the blood separating agent composition, the concentration of the drug cannot be measured accurately, which causes inconvenience for clinical examination. However, although the conventional blood separating agent compositions described in Patent Documents 1 to 4 can separate the serum layer and the blood cell layer, the drug is easily adsorbed to the blood separating agent composition. Had a negative impact on clinical testing. The main reason is presumed that the polymer constituting the blood separating agent composition tends to have high hydrophilicity and low hydrophobicity. Patent Document 1: JP-A-2-168159

Patent Document 2: JP-A 61-233368

Patent Document 3: JP-A-6-201682

Patent Document 4: Japanese Patent Laid-Open No. 9-15238

Disclosure of the invention

[0004] An object of the present invention is to provide a polymer for blood separating agent and a blood separating agent composition capable of reducing the adsorption of a drug while maintaining good separation between a serum layer and a blood cell layer. There is 〖こ.

[0005] In one embodiment of the present invention, a polymer for blood separating agent comprising a (meth) acrylic acid ester polymer is provided. The (meth) acrylic acid ester polymer is formed from a raw material containing at least one (meth) acrylic acid ester monomer. The specific gravity of the (meth) acrylic acid ester polymer is 1.025 to 1.060, and the weight average molecular weight is 3000 to 50000, 25. The viscosity at C is 10 to 300 Pa'S. The content of oxygen atoms in the (meth) acrylic acid ester polymer is 10-22%.

[0006] Preferably, the raw material further contains a monomer other than the (meth) acrylic acid ester monomer. Preferably, the (meth) acrylic acid ester monomer comprises a (meth) acrylic acid ester having an ester group containing a cyclic alkyl group having 6 to 10 carbon atoms. The content of (meth) acrylic acid ester in the (meth) acrylic acid ester monomer is preferably 5 to 50% by mass. Preferably, the cyclic alkyl group having 6 to 10 carbon atoms is a cyclohexyl group or an isoborn group.

[0007] Preferably, the monomer other than the (meth) acrylic acid ester monomer includes an aromatic vinyl monomer. The content of the aromatic bulle monomer in the monomer other than the (meth) acrylate monomer is preferably 1 to 50% by mass. Preferably, the aromatic vinyl monomer is styrene or _α -methylstyrene. Preferably, the (meth) acrylic acid ester polymer is obtained by a high temperature continuous polymerization method. Preferably, the raw material contains at least two (meth) acrylic acid ester monomers.

[0008] In another aspect of the present invention, there is provided a blood separating agent composition comprising the aforementioned polymer for blood separating agent and silica. BEST MODE FOR CARRYING OUT THE INVENTION

[0009] Hereinafter, embodiments that are considered to be the best of the present invention will be described in detail. The polymer for blood separating agent according to this embodiment is used as a main component of a blood separating agent composition for separating a serum layer and a blood cell layer. This polymer for blood separating agents comprises a (meth) acrylic acid ester polymer. This (meth) acrylic acid ester polymer is formed from a raw material containing at least one (meth) acrylate monomer. This raw material may further contain a monomer other than the (meth) acrylic acid ester monomer. Therefore, in the present application, the concept of “(meth) acrylate polymer” refers to a homopolymer composed of one (meth) acrylate monomer and two or more (meth) acrylate monomers. A copolymer composed of a monomer, and a copolymer composed of at least one (meth) acrylate monomer and other monomers. In the following description, monomers other than (meth) acrylic acid ester monomers are referred to as “other monomers”, and (meth) acrylic acid ester polymers are simply referred to as “polymers”. The specific gravity of this polymer is 1.025 to 1.060, the weight average molecular weight of the polymer is 3000 to 50 000, and the viscosity of the polymer at 25 ° C. is 10 to 300 Pa ′S. Furthermore, the content of oxygen atoms in the polymer is 10-22%.

[0010] The content of the (meth) acrylic acid ester monomer in the raw material is preferably from 50 to 100% by mass, preferably from 60 to less than LOO% by mass, and more preferably from 70 to LOO% by mass. Preferred. If the content of the (meth) acrylic acid ester monomer is less than 50% by mass, the balance of the specific gravity, thixotropy and fluidity of the polymer for blood separating agents may not be maintained well. .

[0011] As the (meth) acrylic acid ester monomer, for example, an (meth) acrylic acid alkyl ester containing an alkyl group having 1 to 20 carbon atoms (the alkyl group is linear or branched! Good), (meth) acrylic acid polyalkylene glycol ester, (meth) acrylic acid alkylalkyl ester, (meth) acrylic acid hydroxyalkyl ester, (meth) acrylic acid glycidyl ester, (meth) acrylic acid dialkylaminoalkyl Esters, (meth) acrylic acid benzyl esters, (meth) acrylic acid phenoxyalkyl esters, (meth) acrylic acid cyclohexyl esters, (meth) acrylic acid isobornyl esters, and (meth) alkoxysilylalkyl acrylates Examples include esters. These monomers are It is preferable to use two or more kinds of forces that can be used by appropriately selecting one or more of them. That is, the raw material preferably contains at least two (meth) acrylic acid ester monomers. In this case, for example, the specific gravity of the polymer and the oxygen content in the polymer can be easily set within the above-mentioned range.

[0012] As the (meth) acrylic acid ester monomer, it is possible to increase the hydrophobicity of the polymer and reduce the adsorption of the drug. Therefore, an ester containing a cyclic alkyl group having a carbon number of 6 to: LO is used. Particularly preferred are (meth) acrylic acid alkyl esters with a group U. The alkyl (meth) acrylate has a high specific gravity and hydrophobicity, and it is difficult to cause drug adsorption. The cyclic alkyl group having 6 to 10 carbon atoms is preferably a cyclohexyl group or an isoborn group. That is, among the (meth) acrylic acid alkyl esters, (meth) acrylic acid (cyclohexyl), (meth) acrylic acid methylcyclohexyl, and (meth) acrylic acid isopropanol are preferred. Particularly preferred is cyclohexyl acrylate, with cyclohexyl being more preferred.

[0013] 6: The content of the (meth) acrylate ester in the (meth) acrylate monomer having an ester group containing a cyclic alkyl group having an LO carbon number is preferably 5 to 50% by mass. 5 to 30% by mass is more preferable. 10 to 20% by mass is particularly preferable. When the content of the (meth) acrylic acid alkyl ester is less than 5% by mass, the adsorptivity of the drug is increased and the specific gravity is excessively decreased, so that the blood separating performance of the blood separating agent composition is lowered. There is a fear. When the content of the (meth) acrylic acid alkyl ester exceeds 50% by mass, the viscosity of the polymer for blood separating agent becomes excessively high, so that the inversion described later is difficult to occur during centrifugation.

[0014] Since the other monomer is copolymerized with (meth) acrylic acid alkyl ester, specific examples of the other monomer are radicals copolymerizable with (meth) acrylic acid alkyl ester. If it is a polymerizable monomer, it will not specifically limit. Specifically, examples of the other monomer include aromatic-type bull monomers, bull esters, bull ethers, berylpyrrolidone, and (meth) aryl ethers. Examples of aromatic vinyl monomers include styrene, a-methylol styrene, p-methyl styrene, a-methylol p-methylol styrene, p-methoxy styrene, o-methoxy styrene, 2,4 dimethyl styrene. , Ku Examples include chlorostyrene and bromostyrene. Examples of the butyl esters include (meth) acrylic acid, maleic anhydride, fumaric acid, (meth) acrylamide, (meth) acrylic dialkylamide, and vinyl acetate. One or more of these monomers can be appropriately selected and used.

[0015] Among these monomers, styrene and α-methylstyrene are more preferable because aromatic vinyl monomers are preferred. Since these monomers have high specific gravity and high hydrophobicity, they are effective in suppressing the adsorption of drugs while maintaining the blood separating ability of the blood separating agent composition. Furthermore, a copolymer obtained by copolymerization with an aromatic vinyl monomer is stable against sterilization by radiation because its viscosity and molecular weight are unlikely to increase during sterilization by radiation. The content of the aromatic vinyl monomer in the other monomers is preferably 1 to 50% by mass, more preferably 5 to 30% by mass, and even more preferably 10 to 20% by mass. When the content of the aromatic vinyl monomer is less than 1% by mass, the effect of the aromatic vinyl monomer is not sufficiently exhibited. When the content of the aromatic vinyl monomer exceeds 50% by mass, the viscosity of the blood separating agent polymer becomes excessively high and it is difficult to ensure its fluidity.

[0016] The polymer can be obtained by an ordinary radical polymerization method. The radical polymerization method may be any of solution polymerization method, bulk polymerization method and dispersion polymerization method, and may be a living radical polymerization method developed recently. However, a high temperature continuous polymerization method (high temperature continuous radical polymerization method) of 150 to 270 ° C. is most preferable. According to this polymerization method, since it is high temperature polymerization, a cleavage reaction starting from a hydrogen abstraction reaction from the polymer chain occurs. Therefore, since a large amount of radical polymerization initiator, chain transfer agent, etc. are not required for controlling the molecular weight of the produced polymer, the polymer does not contain these impurities, and the polymer can be produced easily. Can do. Furthermore, a polymer having a relatively narrow composition distribution and molecular weight distribution can be obtained by using a stirred tank reactor as the reactor.

[0017] The high temperature continuous polymerization method is specifically carried out in accordance with known methods disclosed in JP-A-57-502171, JP-A-59-6207, and JP-A-60-215007. The For example, a pressurizable reactor is set to a predetermined temperature under pressure. Next, each monomer and, if necessary, a raw material containing a polymerization solvent are supplied to the reactor at a constant supply rate. Then, a sufficient amount of the polymerization liquid corresponding to the supply amount of the raw material is extracted. The raw material may contain a radical polymerization initiator if necessary! The ratio of the radical polymerization initiator is preferably 0.001 to 3 parts by mass per 100 parts by mass of the raw material.

[0018] As described above, the polymerization temperature is preferably 150 to 270 ° C, more preferably 170 to 230 ° C, and particularly preferably 180 to 220 ° C. If the polymerization temperature exceeds 270 ° C, the polymer may have problems of coloring and heat deterioration. When the polymerization temperature is less than 150 ° C, a branching reaction occurs and the molecular weight distribution of the polymer tends to be wide. Furthermore, a large amount of radical polymerization initiator and chain transfer agent are required to control the molecular weight of the polymer. For this reason, the content of contaminants derived from the radical polymerization initiator and the chain transfer agent in the polymer increases, and the contaminants may adversely affect blood separation and measurement. Also, production problems such as heat removal may occur. The pressure depends on, for example, the polymerization temperature and the boiling point of the monomer used and the polymerization solvent, and the pressure does not affect the polymerization reaction but can maintain the polymerization temperature.

[0019] The average residence time of the raw material in the reactor is preferably 1 to 60 minutes, more preferably 5 to 30 minutes. If the residence time is less than 1 minute, the monomers may not react sufficiently. When the residence time exceeds 60 minutes, the productivity of the polymer is poor, and further coloration and thermal deterioration of the polymer may occur. Further, it is preferable to use a continuous stirred tank reactor instead of a tubular reactor as the reactor because the width of the polymer composition distribution and molecular weight distribution can be narrowed.

[0020] Specific examples of the polymerization solvent are not particularly limited. However, since the solubility of the polymer is high, an alcohol solvent (for example, isopropyl alcohol), a ketone solvent (for example, methyl ethyl ketone), and an ester solvent (for example, acetic acid). (Putyl) is preferred. Polymerization solvents with low polymer solubility are prone to production problems because scales are likely to grow on the walls of the reactor, for example because the scale must be removed in a washing step.

[0021] Specific examples of the radical polymerization initiator are not particularly limited as long as they are polymerization initiators that generate radicals at a predetermined reaction temperature. Specifically, the radical polymerization initiator includes, for example, a peroxide polymerization initiator, an azo polymerization initiator, and a metal complex used for living polymerization. Further, as a radical polymerization initiator, for example, styrene or the like by heating. Thermal polymerization initiating radicals that generate radicals may be used. Among these specific examples, ditertiary butyl peroxide, ditertiary mil peroxide, diterial mil peroxide and azo initiator are particularly preferable. The azo initiator is inexpensive and hardly causes hydrogen abstraction by the radical polymerization initiator. If the frequency of the hydrogen abstraction reaction increases, the molecular weight distribution of the polymer becomes wider, causing problems that low molecular weight components are cleaved during centrifugation and mixed into serum.

[0022] The specific gravity at 25 ° C of the polymer obtained as described above is 1.025 to 1. In order to separate the serum layer and the blood cell layer by the specific gravity difference and to form a partition between them. 060 is set, and 1.030-1.050 is preferred. In order to separate the serum layer and the blood cell layer, the specific gravity of the blood separation agent composition is preferably 1.040 to 1.060. Therefore, if the specific gravity of the polymer is less than 1.025, it is necessary to add a large amount of inorganic pigment such as silica to the blood separating agent composition in order to adjust the specific gravity of the blood separating agent composition to the above range. As a result, for example, the fluidity and reversibility of the blood separating agent composition are hindered. When the specific gravity of the polymer exceeds 1.060, it is necessary to add a large amount of plasticizer or the like having a small specific gravity to the blood separating agent composition, resulting in high drug adsorbability or suspension in the serum. May occur.

[0023] The weight average molecular weight of the polymer is set to 3000 to 50000 in order to improve the fluidity of the polymer and ensure the strength of the partition wall, preferably 4000 to 30000 force S, 5000 to 20000 force S better than S When the weight average molecular weight of the polymer is less than 3000, the strength of the partition wall for separating blood is insufficient, or suspended matter is generated in serum. If the weight average molecular weight of the polymer exceeds 50000, the fluidity during centrifugation will deteriorate and the reversibility will be hindered.

[0024] The viscosity of the polymer at 25 ° C is set to 10 to 300 Pa's in order to improve the fluidity of the polymer and obtain the strength of the partition wall, and 30 to 200 &'5 More preferably, 50 to 150 Pa's is more preferable. When the viscosity of the polymer is less than lOPa's, the strength of the partition wall for separating blood is insufficient, and separation between the serum layer and the blood cell layer cannot be maintained. When the viscosity of the polymer exceeds 300 Pa's, the fluidity of the blood separating agent polymer is lowered, and the reversibility during centrifugation is hindered. [0025] The content of oxygen atoms in the polymer is set to 10 to 22% in order to suppress the adsorption of the drug in order to balance the hydrophilicity and hydrophobicity of the polymer, and 13 to 21% 15 to 20% is more preferable. The amount of adsorbed drug tends to increase as the hydrophilicity of the blood separating composition increases, in other words, it tends to increase as the oxygen atom content in the polymer increases. Therefore, it is necessary to balance the hydrophilicity and hydrophobicity of the polymer, and the oxygen atom content is set to 10 to 22% as an index. The oxygen atom content can be calculated based on the following equation.

[0026] First, the oxygen atom content in the case of a homopolymer can be determined by the following equation.

[0027] Oxygen atom content (%) = (atomic weight of oxygen X total number of oxygen atoms in monomer Z molecular weight of Z monomer) X 100

Therefore, for example, in the case of a homopolymer of butyl acrylate, the oxygen atom content is 25% from the result of the following formula.

[0028] Oxygen atom content = (32/128) X 100 = 25%

In the case of a copolymer, the oxygen atom content in the copolymer is determined as follows. First, the oxygen atom content in the case of a homopolymer of each monomer contained in the raw material forming the copolymer is determined in accordance with the above. Next, the content of each oxygen atom thus obtained is multiplied by the mass fraction based on the copolymerization ratio of each monomer, and the value calculated thereby is added together to obtain the content in the copolymer. The oxygen atom content is required.

[0029] When the oxygen atom content is less than 10%, the hydrophobicity of the polymer becomes excessively high, so that the thixotropic property becomes insufficient and the dispersibility of the inorganic pigment also deteriorates. When the oxygen atom content exceeds 22%, the drug concentration on the polymer, for example, the antiepileptic drugs phenovalpital, carbamazepine, and pheutoin, should be evaluated correctly. Can not be.

[0030] Next, clinical tests relating to blood and blood separating agent compositions will be described. A gel-like blood separating composition having thixotropic properties is accommodated at the bottom of a blood separation tube used for clinical examination. Then, blood is collected in a blood separation tube and allowed to stand for an appropriate time, and then a centrifugal separation operation is performed. At this time, the gel-like blood separating agent composition is subjected to centrifugal force. Therefore, it becomes a fluid state. Since this blood separating agent composition is adjusted in advance to have an intermediate specific gravity between the serum component or plasma component and the blood clot component or blood cell component, it gradually rises from the bottom of the tube, and the serum layer and blood cell layer And can be separated by forming a partition wall. Using the serum and plasma thus obtained, the amounts of various substances in the living body are measured and used for diagnosis and treatment of diseases.

[0031] Constituent components of the present blood separating agent composition include the polymer as a main agent and silica (particularly fine powder silica) as an auxiliary agent. Further, the blood separating agent composition includes an organic gelling agent (for example, dibenzylidene sorbitol), a dispersing agent for an organic gelling agent (for example, 1-methyl 2-pyrrolidone), a compatibilizing agent, an antioxidant, an antiaging agent, and Additives such as viscosity reducing agents may be further blended.

[0032] The fine powder silica is blended for the purpose of imparting thixotropy to the blood separating agent composition and adjusting the specific gravity of the blood separating agent composition. A specific example of the fine powder silica is not particularly limited as long as it is a commercially available fine powder silica. The surface of finely divided silica may have hydrophobicity or hydrophilicity. By using a combination of hydrophobic silica and hydrophilic silica force, thixotropic property can be imparted to the blood separating agent composition. Specific examples of the fine powder silica include, for example, trade name Leo mouth seal [manufactured by Tokuyama Co., Ltd.], and Aerosil [manufactured by Nippon Aerosil Co., Ltd.].

[0033] The organic gelling agent can impart thixotropic properties to the blood separating agent composition in a small amount. As the organic gelling agent, trade names Gelol D and Gelol MD (dibenzylidene sorbitol, manufactured by Shin Nippon Rika Co., Ltd.) are preferable. Since such an organic gelling agent is a solid and has a high melting point, it may be dissolved in a highly soluble solvent and added. Examples of such solvents include NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), and cellosolve.

[0034] The blood separating agent composition is prepared by kneading the polymer, fine powder silica and, if necessary, additives. Specific examples of the kneading method are not particularly limited, and a kneading method generally used industrially is employed. In order to exert an excellent kneading effect, each component can be heated to 50-200 ° C. The specific gravity of the present blood separating agent composition is adjusted by the amount ratio of the polymer and fine powder silica so as to be intermediate between the serum layer and the blood cell layer, preferably 1.040 to 1.060. And more preferably adjusted to 1.040-1.050.

[0035] Now, the operation of the present embodiment will be described. The blood separating agent composition used for clinical examinations is obtained by kneading other additives with the polymer as a main ingredient. The polymer for blood separating agent comprises the above polymer. This polymer has the specific gravity, weight average molecular weight and viscosity described above, and the oxygen atom content in the polymer is set in the range of 10 to 22%. In particular, by setting the oxygen atom content, the hydrophilicity of the polymer can be suppressed to increase the hydrophobicity, and non-affinity with respect to the drug is expressed. For this reason, adsorption of a drug such as an antiepileptic drug in the blood to the polymer can be suppressed.

[0036] This embodiment has the following advantages.

[0037] The polymer for blood separating agent of the present embodiment is composed of a polymer having the following requirements.

[0038] (1) The specific gravity is 1.025 to 1.060.

[0039] (2) The weight average molecular weight is 3000-50000.

[0040] (3) The viscosity at 25 ° C is 10 to 300 Pa'S.

[0041] (4) The content of oxygen atoms in the polymer is 10 to 22%.

[0042] In particular, when the oxygen atom content in the polymer is set in the above-described range, a balance is achieved so that the hydrophilicity is low and the hydrophobicity is high in order to suppress the adsorption of the drug. Yes. Therefore, the blood separating agent polymer can reduce the adsorption of the drug while maintaining good separation between the serum layer and the blood cell layer by having the above four requirements.

[0043] The (meth) acrylic acid ester monomer preferably includes a (meth) acrylic acid ester having an ester group containing a cyclic alkyl group having 6 to 10 carbon atoms. In this case, the content of the (meth) acrylic acid ester in the (meth) acrylic acid ester monomer is preferably 5 to 50% by mass. As a result, the adsorption of the drug can be reduced as the hydrophobicity of the polymer for blood separating agent increases.

[0044] When the cyclic alkyl group having 6 to 10 carbon atoms is a cyclohexyl group or an isobornyl group, the effect of suppressing the adsorption of the drug can be further exhibited.

[0045] It is preferable that the other monomer includes an aromatic vinyl monomer. In this case, the content of the aromatic vinyl monomer in other monomers is preferably 1 to 50% by mass. That's right. As a result, the hydrophobicity of the blood separating agent polymer can be increased and the adsorption of the drug can be reduced. Furthermore, since the viscosity and molecular weight of the blood separating agent polymer are unlikely to increase during sterilization by radiation, the stability of the blood separating agent polymer can be improved. The above effects can be further exhibited by using styrene or α-methylstyrene among aromatic bur monomers.

[0046] In addition, a copolymer is obtained from a raw material containing a strong aromatic bull monomer in which an electron beam or γ-ray is used for the sterilization treatment of the blood separating agent composition. The composition can be stabilized against electron and gamma rays.

[0047] Since the blood separating agent composition contains the polymer for blood separating agent and silica, the effects of the polymer for blood separating agent can be exhibited.

Example

[0048] The embodiment will be described more specifically with reference to production examples, examples, and comparative examples. However, the scope of the present invention is not limited to these examples.

(Production method of copolymer cocoon)

The temperature of the oil jacket in a pressurized stirred tank reactor having an oil jacket and a capacity of 1 liter was kept at 180 ° C. Next, a raw material consisting of 50 g of butyl acrylate (hereinafter abbreviated as BA), 30 g of acrylic acid-2-ethylhexyl (hereinafter abbreviated as HA), 20 g of cyclohexyl acrylate, and 15 g of methyl ethyl ketone Then, ditertiary hexyl silver oxide (hereinafter abbreviated as DTHP) 0. lg was added as a radical polymerization initiator, and the raw material was charged into the raw material tank. Then, the raw material tank force was continuously supplied to the reactor at a constant supply speed, and the reactant was continuously withdrawn from the reactor outlet so that the mass in the reactor was constant at 580 g. The feed rate of the raw material at this time was 48 g Z min, and the residence time of the raw material in the reactor was 12 min. Furthermore, the temperature in the reactor was kept at 180 ° C. A volatile component is continuously separated from the extracted reaction product by using a thin-film evaporator that maintains a reduced pressure of 30 kPa and a temperature of 250 ° C., and the copolymer contains almost no volatile component. A was recovered.

[0049] After starting the supply of the raw material, it was determined that an equilibrium state was reached 36 minutes after the temperature in the reactor was stabilized, and when this time had passed, recovery of copolymer A after evaporation of the thin film Starting point It was. As a result of continuing the supply of raw materials for 60 minutes from the start of recovery, about 2000 g of copolymer A was recovered. With respect to the obtained copolymer A, the weight average molecular weight (hereinafter referred to as Mw) of copolymer A in terms of polystyrene determined by gel permeation chromatography (GPC) is 20,000, and the number average molecular weight (hereinafter referred to as “Mw”). Mn) was 4,600, and the molecular weight distribution Mw / Mn was 4.6. The amount of volatile components in copolymer A by gas chromatography (GC) was 0.2% by mass or less. The copolymer A had fluidity at room temperature and was liquid. The viscosity at 25 ° C. was lOPa 's as measured with an E-type viscometer, and the specific gravity at 25 ° C. was 1.038. Further, when the copolymer A was visually confirmed, it was excellent in color tone without problems such as yellowing.

(Method for producing copolymers B to N)

Copolymers B to N were produced in the same manner as in the production method of the copolymer A with the composition of each monomer shown in Table 1. Table 1 shows the measurement results of Mw, viscosity, specific gravity, and oxygen atom content of the copolymers B to N thus obtained. Further, when each copolymer was visually confirmed, no troubles such as yellowing were observed.

[0050] [Table 1]

[0051] Various physical properties in Examples and Comparative Examples were measured by the following methods.

[0052] (1) The weight average molecular weight (Mw) was measured in terms of polystyrene using a gel permeation chromatograph (GPC) and tetrahydrofuran as an eluent. [0053] (2) The viscosity at 25 ° C was measured at 25 ° C with an E-type viscometer.

[0054] (3) The specific gravity was measured by the following method. That is, after the copolymer was placed in a 500 ml volumetric flask, the specific gravity was measured at 25 ° C. using a float balance.

[0055] (4) The oxygen atom content was determined by calculating the mass fraction from the yarn composition of each monomer and using the formula described above.

[0056] Abbreviations in Table 1 are shown below.

[0057] BA: butyl acrylate, HA: 2-ethylhexyl acrylate, CHA: acrylate hex, St: styrene, MMA: methyl methacrylate, BMA: butyl methacrylate, SA: stearyl acrylate.

(Preparation of blood separating agent composition)

Copolymer A, dibenzylidene sorbitol DBS, NMP, and finely divided silica as organic gelling agent, copolymer A: 94% by mass, dibenzylidene sorbitol DBS: 0.3 mass%, NMP: 1.2 Mass% and fine powder silica: Kneaded at a ratio of 4.5 mass% for 10 minutes to prepare a blood separating agent composition.

[Evaluation of blood drug concentration]

(Example 1)

In a glass blood separation tube (inner diameter: l lmm, length: 100 mm), 0.9 g of the blood separating agent composition containing the copolymer A and fatin were dissolved at a concentration of 15 g / ml. Dispensed 2 ml of pool serum. The blood separation tube was then sealed with a rubber stopper, and stored in an atmosphere at 4 ° C and upright for 24 hours. The blood separation tube was centrifuged for 5 minutes at a centrifugal force of 1500 G, and the supernatant was taken to measure the concentration of phenytoin. As a blank, a blood separation tube containing only fatin and pooled serum was separately prepared, and the concentration of fatin was measured in the same manner as described above. And the following formula force also calculated the drug non-adsorption rate (%).

[0058] Drug non-adsorption rate = [(Drug concentration with blood separating agent composition) / (Blank drug concentration)] X 100

As a result of this evaluation, the drug non-adsorption rate for phenytoin of the blood separating agent composition containing Copolymer A was 96%. In addition to pheintoin, carbamazepine and phenobar The drug adsorption property to the copolymer A was also evaluated for the pital. As a result, the drug non-adsorption rate in the case of force rubamazepine was 96%, and the drug non-adsorption rate in the case of phenobarbital was 99%.

(Examples 2 to 8)

Each blood separator composition containing copolymers B to H was prepared in the same manner as described above (Preparation of blood separator composition). Then, in the same manner as in Example 1, the drug non-adsorption rate (%) for three drugs, ie, phenyline, carbamazepine and phenobarbital was measured. Table 2 shows the results.

(Comparative Examples 1 and 2)

Each blood separator composition containing copolymers J and K was prepared in the same manner as in the above (Preparation of blood separator composition). Then, in the same manner as in Example 1, the drug non-adsorption rate (%) for the three kinds of drugs was measured. Table 2 shows the results.

[Table 2]

As shown in Table 2, the copolymers Α to の of Examples 1 to 8 were difficult to adsorb the drug. This is presumably because the polarities of the respective copolymers are decreasing because the content of oxygen atoms in the copolymers Α to Η is 22% or less. On the other hand, the copolymers J and Κ of Comparative Examples 1 and 2 adsorbed the drug easily. This is because the oxygen atom content of copolymers J and K is 23% or more. This is considered to be because the polarities of the copolymers J and K are higher than those of the copolymers A to H.

[Evaluation of blood separator composition (general examination)]

(Examples 9 to 16)

A blood collection tube was prepared by containing 0.9 g of the blood separating agent composition containing the copolymer B in two hard glass test tubes. Then, 2 ml of pooled serum was dispensed into each blood collection tube and stored for 24 hours in an atmosphere of 4 ° C and upright. Next, each blood collection tube was centrifuged at 1500 G centrifugal force for 5 minutes, and then the supernatant was collected. Regarding the supernatant, each analysis item shown in Table 3 and Table 4 was evaluated. In addition, a separate blood collection tube containing only pooled serum was prepared as a blank, and each analysis item was evaluated in the same manner as described above. The blood separation agent composition containing the polymers C to H was also evaluated for each analysis item in the same manner as described above. The results are shown in Tables 3 and 4.

[Table 3]

As shown in Tables 3 and 4, for each analytical item, there was no significant difference between the results of the blood separating agent composition containing the copolymers B to H and the results of the blank. Therefore, it was quite powerful that each blood separating composition inhibited the test.

(Comparative Examples 3-5)

Each blood separating agent composition containing each of the copolymers L to N was prepared by the same operation as described above (Preparation of blood separating agent composition). In the same manner as in Example 9, 0.9 g of each blood separating agent composition was placed in a hard glass test tube to prepare a blood collection tube. And implementation In the same manner as in Example 9, each analysis item was evaluated. However, since the specific gravity of the copolymer was small, a part of the copolymer floated in the supernatant after centrifugation, and it was impossible to evaluate each analysis item.

[Sterilization evaluation]

(Examples 17 to 21)

A blood collection tube was prepared by containing 0.9 g each of the blood separating agent composition containing the copolymers B to F in a hard glass test tube. These blood collection tubes were sterilized by radiating gamma (γ) rays with a dose of 25 kGy, and the change in the viscosity of the blood separating agent composition before and after that was measured. In addition, a saline solution having a specific gravity of 1.08 was placed in each of the hard glass test tubes, and the test tube was centrifuged for 5 minutes in a centrifuge to evaluate the reversing centrifugal force. The results are shown in Table 5.

Here, the inversion will be described. The blood separating agent composition is accommodated in the bottom of the blood collection tube in a state where it does not have fluidity due to the gelling agent, but becomes fluid when centrifugal force is applied. The specific gravity of the blood separating agent composition is adjusted to 1.040 to 1.060. When saline with a large specific gravity (d = l. 08) is dispensed, the saline is first used as the blood separating agent composition. Force accumulated on the object When centrifugal force is applied, the blood separating agent composition develops fluidity, and the saline solution having a high specific gravity moves to the bottom, and the blood separating agent composition having a low specific gravity moves onto the saline solution. To do. This phenomenon is called inversion.

[0065] [Table 5]

As shown in Table 5, with respect to the blood separating agent composition containing the copolymers B to E of Examples 17 to 20, the treatment with a large change in viscosity when γ-ray treatment was performed was reversed. Distant required It had an effect on mental strength (reversibility). On the other hand, for the blood separating agent composition containing the copolymer F in which St of Example 21 was copolymerized, the increase rate of the viscosity was small, and the treatment did not affect the reversibility.

(Examples 22 to 27)

In Example 22, only the copolymer A was lg accommodated in the blood collection tube, and then the blood collection tube was sealed and irradiated with 25 kGy of gamma rays. Then, the change in the viscosity of the copolymer A before and after irradiation was measured. The polymers B and F to I of Examples 23 to 27 were similarly evaluated. Table 6 shows the results.

[Table 6]

[0068] As shown in Table 6, the viscosities of the polymers of Examples 22 to 24 were greatly increased by γ-ray irradiation. On the other hand, changes in the viscosity of Examples 25 to 27 containing polymers F to H copolymerized with St were small before and after gamma irradiation.

(Examples 28-30)

In Example 28, after only lg polymer A was contained in the blood collection tube, the blood collection tube was sealed and irradiated with an electron beam of 25 kGy. The electron beam acceleration voltage was set to 4.8 MeV. Then, the change in the viscosity of the polymer A before and after the electron beam irradiation was measured. The polymers I and F of Examples 29 and 30 were similarly evaluated. Table 7 shows the results.

[0069] [Table 7] Viscosity (Pa's)

Copolymer increase rate

Electron beam Electron beam (%) Before treatment After treatment

28 A 110 190 73

Example 29 1 130 210 62

30 F 100 116 16

[0070] As shown in Table 7, the viscosities of the polymers A and I of Examples 28 and 29 were increased by electron beam irradiation. On the other hand, for the polymer F of Example 30 in which St was copolymerized, the viscosity change was small.

[0071] The embodiment may be embodied with the following modifications.

[0072] As physical properties of the copolymer, for example, the soft point, kinematic viscosity, and yield value of the copolymer may be set within a predetermined range.

A blood separation agent composition may be prepared by preparing a plurality of polymers having different specific gravity, weight average molecular weight, viscosity at 25 ° C., and oxygen atom content and mixing them appropriately.

Claims

The scope of the claims

[1] A blood separating agent polymer comprising a (meth) acrylic acid ester polymer,

The (meth) acrylic acid ester polymer is formed from a raw material containing at least one (meth) acrylic acid ester monomer,

The specific gravity of the (meth) acrylic acid ester polymer is 1.0025-1.060, and the weight average molecular weight is 3000-50000, 25. A polymer for blood separating agents, wherein the viscosity in C is 10 to 300 Pa ′S, and the content of oxygen atoms in the (meth) acrylate polymer is 10 to 22%.

[2] The blood separating agent polymer according to claim 1, wherein the raw material further contains a monomer other than the (meth) acrylic acid ester monomer.

[3] The (meth) acrylic acid ester monomer includes a (meth) acrylic acid ester having an ester group containing a cyclic alkyl group having 6 to 10 carbon atoms,

The blood separating agent polymer according to claim 1 or 2, wherein a content of the (meth) acrylic acid ester in the (meth) acrylic acid ester monomer is 5 to 50% by mass.

[4] The blood separating agent polymer according to [3], wherein the cyclic alkyl group having 6 to 10 carbon atoms is a cyclohexyl group or an isobornyl group.

[5] Monomers other than the (meth) acrylate monomer include aromatic vinyl monomers,

The content of the aromatic vinyl monomer in the monomer other than the (meth) acrylic acid ester monomer is 1 to 50% by mass, according to any one of claims 1 to 4. Polymer for blood separating agent.

6. The polymer for blood separating agents according to claim 5, wherein the aromatic bulle monomer is styrene or α-methylstyrene.

7. The blood separation agent polymer according to any one of claims 1 to 6, wherein the (meth) acrylic acid ester polymer is obtained by a high temperature continuous polymerization method.

[8] The blood separating agent polymer according to any one of [1] to [7], wherein the raw material contains at least two kinds of the (meth) acrylic acid ester monomers.

[9] The polymer for blood separation agent according to any one of claims 1 to 8, and silica. A blood separating agent composition characterized by comprising.