Separation gel for blood collection tube

Abstract

The invention relates to a separation gel for blood collection tubes for separating blood cells from serum or plasma, comprising an acrylate copolymer, silicic acid and a silicone oil and / or at least one polyalkylene glycol, in which the separation gel contains < = 1000 ppm, preferably < = 300 ppm, of a solvent, and to a method for producing the separation gel, relates to a separation gel, to a blood collection tube having the separation gel, and to a method for producing the acrylate copolymer, in which at least one solvent is separated by multi-stage distillation in order to purify the acrylate copolymer, such that a residual solvent content of < = 1000 ppm, in particular < = 300 ppm, is achieved.

Description

Technical Field

[0001] This invention relates to a separation gel for blood collection tubes used to separate blood cells from serum or plasma, comprising an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, a method for preparing said separation gel, a blood collection tube for separating serum or plasma from blood cells using the separation gel, a method for separating serum or plasma using a blood collection tube, and a method for preparing an acrylate copolymer for use as a separation gel in blood collection tubes. Background of the Invention

[0002] Clinical analytical techniques used to detect biochemical substances require the separation of whole blood into its components, namely serum or plasma and blood cells. The separated fraction should be as cell-free as possible to avoid affecting clinical analysis.

[0003] For laboratory analysis, blood collection tubes with a separating gel are frequently used to obtain serum or plasma. The separating gel at the bottom of the tube has a lower density than the coagulated clotting proteins and blood cells, and moves between the blood cells and serum during centrifugation because its physical density is between the two components. This forms a separating layer that prevents diagnostic samples (especially serum) from being contaminated with blood cell components, and also, for example, prevents glucose from being degraded by blood cells.

[0004] To determine clinical parameters such as glucose, potassium, and phosphorus, serum must be rapidly separated from blood cells, otherwise the measurements will be distorted.

[0005] The determination of clinical analytes, such as steroids, hormones, vitamins, and drugs, is also possible after prolonged cooling and storage, thanks to the diffusion barrier layer formed by the separation gel.

[0006] US 5438000 describes a serum release agent exhibiting an excellent balance between flow and specific gravity properties, as well as excellent storage stability. The serum release agent has a specific gravity of 1.035 to 1.065 at 20°C, a viscosity of 100 to 400 Pa·s, and a yield stress of 100 to 400 dynes / cm². 2The polymer comprises (A) 100 parts by weight of a polymer having a specific gravity of 0.94 to 1.06 and a viscosity of 10 to 140 Pa·s at 20°C, said polymer being derived from alkyl acrylate monomers or alkyl methacrylate monomers; (B) 0.5 to 10 parts by weight of at least one component selected from silica and bentonite; and (C) 0.01 to 2 parts by weight of at least one surfactant selected from the group consisting of: (C-1) fluorocarbon-based surfactants; (C-2) surfactants based on polyester-modified alkyl polysiloxanes; and (C-3) surfactants based on polyether-modified alkyl polysiloxanes; and optionally, (D) 0.01 to 1 part by weight of at least one component selected from titanium dioxide and calcium carbonate; and (E) 0.02 to 1 part by weight of a titanium-based adhesion promoter based on 100 parts by weight of polymer (A).

[0007] Compositions for separating serum or plasma from a blood collection container are known from EP3734273A1. The composition comprises a (meth)acrylate-based polymer, silica, and silicone oil, wherein the polymer is flowable at room temperature and has a molecular weight of 15,000 or greater and 100,000 or less.

[0008] Blood collection tubes with separation gels known in the prior art have residual solvent contents of toluene or N-methyl-2-pyrrolidone (NMP) greater than 1000 ppm. These substances are classified as hazardous substances according to Regulation (EG) 1272 / 2008.

[0009] In blood collection tubes with a separation gel known from existing technologies, toluene is decanted as a harmful substance with a content greater than 0.1%.

[0010] Another type of blood collection tube on the market with a separation gel contains N-methyl-2-pyrrolidone (NMP), a hazardous substance classified as an SVHC, at a concentration of approximately 3000 ppm.

[0011] This residual solvent content is typically obtained by removing the solvent via conventional distillation. Summary of the Invention

[0012] The purpose of this invention is to overcome the shortcomings of the prior art and to provide an apparatus and method by which a user can easily separate blood cells from serum or plasma.

[0013] This objective is achieved through the separation gel, acrylate copolymer, blood collection tube, and method for preparing the separation gel and acrylate copolymer of the present invention.

[0014] The separation gel for blood collection tubes used to separate blood cells from serum or plasma comprises an acrylate copolymer, silicic acid and silicone oil and / or at least one polyalkylene glycol having a solvent of ≤1000 ppm, preferably ≤300 ppm, whereby the separation gel is not classified as a hazardous substance and thereby reduces safety precautions and regulations for the product, especially for blood collection tubes, where the separation gel according to the invention is used.

[0015] Furthermore, by using the separation gel according to the invention in blood collection tubes, high-purity components are achieved, which minimizes the risk of contaminating blood samples.

[0016] This also results in better sample quality, which may have an impact on subsequent applications in the analysis.

[0017] The separation gel and its preparation method of the present invention are very durable and reliable.

[0018] To polymerize acrylate copolymers to prepare polymer components, at least two monomers, particularly n-butyl acrylate and 2-ethylhexyl acrylate, a solvent, and an initiator are used. Thus, by selecting the components, especially the monomers, it is possible to economically prepare separation gels.

[0019] Preferably, the monomer ratio of n-butyl acrylate to 2-ethylhexyl acrylate used to prepare the polymer component is 2:1 to 9:1, particularly 3:1 to 5:1, and preferably 4:1, because this allows for the optimal setting of the desired polymer density.

[0020] Preferably, the acrylate copolymer for separating the gel has a concentration of 1.010 g / cm³ at 20°C. 3 Up to 1.040 g / cm 3 The preferred value is 1.025 g / cm³. 3 Up to 1.035 g / cm 3 Especially at 1.030 g / cm³ 3 Up to 1.033 g / cm 3 The density between these parameters allows for the formation of a stable separation gel with sufficient strength, which can be achieved even under temperature fluctuations.

[0021] The acrylate copolymer of the separation gel has a viscosity of 60 Pa·s to 180 Pa·s, preferably 70 Pa·s to 130 Pa·s, and especially 90 Pa·s to 110 Pa·s at 20°C, thereby achieving satisfactory flowability of the separation gel at room temperature.

[0022] In a preferred embodiment, the acrylate copolymer contains ≤1000 ppm, preferably ≤300 ppm, of solvent, thereby reducing the chemical impact on blood analysis due to the residual solvent content compared to commercially available blood collection tubes. Consequently, sample quality and analyte stability are also improved, and more reproducible analytical results can be achieved.

[0023] The acrylate copolymer preferably has a residual content of ≤50 ppm, particularly ≤20 ppm, of n-butyl acrylate monomer and / or ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm, of 2-ethylhexyl acrylate monomer, thereby minimizing the risk of sample contamination and improving the quality of blood samples and the resulting analysis of clinical parameters.

[0024] Because the amount of monomers is smaller, there are fewer processing problems during sterilization.

[0025] To prevent bacterial contamination of patients and samples by blood collection tubes, the tubes are sterilized during manufacturing using electron radiation, gamma rays, or X-rays to meet ISO standards. Due to the high purity, the separation gel exhibits improved stability during subsequent sterilization processes, as monomeric impurities can cause undesirable cross-linking of the separation gel. This cross-linking can lead to undesirable changes in thixotropic properties.

[0026] Silicone oil and / or at least one polyalkylene glycol are included in the separation gel in a total amount of 0.01% to 1% by weight, preferably 0.05% to 0.75% by weight, and particularly 0.1% to 0.5% by weight, thereby achieving the desired thixotropic properties of the separation gel while ensuring good dispersibility of silicic acid. Additionally, phase separation due to the outflow of low-viscosity components from the phase during storage can be prevented.

[0027] As silicic acid, it preferably comprises pyrolyzed untreated hydrophilic and / or modified hydrophobic silicic acid, particularly in amounts of 0.5% to 5% by weight, preferably 1% to 4% by weight, and especially 2% to 3% by weight.

[0028] In an improved embodiment of the separation gel, titanium dioxide is included, particularly in an amount of 0.001 wt% to 0.1 wt%, preferably 0.005 wt% to 0.08 wt%, and especially 0.01 wt% to 0.05 wt%, thereby adjusting the density of the separation gel together with silica.

[0029] Advantageously, at 20°C, the separation gel has a strength of 1.038 g / cm³. 3 Up to 1.058cm 3 Preferred concentration: 1.040 g / cm³ 3 Up to 1.050 g / cm 3 Especially 1.044 g / cm3 Up to 1.048 g / cm 3 The density allows for the formation of a stable separation layer with sufficient strength.

[0030] At 20°C, the separation gel has a viscosity of 200 Pa·s to 520 Pa·s, preferably 220 Pa·s to 280 Pa·s, thereby forming a stable and robust separation layer for storing blood samples separated in the phase.

[0031] Advantageously, the separation gel has a thixotropic index between 1.2 and 2.2, particularly between 1.2 and 1.7, and preferably between 1.3 and 1.6, because this ensures shear liquefaction of the separation gel and the formation of a gel separation layer under the corresponding centrifugation conditions.

[0032] In the method for preparing the separation gel of the blood collection tube for separating serum or plasma according to the present invention, the separation gel comprises an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, and the acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol or at least one polyalkylene glycol and optionally titanium dioxide are mixed and thus provide a durable and reliable preparation process.

[0033] It has proven advantageous to use at least 30% to 50% by weight, preferably 35% to 45% by weight, particularly 38% to 42% by weight, of n-butyl acrylate and 2% to 20% by weight, preferably 5% to 15% by weight, particularly 8% to 12% by weight, of 2-ethylhexyl acrylate as the polymer component in the preparation of the acrylate copolymer, thereby allowing the polymer density to be adjusted.

[0034] In a preferred embodiment, an aromatic solvent, particularly toluene or xylene, is used to prepare the polymer component, preferably in an amount of 30% to 70% by weight, more preferably 40% to 60% by weight, and particularly 45% to 55% by weight, which has lower toxicity compared to benzene, which is commonly used as a solvent.

[0035] An organic peroxide, particularly 1,1,3,3-tetramethylbutylperoxide-2-ethylhexanoate, is used as an initiator for polymerizing at least two monomers to prepare the polymer component, preferably in amounts of 0.05% to 5% by weight, more preferably 0.1% to 1% by weight, and particularly 0.3% to 0.6% by weight, wherein the viscosity of the polymer can be adjusted by the concentration of the initiator. This initiator has the advantage over the commonly used initiator azobisisobutyronitrile (AIBN) in that no toxic tetramethylsuccinate (TMSN) is retained as a residue in the separation gel.

[0036] In an improved version of this method, untreated hydrophilic silicic acid is pre-modified via a drying step. This ensures a low moisture content in the silicic acid and thus guarantees the consistent quality of the separation gel prepared from it. The thixotropic properties resulting from the interaction between the silicic acid and silicone oil or polyalkylene glycol are also thus improved.

[0037] Blood collection tubes for separating blood cells from serum or plasma have a separation gel composed of at least an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, wherein the separation gel contains ≤1000 ppm, preferably ≤300 ppm, of a solvent. The advantage of the separation gel is that it is not classified as a hazardous substance and therefore does not require restrictions in terms of workplace protection.

[0038] Because the blood collection tubes are filled with a separation gel with minimal residual solvent, the stability of the analyte is significantly improved during the time between centrifugation and analysis. This stability benefit across the gel barrier is also advantageous during the transport and storage of blood into the blood collection tubes. Furthermore, the stable barrier between serum and blood clots further enhances the stability of the analyte.

[0039] The blood collection tubes according to the invention can also optimize the workflow from blood collection to analysis. Therefore, the short centrifugation time allows for sample processing and archiving in the primary tubes without the risk of confusion caused by using secondary tubes.

[0040] Preferably, the acrylate copolymer for the separation gel of blood collection tubes of the present invention comprises at least two monomers and a solvent, comprising a first monomer of ≤50 ppm, particularly ≤20 ppm; a second monomer of ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm; and a solvent of ≤1000 ppm, particularly ≤300 ppm, wherein the low content of residual monomers and solvents and the resulting high purity of the acrylate copolymer for the separation gel minimize the risk of sample contamination by monomer or solvent residues and improve the quality of blood samples and the clinical parameter analysis thereby performed.

[0041] The present invention provides a method for preparing an acrylate copolymer for blood collection tubes by free radical solvent polymerization of a polymer solution during the feeding process, wherein the acrylate copolymer is purified by at least multi-stage distillation to separate the solvent, achieving a residual solvent content of ≤1000 ppm, particularly ≤300 ppm. This reduces the marketability of hazardous materials, as the hazardous materials are separated during the process and transported to recycling.

[0042] By means of the method of the present invention, residual monomers can also be separated from the polymer solution of acrylate copolymers by multi-stage distillation, thereby obtaining a high-purity separation gel containing ≤50 ppm, particularly ≤20 ppm, of the first monomer, particularly n-butyl acrylate, and ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm, of the second monomer, particularly 2-ethylhexyl acrylate. This allows for reproducible analysis of blood samples, particularly analytes, from serum or plasma.

[0043] Preferably, distillation is performed continuously using a thin-film rotary evaporator, thereby achieving a lower solvent value in the acrylate copolymer to prepare the separation gel.

[0044] In an improved version of this method, the polymer discharged from the thin-layer rotary evaporator is fed to the flash stage and, if necessary, to the intermediate heating stage in advance, thereby enabling better removal of any remaining solvent and monomer.

[0045] Preferably, the separation of solvent and optional residual monomer is carried out under vacuum, as this yields better results.

[0046] In the subsequent short-path evaporation stage, the solvent and optional residual monomer are distilled to the desired final content, thus providing an acrylate copolymer optimized for further processing.

[0047] In an improved version of this method, the solvent and optional residual monomers are frozen in a downstream cold trap system and subsequently discharged, whereby they can be transported to a recycling unit. Attached Figure Description

[0048] To better understand this invention, the following figures will be used to explain it in detail.

[0049] These are illustrated in very simplified diagrams:

[0050] Figure 1 : Flowchart for the preparation and purification of acrylate copolymers and the preparation of separation gels.

[0051] The present invention comprises a separation gel based on highly purified acrylate copolymers, which, by adding rheology additives, particularly modified silicone oil or at least one polyalkylene glycol, and silicic acid, exhibits desired rheological properties related to shear liquefaction, while also having an ideal density, to achieve the separation of blood cells from serum or plasma.

[0052] During centrifugation of blood samples, shear forces act on the separation gel, causing it to liquefy. Additionally, buoyancy acts on the separation gel during centrifugation, causing it to detach from the bottom of the blood collection tube and rise. Depending on its density, the separation gel aggregates in the region between the blood cells and the supernatant, particularly serum or plasma, forming a stable separation layer between the phases.

[0053] Besides the thixotropic properties of the release agent, setting the correct density and maintaining strict specification limits are essential for proper centrifugation and the formation of the release layer. The high purity of the separation gel minimizes the risk of sample contamination and improves the quality of blood samples and the resulting analysis of clinical parameters. Furthermore, it enhances the safety of the material in further processing and applications.

[0054] The present invention includes a separation gel for blood collection tubes for separating blood cells from serum or plasma, the separation gel comprising an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, wherein the separation gel contains ≤1000 ppm, preferably ≤300 ppm, of solvent.

[0055] The separation gel according to the invention is used to separate serum or plasma from other components of blood, forming a dense separation layer and diffusion barrier layer, so that no cellular components enter the serum or plasma even after prolonged storage. This prevents cellular interference, such as hemolysis, glucose degradation, or potassium release.

[0056] In hemolysis, the cell membranes of red blood cells are disrupted, allowing intracellular components to enter the serum or plasma. If the serum or plasma is not separated from the cells, the components leak from the cells into the plasma or serum after separation of the gel or centrifugation via pipetting to a secondary container. Although the cell walls are not disrupted in this method as in hemolysis, the effect on the sample is similar. The result is, for example, an increase in LDH and potassium levels. Blood glucose is broken down by glucose analysis. Here, cells also absorb glucose from the serum or plasma in vitro. Consequently, blood glucose levels change continuously over time. If the serum or plasma is not separated from the cells, the process has already caused significant changes after two hours.

[0057] The separation gel according to the invention is not classified as a hazardous material and reduces work-related health hazards, thus posing less risk to personnel in the health field and also significantly simplifying the process for employers.

[0058] The separation gel of the present invention comprises at least one acrylate copolymer, silicic acid, and silicone oil or at least one polyalkylene glycol.

[0059] In the context of this invention, silicon dioxide and silicic acid are used in an equivalent manner and include pyrolytic silicon dioxide or silicic acid and precipitated silicon dioxide or silicic acid.

[0060] The separation gel for separating serum or plasma according to the present invention comprises an acrylate copolymer formed by polymerizing at least two different polymerizable monomers.

[0061] In a preferred embodiment, to prepare the polymer component of the acrylate copolymer, at least two monomers, particularly n-butyl acrylate (NBA) and 2-ethylhexyl acrylate (EHA), at least one solvent, and at least one initiator are used.

[0062] Within the scope of this invention, polymer components are understood to be polymer solutions in the preparation process of acrylate copolymers, and polymers or copolymers are understood to refer to purified polymers that are virtually free of monomers and solvents.

[0063] The acrylate copolymers are preferably prepared by free radical solvent polymerization, and more preferably by the free radical polymerization method according to the invention.

[0064] The polymerizable monomers that can be used to prepare the acrylate copolymers of the present invention are so-called alkyl acrylates or alkyl methacrylates. Examples of such monomers are methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, lauryl (meth)acrylate, tridecyl (meth)acrylate, and octadecyl (meth)acrylate. Among these, n-butyl (meth)acrylate or 2-ethylhexyl (meth)acrylate, or copolymers obtained by using a combination of these monomers, are preferred because these polymers have suitable viscosity, are easy to handle, and can readily disperse silica to adjust the desired density or viscosity.

[0065] Furthermore, any copolymerizable monomer can be used in combination with it. Typical examples of such copolymerizable monomers are ethylene glycol diacrylate, propylene glycol diacrylate, neopentyl glycol diacrylate, 1,6-hexanediol diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, tetraethylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol dimethacrylate, neopentyl glycol dimethacrylate, 1,6-hexanediol dimethacrylate, diethylene glycol dimethacrylate, 1,2,3-propanediol dimethacrylate, divinylbenzene, etc.

[0066] Other examples of monomers include radical polymerizable monomers capable of copolymerizing with (meth)acrylate monomers.

[0067] Examples of free radical polymerizable monomers also include aromatic vinyl monomers, vinyl esters, vinyl ethers, vinyl pyrrolidones, and (methyl)allyl ethers.

[0068] As monomers for free radical polymerization, only one monomer for free radical polymerization can be used, or two or more monomers for free radical polymerization can be used in combination.

[0069] Examples of aromatic vinyl monomers include styrene, α-methylstyrene, p-methylstyrene, α-methylp-methylstyrene, p-methoxystyrene, o-methoxystyrene, 2,4-dimethylstyrene, chlorostyrene, and bromostyrene.

[0070] Examples of vinyl esters include (meth)acrylates, maleic anhydride, fumarates, (meth)acrylamide, dialkyl (meth)acrylamide, and vinyl acetate. Free radical polymerizable monomers are preferably aromatic vinyl monomers.

[0071] The highly purified acrylate copolymers according to the present invention are obtained by polymerizing alkyl acrylates and / or alkyl methacrylates.

[0072] In a preferred embodiment, the monomer ratio of (n-)butyl acrylate to 2-ethylhexyl acrylate is 2:1 to 9:1, particularly 3:1 to 5:1, and preferably 4:1. The density of the acrylate copolymer can be adjusted by varying the monomer ratio.

[0073] In order to prepare the polymer component, at least 30% to 50% by weight of n-butyl acrylate is used, preferably 35% to 45% by weight, particularly 38% to 42% by weight, and 2% to 20% by weight of 2-ethylhexyl acrylate is used, preferably 5% to 15% by weight, particularly 8% to 12% by weight.

[0074] Therefore, the total mass ratio of the polymer solution used to prepare the acrylate copolymer for separating the gel is preferably about 50% by weight of solvent, 40% by weight of n-butyl acrylate, 10% by weight of 2-ethylhexyl acrylate, and less than 1% by weight of initiator.

[0075] An aromatic solvent, preferably toluene or xylene, is used to prepare the polymer component of the acrylate copolymer for preparing the separation gel.

[0076] In a preferred embodiment, the at least one solvent is preferably used in the preparation of the polymer component in an amount of 30% to 70% by weight, more preferably 40% to 60% by weight, and particularly 45% to 55% by weight.

[0077] Toluene is a CMR substance. CMR substances (carcinogens, mutagens, reproducible toxicants) are substances classified as carcinogens, mutagens, and reproducible toxicants. Even if a CMR substance or its preparation has only minor or no obvious negative characteristics, exposure to it can cause harm to an organism in an inconspicuous and dangerous manner over a prolonged period, but would not be perceived as dangerous by a trained person.

[0078] Since toluene is a CMR substance, the safety of the separation gel is significantly improved due to its low solvent content. The separation gel according to the invention is not classified as a hazardous substance, thus offering advantages particularly in terms of transportation and workplace safety.

[0079] In a preferred embodiment, toluene is used as a solvent to prepare the polymer component of the separation gel. In an alternative embodiment, xylene may also be used as a solvent to prepare the polymer component of the separation gel. Xylene is not classified as a CMR substance, nor is it classified as a mutagen, carcinogen, or reproducible toxicity.

[0080] Organic peroxides, particularly 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, are used as initiators for polymerizing at least two monomers to prepare polymer components.

[0081] Preferably, the polymerization of the at least two monomers is carried out using an organic peroxide as a polymerization initiator. For example, an organic peroxide can be used... As an organic peroxide, it does not form tetramethylsuccinyl nitro (TMSN) as a decomposition product, as opposed to using azobisisobutyronitrile (AIBN) as a polymerization initiator.

[0082] However, the at least two monomers can also be free radical polymerized using nitrogen-based heterocyclic polymerization initiators.

[0083] The acrylate copolymer used to prepare the separation gel had a strength of 1.010 g / cm³ at 20°C. 3 Up to 1.040 g / cm 3 The preferred concentration is 1.025 g / cm³. 3 Up to 1.035 g / cm 3 Especially at 1.030 g / cm³ 3 Up to 1.033 g / cm 3 The density between the two. The density of the acrylate copolymer was determined at 20°C using a flexural vibration density meter DMA4500M (Anton pair) or a gas hydrometer (Pycnomotic ATC).

[0084] The viscosity of the acrylate copolymer was determined at 20°C in the range of 60 Pa·s to 180 Pa·s, preferably 70 Pa·s to 130 Pa·s, and particularly 90 Pa·s to 110 Pa·s. The viscosity was measured using a Brookfield viscometer at a shear rate of 5 / s and at 20°C using a conical plate measuring system (CPA-52Z angle 3°).

[0085] The purified acrylate copolymer has a solvent content of ≤1000 ppm, preferably ≤300 ppm. Gas chromatographic measurements of different batches of the purified acrylate copolymer showed that even when toluene was used as a solvent during polymerization, it contained less than 50 ppm of toluene, especially 10 ppm to 50 ppm of toluene.

[0086] The acrylate copolymers, after purification, have a residual content of ≤50 ppm, particularly ≤20 ppm, of n-butyl acrylate. Gas chromatography measurements of different batches of purified acrylate copolymers also show less than 5 ppm of the monomer-butyl acrylate.

[0087] The separation gel according to the invention comprises purified acrylate copolymer, with a residual content of ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm, and 2-ethylhexyl acrylate monomer. Gas chromatography measurements show that less than 20 ppm of 2-ethylhexyl acrylate monomer is present after purification of the acrylate copolymer.

[0088] Table 1 below shows a detailed description of a preferred embodiment of the purified acrylate copolymer according to the present invention, used for the preparation of a separation gel.

[0089] Table 1

[0090] parameter Viscosity at 20℃ 90-110 Pa·s Density at 20℃ <![CDATA[1.030-1.033g / cm 3 ]]> Toluene ≤300ppm n-Butyl acrylate ≤20ppm 2-Ethylhexyl acrylate ≤80ppm

[0091] The following quantitative data on the composition of the separation gel are based on 100% by weight of the composition of the separation gel used for separating serum or plasma.

[0092] According to the invention, in addition to the acrylate copolymer, silicone oil or at least one polyalkylene glycol is also present in the separation gel. Based on 100% by weight of the composition used for separating serum or plasma, the content of silicone oil or at least one polyalkylene glycol is preferably 0.01% by weight to 1% by weight, more preferably 0.05% by weight to 0.75% by weight, and particularly 0.1% by weight to 0.5% by weight. If the content of silicone oil or at least one polyalkylene glycol deviates from the limits defined above, this will result in the dissolution of the phase separation and the mixing of phases of different densities.

[0093] As a rheology modifier, silicone oil containing polyether-modified polysiloxanes is preferred in the separation gel. The silicone oil is used to adjust viscosity, thereby achieving the desired thixotropy when combined with silicic acid.

[0094] Possible examples of silicone oils include dimethyl silicone oil, methylphenyl silicone oil, methylhydrosilicone oil, alkyl-modified silicone oil, aralkyl-modified silicone oil, fluorine-modified silicone oil, polyether-modified silicone oil, amino-modified silicone oil, epoxy-modified silicone oil, phenol-modified silicone oil, carboxyl-modified silicone oil, methacrylate-modified silicone oil, and alkoxy-modified silicone oil.

[0095] As a silicone oil, silicone oil can be used alone, or two or more types of silicone oil can be used in combination.

[0096] Alternatively, the separation gel may also contain at least one polyalkylene glycol as a rheology modifier with a number average molecular weight (Mn) in the range of 100 to 10,000 Da, preferably in the range of 200 to 5,000 Da, and most preferably in the range of 400 to 4,000 Da. Possible polyalkylene glycols are polyalkylene glycols (PEG) (R = CH2-CH2-O), such as polyalkylene glycol-400; polypropylene glycol (PPG) (R = CH2-CH2-(CH3)-O), such as polypropylene glycol-400 and polypropylene glycol-1000; block copolymers; and statistical copolymers of ethylene oxide and propylene oxide units, such as poly(propylene glycol)block poly(ethylene glycol)block poly(propylene glycol), and poly(ethylene glycol)block poly(propylene glycol)block poly(ethylene glycol) units. In addition, polyalkylene glycols whose OH ends can be completely or partially replaced by alcohols can be used, such as polypropylene glycol monobutyl ether.

[0097] The separation gel of the present invention also contains silica. Silica is preferably present in the form of synthetic, amorphous silicic acid, particularly in an amount of 0.5% to 5% by weight, preferably 1% to 4% by weight, and especially 2% to 3% by weight.

[0098] As for silicic acid, either untreated hydrophilic silicic acid, modified hydrophobic silicic acid, or a mixture thereof can be used.

[0099] Modified silica contains covalently bonded organic groups on its surface to achieve hydrophobicity. It is usually prepared by reacting free silanol groups (Si-OH) with silanes, silazanes, or siloxanes on the surface of untreated silica.

[0100] Examples of these organic compounds include dimethyldichlorosilane, octamethylcyclotetrasiloxane, polydimethylsiloxane, silane methacrylate, octylsilane, hexamethyldisilazane, and hexadecylsilane.

[0101] Silicic acid is used to form gel networks and as a means of controlling density. By combining silicic acid with silicone oil or at least one polyalkylene glycol, both thixotropy and the density of the separated gel can be adjusted.

[0102] Preferably, the average equivalent diameter of the silica particles is in the range of 10 nm to 100 nm, particularly in the range of 5 nm to 30 nm. The particle diameter is determined by laser diffraction.

[0103] The separating gel may contain additional inorganic powder, particularly titanium dioxide, in amounts of 0.001% to 0.1% by weight, preferably 0.005% to 0.08% by weight, and especially 0.01% to 0.05% by weight.

[0104] Titanium dioxide and silica are encapsulated in the gel as insoluble particles and are used to precisely adjust the density of the separation gel.

[0105] Other inorganic powders may also be contained in the separation gel, such as zinc oxide powder, aluminum oxide powder, fine glass powder, talc powder, kaolin powder, bentonite powder, and zirconium powder.

[0106] The separation gel of the present invention may contain other components besides those mentioned above, as long as it does not impair the effect of the present invention. In particular, the separation performance of the separation gel can be guaranteed, while keeping hazardous materials out of reach.

[0107] Other possible components of the invention may include, for example, antioxidants and dyes. As any other component, only one component may be used, or two or more components may be combined and contained in the release gel.

[0108] The separation gel of this invention has a strength of 1.038 g / cm³ at 20°C. 3 Up to 1.058cm 3 The density is preferably 1.040 g / cm³. 3 Up to 1.050 g / cm 3 Especially 1.044 g / cm 3 Up to 1.048 g / cm 3 The density of the separating gel in the selected region is such that a stable separating wall with sufficient strength can be formed between the serum or plasma and the rest of the blood, even in the presence of a small number of blood cells or blood cell components, at low temperatures and / or under the application of small centrifugal forces.

[0109] The density of the separated gel was determined at 20°C using a DMA4500M bending vibration density measuring device (Anton pair) or a gas hydrometer (Pyconomatic ATC).

[0110] At 20°C, the viscosity of the separated gel was in the range of 200 Pa·s to 520 Pa·s, preferably in the range of 220 Pa·s to 280 Pa·s. The viscosity was measured using a Brookfield viscometer at a shear rate of 1 / s and at 20°C using a conical plate measuring system (CPA-52Z angle 3°) until a stable measurement was established.

[0111] The thixotropic index (TI) of the separation gel according to the invention is between 1.2 and 2.2, particularly between 1.2 and 1.7, and preferably between 1.3 and 1.6.

[0112] The thixotropic index is the quotient of two viscosity measurements at different shear rates. For this purpose, viscosity was measured using a Brookfield viscometer at 20°C using a conical-plate measuring system (CPA-52Z measuring cone, 3° angle). First, measurements were taken at a shear rate of 1 / second until a stable value was established, and then at a shear rate of 5 / second until a stable value was established. The thixotropic index was calculated according to Formula 1.

[0113] Formula 1

[0114]

[0115] Gas chromatographic measurements of the separation gel revealed low levels of the solvent toluene and small amounts of the monomers n-butyl acrylate and 2-ethylhexyl acrylate. Measurements were performed using headspace gas chromatography with a flame ionization detector. When prepared using purified acrylate copolymers, the separation gel of the present invention has a residual content of ≤50 ppm, particularly ≤20 ppm, of n-butyl acrylate monomer and a residual content of ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm, of 2-ethylhexyl acrylate monomer.

[0116] In a particularly preferred embodiment, the separating gel has a residual content of ≤5 ppm n-butyl acrylate monomer and ≤20 ppm 2-ethylhexyl acrylate monomer, while having a residual toluene content of ≤50 ppm.

[0117] Table 2 below illustrates a specific embodiment of the separation gel according to the present invention.

[0118] Table 2

[0119] parameter Viscosity at 20℃ 200-520 Pa·s Thixotropic index 1.2-2.2 Density at 20℃ <![CDATA[1.038-1.058g / cm 3 ]]> Toluene (GC) ≤300ppm n-Butyl acrylate (GC) ≤20ppm 2-Ethylhexyl acrylate (GC) ≤80ppm

[0120] The separation gel of the blood collection tube for separating serum or plasma of the present invention can be prepared, for example, by mixing the purified acrylate copolymer of the present invention, silicic acid and silicone oil or at least one polyalkylene glycol and optionally titanium dioxide and optionally other optional components.

[0121] In a preferred embodiment, the untreated hydrophilic silicic acid is pre-conditioned by a drying step. Drying can be carried out by increasing the temperature, decreasing the pressure (vacuum), or by a flow of dry gas (entrained gas). Combinations of two or all three of these methods improve drying efficiency in terms of duration and available residual moisture. The silicic acid is flowed through a heated container at 60°C under vacuum with entrained gas (dry compressed air). To monitor the progress of drying, the humidity of the exhaust gas is measured, and the process terminates when the relative humidity in the exhaust stream is <1%.

[0122] Figure 1 A flowchart of the preparation method of the separation gel of the present invention is shown, including the polymerization and purification of the acrylate copolymer and the mixing of the components of the separation gel of the present invention.

[0123] To prepare the polymer component of the acrylate copolymer, at least two monomers, preferably n-butyl acrylate and 2-ethylhexyl acrylate, are mixed, and then an initiator is fed into the initially supplied boiling solvent during the feed process, which is then fed into a reactor for free radical solvent polymerization.

[0124] To separate the polymerized solvent and monomer from the polymer component of the acrylate copolymer, evaporation is carried out in multiple stages, preferably thin-film distillation, followed by a flash evaporation stage and a short-path evaporation stage.

[0125] Methods for preparing separated gels can be carried out using known mixers, such as planetary mixers, ball mills, or dispersers.

[0126] In a method for preparing a separation gel comprising an acrylate copolymer, silicic acid, and silicone oil or at least one polyalkylene glycol for separating serum or plasma, the acrylate copolymer, silicic acid, and silicone oil or at least one polyalkylene glycol, and optionally titanium dioxide, are mixed in a vacuum planetary separator at 60°C, a pressure ≤40 mbar, and for about 60 minutes. Preferably, the circumferential speed of the dissolving disc can be from about 18 m / s to 30 m / s. Higher mixing speeds have proven advantageous during the mixing process. Here, established methods for preparing the separation gel of the present invention can be used.

[0127] To achieve the desired thixotropy and obtain satisfactory dispersibility of silicic acid, the acrylate copolymer and silicone oil or at least one polyalkylene glycol are first mixed, then the silicic acid and optionally titanium dioxide are mixed, and other components are optionally added to the resulting mixture. In a preferred embodiment, the silicic acid is pretreated by drying before being added to the acrylate copolymer-silicone oil mixture and / or the acrylate copolymer-polyalkylene glycol mixture.

[0128] The separating gel of the present invention is contained in a blood collection tube for separating serum or plasma. According to the present invention, the tube contains at least the separating gel of the present invention, wherein the separating gel is contained within the blood collection tube. Preferably, the separating gel is contained within a region of a closed end of the blood collection tube.

[0129] To obtain serum, blood clotting is activated, for example, by silica particles on the inner wall of blood collection tubes or by additional thrombin in serum tubes.

[0130] CAT serum coagulation activator tubes are coated with micronized silica particles that activate coagulation and are suspended in the blood sample by rotating the filled blood collection tube.

[0131] CAT serum rapid separation tubes contain a separation gel at the bottom of the blood collection tube. Unlike regular serum tubes, rapid serum tubes also contain thrombin to accelerate the clotting process.

[0132] Serum tubes are used in clinical chemistry and immunology, hormone, therapeutic drug monitoring (TDM), and serological assays.

[0133] If an anticoagulant is used for clotting, the blood cannot be completely drained, and plasma is obtained by centrifugation. Plasma contains all clotting and fibrinogens in their active form. Plasma tubes are also used to determine blood parameters for clinical chemistry.

[0134] During centrifugation, the separating gel migrates to the interface between the liquid and cellular components of the blood, where it forms a stable barrier and separates the supernatant from the cellular components. Blood collection tubes are used in clinical chemistry and immunology, hormone, TDM, and serological assays.

[0135] The materials used for blood collection tubes may be, for example, thermoplastics such as polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene terephthalate (PET), polyethylene furan-2,5-dicarboxylate (PEF), polymethyl methacrylate, polyacrylonitrile, polyamide, acrylonitrile-styrene copolymer, and ethylene-vinyl alcohol copolymer; or thermosetting plastics such as unsaturated polyester resin, epoxy resin, and epoxy acrylate resin; modified natural resins such as cellulose acetate, cellulose propionate, ethyl cellulose, and ethyl chitosan; silicates such as soda-lime glass, phosphosilicate glass, and borosilicate glass; glasses such as quartz glass and combinations thereof; or materials mainly comprising one of the above materials.

[0136] The blood collection tubes of the present invention are preferably made of PET plastic, which provides improved safety and hygiene during sampling, and have the advantage of being glass-like transparent.

[0137] Blood collection tubes can be sealed with sealing elements, preferably sealing plugs.

[0138] Preferably, the lumen of the blood collection tube is emptied and has a sealing plug.

[0139] To prevent infection, blood collection tubes may be disinfected, for example, by electronic radiation, such as gamma rays or X-rays.

[0140] Furthermore, other components can be installed on the inner wall of the blood collection tube. Therefore, for example, a blood clotting accelerator can be installed.

[0141] If blood collection tubes are used to obtain plasma, then the blood collection tubes contain an anticoagulant, which can also adhere to the inner wall of the blood collection tube. Anticoagulants such as heparin, EDTA, or citrate, and other substances known in the art can be applied.

[0142] In a preferred embodiment, 1.4 g of separation gel for separating serum or plasma into pressurized blood collection tubes 100 mm long and 16 mm in outer diameter is filled with a rubber stopper and then sterilized.

[0143] In the method for separating serum or plasma using a blood collection tube according to the present invention, whole blood in the blood collection tube is centrifuged to obtain a sufficient quantity and quality of plasma or serum. Whole blood is first collected in the blood collection tube. Through centrifugation, a separation gel is formed between a layer containing blood cells and a layer containing serum or plasma. The density of blood cells is higher than that of plasma or serum, and is approximately 1.06 g / cm³. 3 Up to 1.11 g / cm 3 Within the range, while the density of serum or plasma is 1.025 g / cm³. 3 Up to 1.030 g / cm 3Within the range. The density of the separation gel is in the middle, at 1.038 g / cm³. 3 Up to 1.058 g / cm 3 .

[0144] The acrylate copolymer for use in the separation gel of blood collection tubes comprises at least two monomers and a solvent, wherein the first monomer, particularly n-butyl acrylate, is ≤50 ppm, especially ≤20 ppm, and the second monomer, particularly 2-ethylhexyl acrylate, is ≤200 ppm, preferably ≤100 ppm, especially ≤80 ppm, and the solvent content, particularly toluene content, is ≤1000 ppm, especially ≤300 ppm.

[0145] To prepare the polymer component of the acrylate copolymer, the ratio of the monomer n-butyl acrylate to 2-ethylhexyl acrylate is 2:1 to 9:1, particularly 3:1 to 5:1, and preferably 4:1.

[0146] To prepare the polymer component, at least 30% to 50% by weight of n-butyl acrylate, preferably 35% to 45% by weight, particularly 38% to 42% by weight, and 2% to 20% by weight of 2-ethylhexyl acrylate, preferably 5% to 15% by weight, particularly 8% to 12% by weight, are used.

[0147] As a solvent, an aromatic solvent, preferably toluene and / or xylene, is used to prepare the polymer component in an amount of 30% to 70% by weight, preferably 40% to 60% by weight, and particularly 45% to 55% by weight.

[0148] An organic peroxide, preferably 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, is preferably used as an initiator for polymerizing at least two monomers in an amount of 0.05% to 5% by weight, more preferably 0.1% to 1% by weight, and particularly 0.3% to 0.6% by weight, to prepare the polymer component.

[0149] The polymer component of the acrylate copolymer for separating gels is preferably prepared using about 50% by weight of solvent, 40% by weight of n-butyl acrylate, 10% by weight of 2-ethylhexyl acrylate, and less than 1% by weight of initiator.

[0150] The purified acrylate copolymer has a concentration of 1.01 g / cm³ at 20°C. 3 Up to 1.04 g / cm 3 The preferred value is 1.025 g / cm³. 3 Up to 1.035 g / cm 3 Especially 1.030 g / cm 3 Up to 1.033 g / cm 3The density is between 60 Pa·s and 180 Pa·s, preferably 70 Pa·s and 130 Pa·s, especially 90 Pa·s and 110 Pa·s at 20°C.

[0151] The acrylate copolymer purified according to the present invention for preparing a separation gel for blood collection tubes has a residual content of ≤50 ppm, especially ≤20 ppm, of n-butyl acrylate monomer and a residual content of ≤200 ppm, preferably ≤100 ppm, especially ≤80 ppm, of 2-ethylhexyl acrylate monomer.

[0152] In a particularly preferred embodiment, the acrylate copolymer has a residual content of ≤5 ppm of n-butyl acrylate monomer and ≤20 ppm of 2-ethylhexyl acrylate monomer, while having a residual content of ≤50 ppm of toluene.

[0153] The acrylate copolymer for the separation gel of blood collection tubes of the present invention is preferably prepared from a polymer solution by free radical solvent polymerization during the feeding process, wherein, in order to purify the acrylate copolymer, the solvent is separated by at least multi-stage distillation to achieve a residual solvent content of ≤1000ppm, particularly ≤300ppm.

[0154] The polymerization initiation temperature of the acrylate copolymer is the boiling point of the solvent used in each case. The monomer is added over a period of at least 60 minutes, preferably a longer period of 120 minutes, wherein the monomer ratio of NBA to EHA is preferably 4:1. Simultaneously, the initiator is added to the polymerization solution for the same duration or longer, particularly up to 240 minutes.

[0155] In an alternative embodiment, the preparation of the polymer component of the acrylate copolymer for the separation gel of the blood collection tube can also be carried out using an azo-based polymerization initiator, such as azobisisobutyronitrile (AIBN).

[0156] The residual monomers are also separated from the polymer solution of the acrylate copolymer by multi-stage distillation, resulting in a first monomer of ≤50 ppm, particularly ≤20 ppm, especially n-butyl acrylate, and a second monomer of ≤200 ppm, preferably 100 ppm, particularly ≤80 ppm, particularly 2-ethylhexyl acrylate.

[0157] Distillation is carried out continuously using a thin-film rotary evaporator.

[0158] The evaporation of volatile substances, mainly toluene and / or xylene, as well as monomers n-butyl acrylate and 2-ethylhexyl acrylate, is carried out at a temperature of 130°C to 150°C and a pressure of 90 mbar to 100 mbar.

[0159] The polymer discharged from the thin-layer rotary evaporator is supplied to the flash stage or flash evaporation stage, and, if appropriate, is pre-supplied to the intermediate heating stage.

[0160] Solvent and optional residual monomers are removed under vacuum.

[0161] Optionally, in a subsequent short-path evaporation stage, the solvent and optional residual monomers are distilled off to the desired final content.

[0162] Short-path evaporation is preferably carried out at a jacket temperature of 150°C and a pressure of less than 0.1 mbar.

[0163] The solvent and optional residual monomers are frozen in the downstream cold trap system and then discharged.

[0164] The present invention will be described in more detail through the following embodiments. However, the present invention is not limited to these embodiments. Detailed Implementation

[0165] Preparation of acrylate copolymers

[0166] The acrylate copolymer was prepared by free radical solvent polymerization at atmospheric pressure and boiling at 111°C during the feed process. The boiling temperature of the polymer solution increased to a maximum of approximately 117°C during the reaction. The monomer was introduced into the reactor simultaneously over a period of 120 minutes in the initially introduced boiling solvent, and the initiator was introduced over a period of 240 minutes.

[0167] Composition and chemical and physical properties of acrylate copolymers

[0168] Table 3 shows the different compositions of the acrylate copolymers that form the basis for preparing the separation gel of the present invention. As components of the different compositions for preparing the acrylate copolymers, toluene is used as a solvent, n-butyl acrylate (NBA) and 2-ethylhexyl acrylate (EHA) as monomers, and 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate (e.g., Nouryon's) is used. 421 (T421) or azo (diisobutyronitrile) (AIBN) can be used as initiators.

[0169] Table 3 lists the viscosity, density, and residual amount of the monomer and solvent toluene, with parameters determined by the measurement methods described above.

[0170] Table 3

[0171]

[0172] (1 Measurement method: Gas hydrometer

[0173] (2 Measurement method: Bending vibration density measuring instrument

[0174] If the GC measurement results are undetectable or less than 5 ppm relative to the remaining amount of toluene, NBA, or EHA, then the results are listed in Table 3 as less than 5.

[0175] Composition, chemical and physical properties of separation gels

[0176] Table 4 lists the composition, viscosity, and density of separation gels prepared using examples of the acrylate copolymers described in Table 3, wherein the parameters were also determined by the measurement methods described above.

[0177]

[0178] (1 Measurement method: Gas hydrometer

[0179] (2 Measurement method: Bending vibration density measuring instrument

[0180] ProduktliniebyEVONIKIndustries AG

[0181] XIAMETER TM Produktlinie from DOW Corning

[0182] Titanium dioxide KRONOS1171

[0183] All of the above-mentioned separation gels showed residual amounts of 10 ppm to 50 ppm toluene and ≤20 ppm n-butyl acrylate and ≤80 ppm 2-ethylhexyl acrylate. Measurements of residual solvents and monomers in the acrylate copolymers used to prepare the separation gels are also applicable to the separation gels, since no further introduction of monomers or solvents occurs during the mixing of the components used to prepare the separation gels.

[0184] In a preferred embodiment, the separation gel has a composition of 97.1 wt% purified acrylate copolymer, 2.75 wt% silicic acid, 0.15 wt% silicone oil and 0.0125 wt% titanium dioxide.

[0185] In another embodiment, the separation gel has a composition of 97.1% by weight of purified acrylate copolymer, 2.75% by weight of silica, 0.15% by weight of PEG and / or PPG, and 0.0125% by weight of titanium dioxide.

[0186] In one study, blood collection tubes for obtaining serum and plasma, respectively equipped with the separation gel (A, D) according to the present invention and commercially available separation gels (H, J), were compared. For this purpose, blood was collected from 20 subjects using different blood collection tubes and examined. The average value of the analytes measured in the blood collection tubes equipped with the separation gel of the present invention was compared with the average value of the analytes measured in the blood collection tubes equipped with commercially available separation gels (from the 20 subjects themselves).

[0187] Table 5 below shows the measurement results of the blood collection tubes used to obtain serum.

[0188] Table 5

[0189]

[0190] Table 6 shows the analyte results for the blood collection tubes from which plasma was obtained.

[0191] Table 6

[0192]

[0193] Based on a comprehensive metabolomics study, one or more parameters from each group (general test, electrolytes, proteins, liver function, kidney function) were selected for the study.

[0194] In the first step, the selected parameters are examined to assess health status and provide an overall picture of the body’s chemical balance and metabolism in routine examinations as well as fixed or outpatient examinations.

[0195] The percentage-based criteria list acceptance criteria commonly used in clinical chemistry (e.g.) CLIR). When the percentage difference between the two averages is below the acceptance criteria, the equivalence between a blood collection tube with the separation gel according to the invention and a blood collection tube with a separation gel known in the art is determined.

[0196] In the study, no clinically significant differences were found between blood collection tubes with the separation gel of the present invention and blood collection tubes with commercially recognized, established separation gels for the parameters described.

[0197] The various embodiments illustrate possible implementations, and it should be noted that the invention is not limited to the embodiments specifically shown, but different combinations of the various embodiments are also possible and these variations are within the capabilities of those skilled in the art based on the teachings of the specific invention on the technical process.

[0198] The scope of protection is defined by the claims. However, the claims should be interpreted with reference to the description and drawings. A single feature or combination of features from the different embodiments shown and described can be an independent inventive solution in itself. Objectives based on independent inventive solutions can be derived from the description.

[0199] All descriptions of value ranges in this specification should be understood as including both any and all of the partial ranges therein. For example, the description of 1 to 10 should be understood as including all partial ranges based on a lower limit of 1 and an upper limit of 10, that is, all partial ranges that begin with a lower limit of 1 or greater and end with an upper limit of 10 or less, such as 1 to 1.7 or 3.2 to 8.1 or 5.5 to 10.

[0200] As required, it must be noted that, for better understanding of the construction, some elements are shown partially out of scale and / or enlarged and / or reduced.

Claims

1. A separation gel for blood collection tubes used to separate blood cells from serum or plasma, comprising an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, characterized in that, The separation gel contains ≤1000ppm, preferably ≤300ppm, of solvent.

2. The separation gel according to claim 1, characterized in that, To polymerize acrylate copolymers to prepare polymer components, at least two monomers, particularly n-butyl acrylate and 2-ethylhexyl acrylate, a solvent, and an initiator are used.

3. The separation gel according to claim 1 or 2, characterized in that, The ratio of monomers used to prepare the polymer component is 2:1 to 9:1, particularly 3:1 to 5:1, and preferably 4:1, of n-butyl acrylate to 2-ethylhexyl acrylate.

4. The separation gel according to at least one of claims 1 to 3, characterized in that, The acrylate copolymer contains ≤1000ppm, preferably ≤300ppm, of solvent.

5. The separation gel according to at least one of claims 1 to 4, characterized in that, The acrylate copolymer has a residual content of ≤50 ppm, particularly ≤20 ppm, of n-butyl acrylate monomer.

6. The separation gel according to at least one of claims 1 to 5, characterized in that, The acrylate copolymer has a residual content of ≤200ppm, preferably ≤100ppm, and especially ≤80ppm of 2-ethylhexyl acrylate monomer.

7. A method for preparing a separation gel for blood collection tubes used to separate serum or plasma according to any one of claims 1 to 6, said separation gel comprising an acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol, characterized in that, The acrylate copolymer, silicic acid and silicone oil or at least one polyalkylene glycol and optional titanium dioxide are mixed.

8. The method for preparing a separation gel according to claim 7, characterized in that, To prepare the polymer component of the acrylate copolymer, at least 30% to 50% by weight, preferably 35% to 45% by weight, particularly 38% to 42% by weight, of n-butyl acrylate and 2% to 20% by weight, preferably 5% to 15% by weight, particularly 8% to 12% by weight, of 2-ethylhexyl acrylate are used.

9. The method for preparing a separation gel according to claim 7 or 8, characterized in that, To prepare the polymer components, aromatic solvents, preferably toluene and / or xylene, are used, preferably in amounts of 30% to 70% by weight, more preferably 40% to 60% by weight, and particularly 45% to 55% by weight.

10. A method for preparing a separation gel according to at least one of claims 7 to 9, characterized in that, In order to prepare the polymer components, an organic peroxide, particularly 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate, is used as an initiator for polymerizing at least two monomers, preferably in an amount of 0.05% to 5% by weight, more preferably 0.1% to 1% by weight, and particularly 0.3% to 0.6% by weight.

11. A blood collection tube for separating blood cells from serum or plasma, having a separation gel according to any one of claims 1 to 6.

12. A method for preparing an acrylate copolymer for blood collection tubes by free radical solvent polymerization of polymer components during the feeding process, characterized in that, To purify the acrylate copolymer, at least one solvent is separated by multi-stage distillation to achieve a residual solvent content of ≤1000 ppm, particularly ≤300 ppm.

13. The method according to claim 12, characterized in that, The multi-stage distillation is carried out by thin-film distillation, thereby separating the residual monomers from the polymeric components of the acrylate copolymer to achieve ≤50 ppm, particularly ≤20 ppm, of the first monomer, particularly n-butyl acrylate, and ≤200 ppm, preferably ≤100 ppm, particularly ≤80 ppm, of the second monomer, particularly 2-ethylhexyl acrylate.

14. The method according to at least one of claims 12 or 13, characterized in that, In the subsequent short-path evaporation stage, the solvent and optional residual monomers are distilled off to the final content.

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