Use of alkali hydroxide solution for apheresis column regeneration

Abstract

The present invention relates to the use of alkaline hydroxide to regenerate an apheresis column for affinity chromatography removal of CRP, a method for simplifying the regeneration of an apheresis column for affinity chromatography removal of CRP using an alkaline hydroxide solution, and an apheresis device that is designed to be resistant to alkaline hydroxide solutions and that can perform continuous operation to regenerate an apheresis column for affinity chromatography removal of CRP.

Description

Detailed description of the invention

[0001] [Technical field] The present invention relates to the use of alkali hydroxide for the regeneration of apheresis columns, particularly apheresis columns used for affinity chromatographic removal of CRP, a method for simplifying the regeneration of apheresis columns used for affinity chromatographic removal of CRP using an alkali hydroxide solution, preferably a sodium hydroxide solution, and an apheresis apparatus configured to be resistant to alkali hydroxide solutions. [Background of the Invention] According to the World Health Organization (WHO), approximately 17,000,000 people died from cardiovascular disease in 2008. This makes cardiovascular disease the most common non-communicable cause of death, accounting for about one-third of all deaths worldwide each year. It is estimated that deaths from cardiovascular disease will increase to approximately 23,000,000 per year by 2030.

[0002] Therefore, cardiovascular disease is not only a leading cause of death worldwide, but also a major source of medical expenses for healthcare systems and insurance companies in various countries, and will continue to be so. The two most common and damaging forms of cardiovascular disease are arteriosclerosis and thrombosis, which in turn are factors that cause heart attacks and strokes.

[0003] In recent years, significant progress has been made in the treatment of cardiovascular disease. This progress has been made possible not only by advances in our understanding of the mechanisms that cause disease, but also by the early identification of patients at high risk of developing the disease. In fact, identifying and treating disease risk early is a key feature of modern medicine. Over the past 25 years, various factors and clinical indicators associated with the current state and future potential of cardiovascular disease have been identified. These risk factors may be measurable biochemical or physiological parameters such as serum cholesterol, HDL, LDL, and fibrinogen levels, or behavioral patterns such as obesity and smoking. When risk factors are not merely signs of the disease or its manifestation, but actually contribute to its development, therapeutic intervention of these risk factors may influence the course of the disease and potentially reduce the risk of its development.

[0004] As an acute-phase protein, CRP is part of the innate immune system, produced in the liver and released into the bloodstream during inflammatory responses. CRP production is primarily induced by cytokines expressed during acute or chronic inflammatory responses. Interleukin-6 (IL-6) is the strongest stimulant of CRP production. Therefore, blood CRP and IL-6 levels are indicators of local or systemic inflammatory responses. Chronic inflammation is considered one of the underlying pathological phenomena that support cardiovascular disease. In this context, CRP is increasingly seen not only as a precursor to cardiovascular disease, but also as having a causal relationship with its expression and potentially influencing its course.

[0005] Normal levels of CRP in human blood vary from person to person, but on average, the CRP level is approximately 0.8 mg per liter of blood. However, in cases of acute or chronic inflammatory responses (e.g., bacterial infection, atherosclerosis, post-heart attack), it can rise significantly, potentially exceeding 100 mg per liter of blood. The half-life of blood CRP (approximately 19 hours) is constant and therefore independent of the patient's health status; thus, only the rate of CRP synthesis is involved in regulating blood CRP levels (Pepys & Hirschfield, J. Clin. Invest., 2003, 111:1805-1812). Consequently, a significant increase in CRP synthesis in acute conditions places a special burden on treatment methods to remove CRP from patients (high-risk patients or patients in the acute phase). This is because a considerable amount of CRP needs to be removed to lower blood CRP levels to normal. Therefore, particularly efficient equipment and boundary conditions are needed for removing CRP from patients' blood.

[0006] Extracorporeal apheresis is a procedure used to physically remove substances from blood or plasma using filtration, precipitation, or adsorption. The term therapeutic apheresis typically refers to a medical procedure to remove pathogenic components from the circulating blood. Removing pathogenic substances from blood or plasma through extracorporeal apheresis using extracorporeal circulation has become an established treatment method in standardized clinical practice for numerous diseases. For example, immunoadsorption can be used to remove antibodies and immune complexes in the bloodstream from a patient's plasma.

[0007] When performing therapeutic extracorporeal removal of C-reactive protein (CRP) from blood or plasma, CRP apheresis columns are known for their advanced technology that allows for the selective removal of CRP from blood or plasma. These columns contain a substrate material (such as agarose) covalently bonded to phosphocholine or a phosphocholine derivative as a ligand for CRP.

[0008] European Patent Application Publication No. 3020726(A1) specifies the Ca of CRP. 2+Column materials functionalized with ω-phosphonooxyalkylammonium groups and / or ω-ammonium alkoxy-hydroxyphosphoryloxy groups for affinity chromatographic removal of CRP by dependent binding are disclosed. The advantage of using such phosphocholine derivatives in CRP apheresis is that they can be selectively removed from plasma components such as other plasma proteins by highly specific ligands. One reason for this is that Ca2+ is adsorbed onto phosphocholine or its derivatives of CRP. 2+ One notable feature is the use of a dependent binding mechanism. The only other substance that binds to phosphocholine is an antibody against phosphatidylcholine. Therefore, the loss of other plasma proteins, such as gamma globulin, is minimized.

[0009] When extracorporeal apheresis is used therapeutically with an extracorporeal circulation system, reusable adsorbents are often used because apheresis is performed in several cycles within a single treatment period. Reusable adsorbents are known from advanced technology and consist of a housing filled with a carrier material and linked binding factors. Reusable adsorbents are generally regenerative because, after plasma passes through them (depending on the amount and concentration of the adsorbed substance), the adsorbent becomes "saturated" and can no longer bind to substances. Two adsorbents are often used for a single treatment. Plasma is pumped through the first adsorbent while the second adsorbent is simultaneously regenerated. In this process, the adsorbent is washed with various regeneration solutions to remove binding substances and prepare it for refilling with new plasma. The number of regeneration cycles is specified by the manufacturer. Reusable adsorbents can only be used for one person and the same patient. To prevent bacterial growth within the adsorbent, it is necessary to fill the adsorbent with an antiseptic liquid after each reuse treatment and to flush it out before each new treatment period. However, reusing the adsorbent can save significant costs. Operating multiple existing devices (combinations of two or more medical devices) is extremely complex and demanding. Furthermore, it is rare to use these medical devices comprehensively.

[0010] The apheresis column is used for a patient over several treatment periods. For this purpose, the apheresis column is stored in a preservation solution after treatment. In the prior art, at the end of the apheresis treatment, the apheresis column is treated with a regeneration solution, then rinsed with a rinsing solution such as physiological saline, and finally, a preservation solution such as a 0.04% polyhexamethylene biguanide solution (PHMB solution), or a solution of sodium azide and PBS (phosphate buffered saline) is introduced into the apheresis column. Therefore, the storage process requires a significant time constraint on clinical staff. If the regeneration solution and the preservative are the same solution, two additional steps for storing the apheresis column could be avoided.

[0011] Generally, in therapeutic apheresis, the patient's blood is first mixed with an anticoagulant (e.g., citrate or heparin) and separated into plasma and cellular components using a blood centrifuge or a plasma filtration device. Then, the plasma is passed through the apheresis column to remove pathogenic substances by adsorption. The treated plasma is then recombined with the cellular components and returned to the patient. During regeneration, the apheresis column is disconnected from the extracorporeal circulation system.

[0012] In apheresis treatment for selectively removing CRP from plasma, an average of 6000 mL of plasma is processed during 6 to 12 cycles in one treatment period. The processing of 6000 mL of plasma usually takes about 4 to 5 hours including the regeneration of the apheresis column. Therefore, the regeneration of the apheresis column is a time factor that affects the overall length of the treatment period. Thus, since the apheresis column cannot be used for CRP removal from blood or plasma during regeneration, it is desirable to minimize the regeneration time.

[0013] Conventional techniques for regenerating apheresis columns, particularly CRP apheresis columns, use glycine / HCl or EDTA solutions. These solutions either denature the binding protein due to a rapid change in pH to an acidic range, or dissolve the adsorbed molecules to be removed, especially CRP, from the apheresis column support by forming complexes with cations that mediate binding, particularly calcium. Conventional techniques do not know of any compounds that can separate the bound molecules to be removed, especially CRP, from the apheresis column support using a different mechanism.

[0014] German Patent No. 4338858(C1) discloses an apparatus for regenerating an apheresis column. The specification also teaches the use of a tank for temporarily holding plasma during apheresis column regeneration. Apheresis column regeneration is performed by a combination of glycine / HCl, PBS, and NaCl solutions, as is known in the prior art. Furthermore, German Patent No. 4338858(C1) does not disclose a bypass line that would allow the plasma flow to be diverted and the apheresis column to be bypassed during column regeneration.

[0015] European Patent Application Publication No. 3020726(A1) discloses the use of citrate solutions for affinity chromatography purification of CRP using phosphocholine and its derivatives. The chromatography uses a binding buffer pH 8.0 (0.1M Tris, 0.2M NaCl, 2mM CaCl2) and an elution buffer pH 8.0 (EDTA) or a regeneration solution pH 2.8 (glycine / HCl), which are known in the prior art.

[0016] The inventors of this invention have discovered that a protein layer forms around substrate particles (e.g., agarose particles) during regeneration using glycine / HCl, particularly during the regeneration of apheresis columns for affinity chromatography removal of CRP. This is likely due to the precipitation of acidic proteins. This effect can be amplified when the patient's blood being purified contains high concentrations of cell-free DNA / RNA. The formation of the protein layer within the apheresis column shields binding sites, reducing the performance of the apheresis material. It is impossible to restore the column to its original state using known methods, such as attempting further regeneration with a glycine / HCl solution. This problem has not been described in the prior art to date. As the apheresis column deteriorates, treatment time for patients increases, leading to longer periods of discomfort for the patient. Furthermore, damaged apheresis columns are often unusable, thus significantly increasing treatment costs.

[0017] Furthermore, the protein layer, or the protein-DNA and protein-RNA layers, can become clogged, increasing the pressure in the system under constant flow rates. Further increases in flow rates lead to further increases in pressure. As a result, treatment may have to be discontinued. Such apheresis columns are not suitable for further use.

[0018] Generally, in affinity chromatography, the column is first prepared using a binding buffer that favorably influences and promotes the interaction between the target substance and the ligand present in the substrate material. After pouring the sample and passing it through the column, the bound target substance is washed away and eluted. To elute the target molecule, the interaction between the target substance and the ligand is broken, for example, by a competing ligand, or by changing the pH, ionic strength, or polarity, using an elution buffer that is particularly based on the binding mechanism. After elution is complete, the column is washed with a wash buffer or again with a binding buffer. Elution is specific to the type of affinity chromatography because it breaks down the specific interaction between the target substance and the ligand.

[0019] When selectively removing pathogenic substances from blood or plasma, conventional therapeutic apheresis relies on the principle of affinity chromatography. This is because this type of separation is based on specific, reversible interactions between substances such as proteins or groups of proteins and specific ligands that bind to the substrate of the support. The advantage of affinity chromatography purification lies in its high selectivity, which allows for the targeted removal of the target substance from blood or plasma during therapeutic apheresis with little to no removal of other components due to nonspecific interactions. Thus, affinity chromatography particularly leverages the biological function of biomolecules or their individual structures. The interaction between the ligand and the target molecule may be the result of electrostatic or hydrophobic interactions, van der Waals forces, or hydrogen bonding.

[0020] German Patent Application Publication No. 10065241(A1) discloses an immunoadsorbent for in vitro apheresis and a method for preparing the same. The disclosed immunoadsorbent is intended for the removal of immunoactive substances such as immunoglobulins, antibodies, and immune complexes from the plasma or whole blood of patients suffering from immune diseases. The disclosed immunoadsorbent is prepared by covalent bonding of ligand-protein A to different carrier materials.

[0021] It is known from prior art that protein A exhibits high affinity to the Fc region of polyclonal and monoclonal IgG antibodies. Therefore, a column composed of protein A that binds to a substrate material is suitable for affinity chromatographic purification of antibodies. In other words, the column is specific to antibodies but not to CRP. For this reason, German Patent Application Publication No. 10065241(A1) does not disclose an apheresis column for affinity chromatographic removal of CRP.

[0022] German Patent Application Publication No. 10065241(A1) describes the use of a binding buffer pH 7.0 and an elution buffer pH 2.2 to adsorb hIgG (Example 1D) onto a protein A adsorbent in a standard cycle (apheresis elution buffer: 0.03-0.05 M citrate, 0.15 M NaCl). The disclosed protein A adsorbent was tested for chemical stability with various regeneration media in the pH range of 2-14 (Example 13D). The regeneration media used contained a 0.1 M sodium hydroxide solution (pH 14). To perform regeneration, each regeneration medium was pressed onto a column and washed with binding buffer pH 7.0. Next, the hIgG binding capacity was measured. The measurement of hIgG binding capacity was performed according to a standard cycle using binding buffer pH 7.0 and elution buffer pH 2.2. Human plasma was not used; instead, an hγ-globulin solution was dissolved in apheresis binding buffer pH 7.0 (concentration 8 mg / mL). The regeneration process disclosed in German Patent Application Publication No. 10065241(A1) is carried out in a separate additional wash step, so that the protein A adsorbent after hIgG injection is treated with elution buffer pH 2.2 and wash buffer before the regeneration is performed.

[0023] For therapeutic apheresis, additional rinsing steps during regeneration and rinsing steps for apheresis column washing also represent an undesirable extension of regeneration time, and therefore total processing time. The longer the rinsing steps, and the more regeneration or washing solutions are used, the longer the total regeneration time of the apheresis column included in the regeneration cycle. In particular, when using two adsorbents in a single treatment, where plasma is being squeezed through the first adsorbent while the second adsorbent is being regenerated simultaneously, increasing the rinsing steps and using multiple regeneration solutions is not appropriate because the regeneration of the second adsorbent must be completed before the first adsorbent is saturated in order to ensure the continuous and smooth removal of pathogenic substances from blood or plasma.

[0024] Furthermore, German Patent Application Publication No. 10065241(A1) only attempts a single treatment using each regenerated medium. However, for therapeutic apheresis to be performed, regeneration must be repeatable; that is, the regenerated medium must be reusable without adverse effects on its binding ability, such as a decrease in its ability to bind to substances to be removed from blood or plasma. In therapeutic apheresis, apheresis columns are typically regenerated several times during a single treatment period.

[0025] Regarding repeated use, German Patent Application Publication No. 10065241(A1) (Example 14D) describes the hIgG binding capacity in response to repeated use of 0.5N NaOH in an additional regeneration step. Here, hIgG binding was performed using human plasma (4.2 mL / mL gel; 6.5 times hIgG; concentration 9.8 mg / mL) according to a standard cycle using binding buffer pH 7.0 and elution buffer pH 2.2. In repeated regeneration after the standard cycle, 0.5N NaOH was injected into the column at a flow rate of 2 mL / min (equivalent to 80 times the gel volume) for 2 hours. After this, washing was performed with water, apheresis buffer pH 2.2, and apheresis buffer pH 7.0. It is disclosed that when 0.5N NaOH was used, the hIgG binding capacity decreased to 50% after only 5 cycles. Another experiment disclosed that when 62.5 mL of adsorbent was regenerated with 0.5 N NaOH for 7 minutes, only 83% of the initial binding capacity was observed after 6 regeneration cycles. Therefore, German Patent Application Publication No. 10065241(A1) teaches that sodium hydroxide solution can only be used as a regeneration medium in a limited range because its binding capacity decreases with repeated regeneration.

[0026] European Patent Application Publication No. 3459552(A1) discloses the provision of “general” plasma obtained from a mixture of plasma from donors whose blood types are A, B, AB, and / or 0. The “general” plasma is intended to have low levels of anti-A and anti-B antibodies and therefore be compatible with all blood types. For this purpose, anti-A and anti-B antibodies are removed from the plasma mixture by immunoaffinity chromatography purification. The substrate has an oligosaccharide group similar to the epitopes of blood types A and / or B. For regeneration, treatment with sodium hydroxide, e.g., 1M NaOH, is cited, but no further explanation is given.

[0027] The binding mechanism on which immunoaffinity chromatographic purification using functionalized substrates, as described in European Patent Application Publication No. 3459552(A1), is based is related to specific carbohydrate-protein interactions. Therefore, European Patent Application Publication No. 3459552(A1) does not disclose apheresis columns for affinity chromatographic removal of CRP, in particular apheresis columns for extracorporeal removal of CRP from blood or plasma, and thus apheresis columns applicable to therapeutic apheresis. Furthermore, European Patent Application Publication No. 3459552(A1) also relates to the field of prepared plasma apheresis, where the plasma is obtained during blood donation. This should be distinguished from therapeutic apheresis, where the processed plasma is returned directly to the patient.

[0028] German Patent Application Publication No. 10065241(A1) and European Patent Application Publication No. 3459552(A1) do not disclose apheresis columns for affinity chromatographic removal of CRP. Regarding apheresis columns for affinity chromatographic removal of CRP, there are no other compounds and methods known in the prior art, except for the use of a glycine / HCl solution or EDTA solution to regenerate the molecule to be removed, particularly CRP, bound to the apheresis column support. Therefore, there is a need for uses, methods, and apparatus that enable particularly smooth flow by preventing binding site shielding and increased apheresis processing time.

[0029] Therefore, the object of the present invention is to provide a method, apparatus, and apparatus that enable particularly smooth flow by preventing shielding of the coupling site and an increase in apheresis processing time.

[0030] A further object of the present invention is to provide a use, method, and apparatus for simplifying the regeneration of apheresis columns, particularly apheresis columns for affinity chromatographic removal of CRP, thereby minimizing the aforementioned drawbacks of apparatus and methods known in the prior art. In other words, an object of the present invention is to provide an apparatus for simplifying the regeneration of apheresis columns, particularly apheresis columns for affinity chromatographic removal of CRP, which is operable with less training effort, and thus reduces both operator effort and overall cost.

[0031] This objective is addressed by the teachings of each independent claim. Further effective embodiments are derived from the description, examples, and appended claims. [Overview of the prefecture] As used herein, the term "CRP" corresponds to "C-reactive protein." In this specification, human C-reactive protein is preferred. C-reactive protein (CRP) has two Ca25 subunits. 2+It is a pentamer that has ions attached to it, and these ions enable it to bind to ligands such as phosphocholine or its derivatives.

[0032] As used in this application, the term “affinity chromatographic” in relation to CRP removal means that CRP removal occurs by the specific binding of CRP to the CRP removal component of the apheresis column. Here it may also be called “selective CRP removal” or “selective CRP apheresis.” Such specific binding between CRP and the components of the apheresis column is based on the structural properties of the CRP protein, and includes, for example, the characteristic binding of CRP to phosphocholine and its derivatives, or the binding of CRP to antibodies against CRP epitopes. Selective or molecularly specific removal of CRP involves CRP binding that has a higher affinity to the substrate in the apheresis column than other structures / molecules. Also, CRP binds to the substrate in the apheresis column with a higher affinity than other substances present in blood. In other words, the substrate has specificity for CRP, or the substrate is specific to CRP. The substrate is preferably a solid phase modified with phosphocholine, and preferably selectively binds CRP. In other words, it binds CRP almost exclusively and does not bind other blood components, such as LDL cholesterol, antibodies, uremic toxins, etc. For this reason, "CRP removal" preferably means selective removal of CRP, as disclosed herein. However, the term "selective" in relation to CRP removal does not mean the exclusive removal of CRP only, as used in this application. Here, it is obvious to those skilled in the art that in such affinity chromatographic removal of CRP, it is unavoidable that other substances will (unintentionally) bind to the column material to some extent, and therefore may be removed to some degree. One example is an antibody against phosphocholine, which can bind to column material that has already been functionalized with phosphocholine. Another possibility is the nonspecific binding of bodily fluid components to the substrate material, which can never be completely prevented.

[0033] As used herein, regeneration refers to the process by which accumulated material is removed from the substrate of an apheresis column comprising a substrate material and a ligand, and the substrate is restored to a state where it can be used for therapeutic purposes, i.e., regenerated.

[0034] The term "regeneration solution," as used herein, refers to a solution poured in an affinity chromatography method for removing a substance from a sample (here, a bodily fluid such as blood or plasma) after the sample has been poured onto the column material and after the substance to be removed has specifically bound to the column material, in order to release this specific binding, that is, to release (or elute) the substance to be removed again from the column material. In addition to the regeneration solution, the term "elution buffer" (also called "elution solution"), as used herein, also refers to a solution poured in an affinity chromatography method for removing a substance from a sample (here, a bodily fluid such as blood or plasma) (here, selective removal of CRP) after the sample has been poured onto the column material and after the substance to be removed has specifically bound to the column material, in order to release this specific binding, that is, to release (or elute) the substance to be removed again from the column material. Unlike the binding buffer, the elution buffer does not make the substance to be removed capable of binding, but rather creates a state within the column material that actually prevents binding.

[0035] Unlike elution buffers, regeneration solutions also serve to regenerate the apheresis column by removing accumulated substances, thus making the column ready for therapeutic use again. In other words, the regeneration solution performs both functions: to break the specific binding of the substance to be removed to the column material in order to remove (or elute) the substance again from the column material, and to remove accumulated substances in order to regenerate the apheresis column, making it ready for therapeutic use again. Therefore, the regeneration solution is used for both elution and regeneration purposes. Consequently, it is preferable that the regeneration solution also elutes the substance to be removed (in this case, CRP). For this reason, the regeneration solution is preferably used to elute CRP from an apheresis column undergoing affinity chromatographic removal of CRP, thereby returning the apheresis column to a state ready for therapeutic use.

[0036] The term "binding buffer" (also referred to as "binding solution"), as used herein, refers to a solution added to a sample (in this case, a body fluid such as blood or plasma) and subsequently poured together with the sample onto the column material in an affinity chromatography method for removing a substance (in this case, selective removal of CRP) from the sample. The binding buffer is intended to ensure appropriate conditions for the specific binding of the substance to be removed to the column material.

[0037] The term "body fluid," as used herein, refers to aqueous solutions present inside mammals, preferably humans, such as cerebrospinal fluid, peritoneal fluid, pleural fluid, ascites, blood, plasma, liver extract, and interstitial fluid. The present invention preferably relates to CRP contained in body fluids.

[0038] It is known from prior art that glycine / HCl solution or EDTA solution is used to regenerate apheresis columns, particularly CRP apheresis columns. Binding proteins denature when the pH value rapidly changes to an acidic range. Alternatively, the binding of adsorbed molecules to be removed, especially CRP, to the apheresis column support is released by the formation of complexes with mediating cations, particularly calcium. Similar to EDTA administration, citrate-containing solutions are suitable as elution buffers for removing bound CRP from the apheresis column. In prior art, no compounds are known that can separate bound molecules to be removed from the apheresis column support using a different mechanism.

[0039] To investigate the resistance of CRP-selective substrate materials to glycine / HCl solutions as described herein, the inventors of the present invention performed a 200-cycle test using 7.5 matrix volume (MV) of glycine / HCl buffer, followed by 4 MV of PBS solution (pH 7.4) and 4 MV of NaCl in succession, without infusing plasma into the CRP apheresis column between cycles. The CRP binding capacity was tested once before the regeneration cycle and once after 200 consecutive regeneration cycles. It was found that repeated pH changes from 7.4 to 2.8 had no effect whatsoever on the CRP binding capacity of the CRP apheresis column used. Degradation of the column material or adsorbent due to the use of pH 2.8 glycine / HCl as a regeneration solution did not reduce the CRP binding capacity.

[0040] The CRP removal study was conducted on a laboratory scale by injecting human plasma into a column containing a substrate material selective for CRP. The column used contained 0.5 g of substrate, and 75 mL (150 substrate volume) of human plasma containing 100, 50, or 10 mg / L of CRP was passed through the column at a flow rate of 1.2 mL / min (equivalent to 17 mL / min on an apheresis column scale). The substrate was washed with buffer (0.1 M Tris, 0.2 M NaCl, and 2 mM CaCl2), and CRP was eluted with elution buffer (EDTA, 0.2 M NaCl, and 0.1 M Tris). The column was then regenerated with glycine / HCl at pH 2.8. The substrate used was found to bind CRP specifically and selectively. When using EDTA elution buffer, which prevents calcium-dependent binding, CRP was completely eluted. When the column was regenerated with glycine / HCl, only small amounts of other proteins were detected. No decrease in CRP binding capacity was observed after using the column multiple times.

[0041] Clinical apheresis was performed in a cycle of pre-washing the adsorber with 0.9% NaCl buffer, injecting plasma to be returned to the patient into the adsorber, and regenerating the adsorber in preparation for the next cycle. Except for plasma, no other solutions used were returned to the patient. To investigate CRP removal from plasma under clinical conditions, 20 mL of substrate material was injected into the column, pre-washed with 200 mL of 0.9% NaCl buffer, and 2.5 L of human plasma with an initial CRP concentration of 100 mg / L was passed through at a flow rate of 30 mL / min for 5 cycles (1 L / cycle). After each cycle, the apheresis column was regenerated with 35 mL of 0.9% NaCl, 50 mL of glycine / HCl buffer, 80 mL of PBS, and 35 mL of 0.9% NaCl. The substrate used contained a ligand for human CRP-derived phosphocholine, which is particularly suitable for therapeutic apheresis. As a result, substrates bound to CRP with high selectivity, and the rate of nonspecific protein binding to other plasma proteins was very low. CRP binds very specifically to phosphocholine and its derivatives through electrostatic interactions between the ligand and CRP.

[0042] In apheresis therapy, which selectively removes CRP from plasma, an average of 6000 mL of plasma is processed over 6–12 cycles in a single treatment period. The processing process for 6000 mL of plasma typically takes about 4–5 hours, including the regeneration of the apheresis column. Regeneration was performed using glycine / HCl buffer, a regeneration solution known in conventional techniques. The minimal further plasma protein loss by CRP apheresis compared to the initial blood concentration is due to the modified infusion and the regeneration of the adsorbent during processing, and the loss is less than that of in vitro methods. Nonspecific binding of plasma proteins to the substrate by the adsorbent is negligibly low. Therefore, because blood loss is minimal and no side effects have been reported to date, it has been shown that patients can be treated indefinitely using CRP apheresis.

[0043] In therapeutic apheresis, which removes CRP from blood or plasma, the plasma is returned to the patient after passing through an apheresis column. Reusable adsorbents can only be used for one and the same patient. However, the inventors of this invention have discovered that when using an apheresis column to remove CRP from circulating blood or plasma in therapeutic apheresis, a protein layer is formed around the substrate particles (e.g., agarose particles) during regeneration with glycine / HCl. This effect can be particularly amplified when the patient's blood being purified contains high concentrations of cell-free DNA / RNA. The formation of the protein layer within the apheresis column shields the binding sites, reducing the performance of the apheresis material. Known means, such as attempting further regeneration with a glycine / HCl solution, do not allow the material to return to its original state.

[0044] As apheresis columns become more damaged, treatment times for patients increase, leading to longer periods of discomfort. Furthermore, damaged apheresis columns are often unusable, significantly increasing treatment costs. Additionally, the protein layer, or protein-DNA and protein-RNA layers, can become clogged, increasing the system pressure at a given flow rate. Further increases in flow rate lead to further increases in pressure, potentially necessitating the discontinuation of treatment. Such apheresis columns are also unsuitable for further use.

[0045] In therapeutic apheresis, the substance to be removed, in this case CRP, is removed from the blood or plasma of a single patient. Therefore, the composition of the plasma is unique to that patient. Consequently, it is natural that the concentration of cell-free DNA / RNA in the plasma of different patients will differ. Therefore, the degree of the aforementioned problems that have been shown to occur when regenerating CRP apheresis columns with glycine / HCl buffer also varies from patient to patient. Thus, it would be particularly effective to use a regeneration solution that can completely regenerate the apheresis column regardless of the concentration of cell-free DNA / RNA in the plasma. Furthermore, using a regeneration solution that improves the reusability of the apheresis column would be particularly effective for regeneration.

[0046] To regenerate the apheresis column, it might be possible to use various regeneration solutions that pass through the apheresis column successively. However, increasing the number of rinsing steps and the number of different regeneration solutions leads to an increase in the total regeneration time. As a result, it affects the treatment time and prolongs the patient's discomfort. The flow rate during blood purification is limited by the patient's blood flow, but in principle, the flow rate can be increased during regeneration to accelerate the process and make the apheresis column available for further use. However, increasing the flow rate also increases the pressure on apheresis, and therefore the pressure on the substrate or column material. Depending on the column material, exceeding a certain pressure can change the shape and strength of the material, which reduces the separation performance of the column material. Therefore, the flow rate used for regenerating the apheresis column depends on the pressure resistance of the column material used. A high flow rate can compress the substrate, which can result in a decrease in flow rate. Therefore, regeneration at an arbitrary flow rate is not possible. However, if the high flow rate is reduced, the compression can be restored. Therefore, regeneration time mainly depends on the volume and flow rate of each rinse step, but ultimately also depends on the number of rinse steps.

[0047] Therefore, using a regeneration solution that has already completely regenerated the apheresis column when used alone would be particularly effective for regeneration. By using a single regeneration solution for apheresis column regeneration, the number of rinsing steps can be reduced to the absolute minimum. This would be particularly effective when using a regeneration solution to elute substances to be removed, in this case CRP, while simultaneously returning the apheresis column to a state where it can be used for treatment.

[0048] It was surprising to discover that apheresis columns that had already been used—that is, apheresis columns that had undergone processing to remove substances from blood—could be regenerated using an alkali hydroxide solution, preferably a sodium hydroxide solution, and that these regenerated apheresis columns could still be used for apheresis. In particular, apheresis columns that, as a result of use, had protein deposits and / or protein-DNA and protein-RNA deposits that could no longer be removed with regeneration solutions used in conventional techniques could be regenerated in this way. Until now, such apheresis columns had been considered unusable.

[0049] Therefore, this patent invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column. In other words, the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, as a regeneration solution in apheresis. Further in other words, the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, as a regeneration solution for an apheresis column.

[0050] More specifically, the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column that performs affinity chromatographic removal of CRP. Therefore, preferably, the present invention relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, where the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP. Particularly preferably, the present invention relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, where the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP from blood or plasma.

[0051] It was surprising to find that basic regeneration using an alkali hydroxide solution, preferably a sodium hydroxide solution, can regenerate even substrates of adsorbents that have already been damaged within the apheresis column. When only an alkali hydroxide solution, preferably a sodium hydroxide solution, is used as a regeneration method, there is no risk of acidic protein precipitation. This is an important aspect in restoring the function of the apheresis column. In particular, it has been shown that basic regeneration using an alkali hydroxide solution, preferably a sodium hydroxide solution, can regenerate even substrates of adsorbents that have already been damaged within the apheresis column performing affinity chromatographic removal of CRP.

[0052] Furthermore, the apheresis column may be effectively stored with an alkali hydroxide solution, preferably a sodium hydroxide solution, as a preservative. In a preferred embodiment, the apheresis column used for affinity chromatographic removal of CRP can be stored using an alkali hydroxide solution, preferably a sodium hydroxide solution. This avoids the time-consuming apheresis column washing step performed after treatment, making apheresis treatment, including preparation for storage of the apheresis column, as efficient as possible. Alkali hydroxide solutions are suitable for storing apheresis columns, and sodium hydroxide solution in particular is extremely suitable for storing apheresis columns due to its high bactericidal activity. Microbial growth is substantially eliminated.

[0053] Therefore, a further aspect of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration and storage of apheresis columns, preferably apheresis columns that perform affinity chromatographic removal of CRP. Thus, the present invention also covers the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration and storage of apheresis columns. In other words, the present invention also covers the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, as a regeneration solution in apheresis and for the storage of apheresis columns. More preferably, the present invention covers the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, as a regeneration solution in apheresis that performs affinity chromatographic removal of CRP and for the storage of apheresis columns that perform affinity chromatographic removal of CRP.

[0054] Unlike conventional methods for regenerating apheresis columns, the alkali hydroxide solution, preferably sodium hydroxide solution, is characterized by not being a chelating agent for cations. The alkali hydroxide, preferably sodium hydroxide, is expected to reduce the binding affinity of the substance to be removed to the support, and, on the other hand, to reduce binding to the support by potentially denaturing the binding protein. The acceleration of regeneration makes it possible to return the column to a usable state during apheresis treatment. Regeneration of an apheresis column can be performed during apheresis treatment, but it does not affect the apheresis treatment itself and is therefore not a diagnostic or therapeutic method. Rather, it is a method for purifying an apheresis column, and even if the regeneration of the apheresis column is performed during apheresis treatment, it is irrelevant to the apheresis patient.

[0055] In the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, according to the present invention for the regeneration of an apheresis column, preferably an apheresis column for affinity chromatographic removal of CRP, the regeneration of the apheresis column can be performed during apheresis treatment, as described herein. Preferably, in the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of the apheresis column, as described herein, the regeneration of the apheresis column is performed during the removal of the target compound, particularly CRP. Thus, preferred embodiments of the present invention relate to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the regeneration is performed during apheresis treatment.

[0056] Therefore, the present invention also relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, wherein the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the regeneration is performed during apheresis treatment. Therefore, the present invention also relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, wherein the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the regeneration is performed during apheresis treatment in which CRP is removed extracorporeally from blood or plasma. During regeneration, the apheresis column is disconnected from the extracorporeal circulation system. In other words, the apheresis column is not connected to the extracorporeal circulation system during regeneration. In other words, the apheresis column is not fluidly connected to the extracorporeal circulation system during regeneration.

[0057] Accordingly, the present invention also relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, wherein the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, the regeneration is performed during apheresis treatment in which CRP is removed extracorporeally from blood or plasma, and the apheresis column is detached from the extracorporeal circulation system during regeneration.

[0058] Therefore, the present invention preferably relates to the use of alkali hydroxide for the regeneration of an apheresis column, where the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, the regeneration is performed during apheresis treatment in which CRP is removed extracorporeally from blood or plasma, and the apheresis column is not connected to an extracorporeal circulation system during regeneration.

[0059] Preferably, the apheresis column is regenerated using an alkali hydroxide solution, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP when plasma is passed through the apheresis column for CRP removal before regeneration.

[0060] Therefore, it is preferable to use an alkali hydroxide solution to regenerate the apheresis column, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the apheresis column contains CRP. Preferably, the apheresis column is also regenerated using an alkali hydroxide solution, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the apheresis column is saturated with CRP.

[0061] "During apheresis treatment" or "during the removal of target compounds, particularly CRP, from blood" means, as used herein, that the apheresis column is being regenerated while the treatment is being performed within the same apheresis device. This may interrupt the removal of target compounds, particularly CRP, from blood, and the apheresis column may be regenerated using the same device. Alternatively, the apheresis column may be regenerated while the removal of target compounds, particularly CRP, from blood continues simultaneously using a different apheresis column. The apheresis column regeneration takes place within the apheresis device. However, the term "during apheresis treatment" does not mean that regeneration and CRP removal from blood are performed simultaneously on the same apheresis column.

[0062] Furthermore, as already explained, the inventors of this invention are aware that deposits (protein layers) form within the apheresis column during regeneration using glycine / HCl. This effect may be amplified if the patient's blood being purified contains high concentrations of cell-free DNA / RNA. The formation of deposits within the apheresis column also irreversibly adheres the substrate. In other words, once this state is reached, it cannot be restored using known means such as attempting further regeneration with a glycine / HCl solution. If the deposition of proteins on the column material of the apheresis column reaches the point of forming a protein layer on the column material, regeneration of the apheresis column by known means such as washing with a glycine / HCl solution is no longer possible because the protein deposits and protein layer cannot be removed with conventional regeneration solutions.

[0063] It was surprising to find that protein deposits could be removed using a 0.01M to 1M alkali hydroxide solution, preferably a 0.04M to 0.4M alkali hydroxide solution, and preferably completely restored to its original state. In particular, it was surprising to find that protein deposits could be removed using a 0.01M to 1M sodium hydroxide solution, preferably a 0.04M to 0.4M sodium hydroxide solution, and preferably completely restored to its original state. For example, basic regeneration solutions with a pH range of 12 to 14 are not known in conventional techniques related to the regeneration of CRP apheresis columns.

[0064] Therefore, preferably, the use of the present invention refers to an apheresis column containing DNA / RNA (free DNA or free RNA), preferably an apheresis column having a substrate, wherein bound DNA or RNA is present, and more preferably an apheresis column in which the DNA or RNA is bound to a ligand of the substrate, respectively.

[0065] Therefore, a preferred embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, preferably an apheresis column for affinity chromatographic removal of CRP, wherein the apheresis column contains DNA and / or RNA precipitates, i.e., on the adsorbent, or as referred herein, on the adsorbent substrate.

[0066] Accordingly, the present invention also relates to the use of an alkali hydroxide solution for the regeneration of an apheresis column, wherein the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, the regeneration is performed during an apheresis treatment in which CRP is removed extracorporeally from blood or plasma, the apheresis column is detached from the extracorporeal circulation system during regeneration, and the apheresis column contains DNA and / or RNA deposits, i.e., on the adsorbent, or as otherwise referred herein, on the adsorbent substrate.

[0067] "Free DNA" or "free RNA" refers to deoxyribonucleic acid or ribonucleic acid, respectively, located outside the cell, as used herein. DNA / RNA bound to a ligand on an apheresis column is also located outside the cell and is therefore referred to as free DNA / free RNA.

[0068] It was surprising to find that the use of an alkali hydroxide solution to regenerate an apheresis column, preferably an apheresis column that performs affinity chromatographic removal of CRP, and to restore the apheresis column to a state usable for treatment, also enables the simultaneous elution of bound CRP. Therefore, it is preferable to regenerate the apheresis column using an alkali hydroxide solution and restore the apheresis column to a state usable for treatment by eluting the bound CRP. Particularly preferable is the use of an alkali hydroxide solution to regenerate the apheresis column, where the apheresis column performs affinity chromatographic removal of CRP, and the CRP bound to the apheresis column is eluted by the alkali hydroxide solution. Therefore, particularly preferable is the use of an alkali hydroxide solution to regenerate the apheresis column, where the apheresis column performs affinity chromatographic removal of CRP, and the bound CRP is eluted while simultaneously restoring the apheresis column to a state usable for treatment.

[0069] The use of an alkali hydroxide solution for regenerating an apheresis column, preferably one used for affinity chromatographic removal of CRP, and the expectation that the elution of bound CRP will occur simultaneously, effectively eliminates the need for further regeneration solutions other than the alkali hydroxide solution according to the present invention. Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column eliminates the need for additional regeneration using glycine / HCl or EDTA to elute bound CRP from the CRP apheresis column.

[0070] In preferred embodiments, there is no additional regeneration solution used for regeneration in addition to the alkali hydroxide solution used for regenerating the apheresis column. In preferred embodiments, there is no additional elution buffer used for eluting CRP in addition to the alkali hydroxide solution used for regenerating the apheresis column. Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column, preferably an apheresis column for affinity chromatographic removal of CRP, is particularly effective because it does not require an increase in the number of rinsing steps in apheresis column regeneration and does not extend the total regeneration time.

[0071] Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and no other regeneration solutions are used. Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and glycine / HCl is not used for elution or regeneration. Therefore, preferably, an alkali hydroxide solution is used for regenerating an apheresis column, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and no elution buffer or other regeneration solutions are used to elute bound CRP before using the alkali hydroxide solution. However, this specification does not preclude the use of rinsing solutions or neutralizing solutions, such as NaCl solution or PBS solution, before or after use.

[0072] Apheresis column regeneration can be performed during apheresis treatment. In such cases, plasma loss can be minimized by removing plasma from a portion of the apheresis apparatus, particularly the apheresis column, before introducing an alkali hydroxide solution, preferably a sodium hydroxide solution, for the purpose of making a rinse solution available. The alkali hydroxide solution, preferably a sodium hydroxide solution, may be further removed from the apheresis column with a neutralizing solution in preparation for apheresis treatment.

[0073] Therefore, the use of alkali hydroxide solution for regenerating apheresis columns is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, in which a rinsing solution is introduced before the introduction of the alkali hydroxide solution, a rinsing solution is introduced after the introduction of the alkali hydroxide solution, or a rinsing solution is introduced after the introduction of the neutralizing solution.

[0074] Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and a wash solution is introduced into the apheresis column before introducing the alkali hydroxide solution. The wash solution is preferably a sodium chloride solution, particularly physiological sodium chloride solution or PBS solution (phosphate-buffered saline). Preferably, NaCl solution, and especially preferably physiological NaCl solution, is used as the wash solution.

[0075] Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column is preferable. The apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and a wash solution is introduced after the introduction of the alkali hydroxide solution. The wash solution is preferably a sodium chloride solution, particularly physiological sodium chloride solution or PBS solution (phosphate-buffered saline). Preferably, an NaCl solution, and especially preferably a physiological NaCl solution, is used as the wash solution.

[0076] Therefore, the use of an alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and after the introduction of the alkali hydroxide solution, a neutralizing solution and then a wash solution are introduced. The wash solution is preferably a sodium chloride solution, particularly physiological sodium chloride solution or PBS solution (phosphate-buffered saline). The wash solution is preferably a NaCl solution, particularly physiological NaCl solution. Preferably, the neutralizing solution is selected from the group comprising PBS solution, NaCl solution, or citrate solution, or from the group consisting of these. Particularly preferably, the neutralizing solution is a citrate solution.

[0077] Particularly preferably, the rinsing solution is not an elution buffer for removing bound CRP. Particularly preferably, the rinsing solution is also not a regeneration solution. In other words, it is particularly preferable that the rinsing solution is not a glycine / HCl buffer. It is even more preferable that no regeneration solution other than an alkali hydroxide solution is used for regenerating the apheresis column. Therefore, it is preferable not to introduce any further regeneration solutions before introducing the rinsing solution, after introducing the alkali hydroxide solution, or after introducing any subsequent rinsing solutions, or after introducing a neutralizing solution and a rinsing solution.

[0078] Therapeutic apheresis is performed in a cycle of alternating injection into the apheresis column and regeneration of the apheresis column. It is preferable to use an alkali hydroxide solution as the regeneration solution in each regeneration cycle. Furthermore, it is even preferable to use the alkali hydroxide solution as the sole regeneration solution.

[0079] Therefore, repeated use of alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP. Therefore, the use of alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the apheresis column is regenerated by repeatedly using alkali hydroxide solution. Therefore, the use of alkali hydroxide solution for regenerating an apheresis column is preferable, and the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the apheresis column is regenerated by using alkali hydroxide solution in each regeneration cycle.

[0080] The effectiveness of using an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, preferably one performing affinity chromatographic removal of CRP, is based on the fact that the alkali hydroxide solution can be effectively used to simultaneously elute bound CRP and remove further substances, thus eliminating the need to increase the number of rinsing steps in apheresis column regeneration compared to the conventional technique using glycine / HCl buffer. Another effect is that the use of an alkali hydroxide solution for apheresis column regeneration prevents acidic protein folding from occurring, thus avoiding the problems that have been shown to occur when using glycine / HCl buffer for apheresis column regeneration. For this reason, the use of an alkali hydroxide solution for apheresis column regeneration significantly improves the reusability of the apheresis column. CRP adsorbents have been shown to be regenerative for 200 cycles using a sodium hydroxide solution with no performance degradation whatsoever.

[0081] Therefore, the use of an alkali hydroxide solution for regenerating the apheresis column is preferable, the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the apheresis column can be reused at least 50 times, preferably at least 100 times, more preferably at least 150 times, and most preferably at least 200 times. [Regeneration solution] Glycine-HCl solutions used as regeneration solutions are known in the prior art. Glycine / HCl solutions have a pH in the range of 2-3, for example, pH=2.8. The concentration of the glycine-HCl solution can be in the range of 0.1M-1M. To prepare a glycine-HCl solution, or glycine-hydrochloride buffer as used synonymously, 15.01 g of glycine is dissolved in 1 liter of water, and 25% hydrochloric acid is added. The pH can be adjusted using hydrochloric acid or sodium hydroxide. The preparation of glycine-HCl solutions is known to those skilled in the art.

[0082] In this specification, "sodium hydroxide solution" means a solution comprising sodium hydroxide in a solvent such as water or an alcohol such as methanol, ethanol, or propanol, or in a mixed solvent of water and at least one alcohol. Preferably, it is a solution comprising or consisting of sodium hydroxide in water. Therefore, an aqueous sodium hydroxide solution (NaOH) aq (Also known as) is preferable.

[0083] Sodium hydroxide is available in various purity levels, preferably 98%, more preferably 99%, even more preferably 99.5%, even more preferably 99.9%, and most preferably 99.99%. A purity range of 98% to 100% is preferred.

[0084] In principle, sodium hydroxide in a sodium hydroxide solution can exist at all available concentrations (based on sodium hydroxide in the solvent or mixed solvent). Typically, the solution is an aqueous solution of sodium hydroxide. However, the concentration of sodium hydroxide in a sodium hydroxide solution is preferably in the range of 0.005 mol / l to 1.0 mol / l, more preferably between 0.01 mol / l and 1.0 mol / l, more preferably between 0.02 mol / l and 0.80 mol / l, more preferably between 0.03 mol / l and 0.60 mol / l, more preferably between 0.04 mol / l and 0.50 mol / l, more preferably between 0.05 mol / l and 0.40 mol / l, more preferably between 0.06 mol / l and 0.30 mol / l, more preferably between 0.07 mol / l and 0.20 mol / l, and more preferably between 0.08 mol / l and 0.10 mol / l.

[0085] A preferred embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the concentration of the alkali hydroxide, preferably sodium hydroxide, in the solution is in the range of 0.01 to 1.0 mol / l.

[0086] Another preferred embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the concentration of the alkali hydroxide, preferably sodium hydroxide, in the solution is in the range of 0.05 to 0.20 mol / l, preferably 0.05 to 0.10 mol / l, and more preferably 0.07 to 0.10 mol / l.

[0087] The basic pH of the alkali hydroxide solution, preferably sodium hydroxide solution, is not limited. Preferably, the alkali hydroxide solution, preferably sodium hydroxide solution, has a pH in the range of 7 to 14, more preferably 7.5 to 14, more preferably 8.0 to 14.0, more preferably 8.5 to 14, more preferably 9.0 to 14.0, more preferably 9.5 to 14.0, more preferably 10.5 to 14.0, more preferably 11 to 14.0, more preferably 11.5 to 14.0, more preferably 12 to 14.0, more preferably 12.5 to 14.0, and even more preferably 13 to 14. Particularly preferably, the sodium hydroxide solution has a pH of 12 to 13.7.

[0088] Therefore, one embodiment of the present invention is the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, wherein the alkali hydroxide solution, preferably a sodium hydroxide solution, has a pH in the range of 12 to 14.

[0089] Equally suitable is the use of an alkali hydroxide solution for regenerating an apheresis column, where the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and the alkali hydroxide solution, preferably a sodium hydroxide solution, has a pH in the range of 12 to 14, more preferably 12 to 13.7.

[0090] As used herein, the terms “alkali hydroxide solution” or “alkali metal hydroxide solution” mean “lithium hydroxide solution,” “sodium hydroxide solution,” “potassium hydroxide solution,” or a mixture of two or three of the aforementioned.

[0091] In this specification, "lithium hydroxide solution" means a solution comprising lithium hydroxide in a solvent such as water or an alcohol such as methanol, ethanol, or propanol, or in a mixed solvent of water and at least one alcohol. Preferably, it is a solution comprising or consisting of lithium hydroxide in water.

[0092] In this specification, "potassium hydroxide solution" means a solution containing potassium hydroxide in a solvent such as water or an alcohol such as methanol, ethanol, or propanol, or in a mixed solvent of water and at least one alcohol. Preferably, it is a solution containing potassium hydroxide or consisting of potassium hydroxide in water.

[0093] In principle, lithium hydroxide in a lithium hydroxide solution, or potassium hydroxide in a potassium hydroxide solution, can exist at all available concentrations (based on lithium hydroxide in the solvent or mixed solvent, or potassium hydroxide in the solvent or mixed solvent). However, the concentration of lithium hydroxide in the lithium hydroxide solution, or the concentration of potassium hydroxide in the potassium hydroxide solution, is preferably in the range of 0.005 mol / l to 1.0 mol / l, more preferably between 0.01 mol / l and 1.0 mol / l, even more preferably between 0.02 mol / l and 0.80 mol / l, even more preferably between 0.03 mol / l and 0.60 mol / l, even more preferably between 0.04 mol / l and 0.50 mol / l, even more preferably between 0.05 mol / l and 0.40 mol / l, even more preferably between 0.06 mol / l and 0.30 mol / l, even more preferably between 0.07 mol / l and 0.20 mol / l, and even more preferably between 0.08 mol / l and 0.10 mol / l.

[0094] When two of the three alkali hydroxide solutions mentioned above are used, the cumulative concentration of these two alkali hydroxide solutions must be in the range of 0.005 mol / l to 1.0 mol / l, more preferably between 0.01 mol / l and 1.0 mol / l, more preferably between 0.02 mol / l and 0.80 mol / l, more preferably between 0.03 mol / l and 0.60 mol / l, more preferably between 0.04 mol / l and 0.50 mol / l, more preferably between 0.05 mol / l and 0.40 mol / l, more preferably between 0.06 mol / l and 0.30 mol / l, more preferably between 0.07 mol / l and 0.20 mol / l, and more preferably between 0.08 mol / l and 0.10 mol / l. This means, for example, that if the concentration of potassium hydroxide in this solution is, for example, 0.06 mol / l, and the concentration of sodium hydroxide in the same solution is, for example, 0.08 mol / l, then the cumulative concentration of alkali hydroxides in this solution is 0.14 mol / l. The same is true when all three of the aforementioned alkali hydroxides are used in a single solution. For example, if lithium hydroxide is 0.04 mol / l, potassium hydroxide is 0.02 mol / l, and sodium hydroxide is 0.05 mol / l, then the cumulative concentration of alkali hydroxides in this solution is 0.11 mol / l.

[0095] Therefore, one embodiment of the present invention relates to using an alkali hydroxide solution selected from the group comprising a sodium hydroxide solution, a lithium hydroxide solution, and / or a potassium hydroxide solution, or a group consisting of these, for the regeneration of an apheresis column.

[0096] However, the use of a sodium hydroxide solution for regenerating apheresis columns is particularly preferable.

[0097] Furthermore, alkali hydroxide solution can regenerate adsorbents that already have protein deposits formed on them that cannot be removed by conventional regeneration methods.

[0098] Therefore, the use of alkali hydroxide solution for regenerating apheresis columns is preferable, as the apheresis column is an apheresis column that performs affinity chromatographic removal of CRP, and regeneration is performed when protein deposits cannot be removed by conventional regeneration methods. [Apheresis Column] How apheresis columns (or cartridges) can be designed or configured is, in principle, part of advanced technology and can be derived from European Patent No. 0237659(B1). Here, the exact dimensions of the column or cartridge used according to the present invention (as an apparatus for selective removal of a target compound, particularly CRP) depend to a considerable extent on the intended use of the apparatus according to the present invention. The apheresis column typically comprises a housing in the form of a cartridge, for example, which is fluidly connected to an extracorporeal circulation system via at least one inlet and at least one outlet, and contains a substrate for affinity chromatographic or adsorption removal of a target compound, particularly CRP.

[0099] In this specification, “target compound” refers to a substance to be removed from blood by apheresis, that is, a substance that is supposed to bind to a substrate during apheresis. Particularly preferably, the target compound to be removed from blood or plasma by apheresis is CRP in this specification.

[0100] The substrate used for affinity chromatography (or adsorption) removal of a target compound, particularly CRP, is composed of a substrate material (column material) to which a compound (ligand) having the property of specifically binding to the target compound, particularly CRP, is bound. According to a preferred embodiment of the present invention, the substrate is integrated or immobilized on the apheresis column used for affinity chromatography removal of the target compound, particularly CRP, in such a way that it cannot be flowed out of the column using the plasma flow. In some embodiments, this can be achieved, for example, by a filter system at the inlet and outlet of the apparatus.

[0101] The present invention is particularly used for the regeneration of apheresis columns for affinity chromatography removal of CRP.

[0102] In principle, suitable substrate materials (column materials) for preparing the substrate are all inert chromatography or column materials that do not react with blood or plasma to such an extent that the blood or plasma can no longer be returned to the patient after contact with the substrate, nor do they alter or contaminate the blood or plasma. Therefore, suitable substrate materials according to the present invention include, but are not limited to, the following: Eupergite®, polyvinylpyrrolidone, methacrylate, methacrylic acid resin, agarose, cross-linked agarose such as Sepharose® (Separation-Pharmacia-Agarose), acrylic beads, cellulose substrates, ceramic substrates, glass beads and / or solid-phase silica, or mixtures and / or derivatives of these materials. Preferably, the substrate material is selected from the group consisting of agarose and Sepharose, or the group consisting of these. Particularly preferably, the substrate material is agarose. The solid-phase silica substrate can be composed of almost any form of fine silica particles, including, for example, colloidal silica, silica gel, precipitated silica, and amorphous silica such as fumed silica or exothermic silica, microcrystalline silica such as diatomaceous earth, and crystalline silica such as quartz.

[0103] While the flow rate during blood purification is limited by the patient's blood flow, it is theoretically possible to increase the flow rate during regeneration to accelerate the process and make the apheresis column available for further use. However, increasing the flow rate also increases the pressure applied during apheresis, and therefore the pressure on the substrate or column material. Depending on the column material, exceeding a certain pressure can alter the material's shape and strength, reducing its separation performance. Therefore, the flow rate used for apheresis column regeneration depends on the pressure resistance of the column material being used.

[0104] This specification has shown that the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, not only makes high pressure available, but also enables the use of high pressures that allow for flow rates that enable the purification of apheresis columns in just a few minutes or even seconds. In particular, the combination of an alkali hydroxide solution, preferably a sodium hydroxide solution, with agarose and its derivatives is suitable for rapid regeneration. Therefore, embodiments of this patented invention relate to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the apheresis column contains agarose and its derivatives. Crosslinked agarose such as agarose or Sepharose® is particularly preferred. The acceleration of regeneration time can certainly be significantly reduced in patient treatment time, and thus in terms of the time of discomfort for the patient. [Substrate material] According to the present invention, the compounds (ligands) that bind to target compounds, particularly substrate materials having the property of specifically binding to CRP, are composed of the following substances, or are selected from the group consisting of the following substances. The following substances are lipids, lysophospholipids, lysophosphatidylcholine, peptides, peptides containing charged amino acids, peptides containing ArgProArg sequences, phosphocholine, phosphocholine derivatives, DNA, DNA derivatives, RNA, RNA derivatives, L-ribonucleic acid aptamers such as Spiegelmere® (RNA-like molecules composed of L-ribose units), glycosides, saccharides, and aptamers.

[0105] In some embodiments, the bound compound is preferably neither a glycoside nor a saccharide. According to the present invention, the bound compound is not a protein. Therefore, the compound (ligand) that binds to the target compound, in particular a substrate material having the property of specifically binding to CRP, is preferably composed of the following substances or selected from the group consisting of the following substances. The following substances are lipids, lysophospholipids, lysophosphatidylcholine, peptides, peptides containing charged amino acids, peptides containing ArgProArg sequences, phosphocholine, phosphocholine derivatives, DNA, DNA derivatives, RNA, RNA derivatives, L-ribonucleic acid aptamers such as Spiegelmere® (RNA-like molecules composed of L-ribose units), and aptamers.

[0106] In the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column according to the present invention, the apheresis column, preferably a CRP apheresis column, is described herein.

[0107] Accordingly, one embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the apheresis column is a CRP apheresis column. Furthermore, a further embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column performing affinity chromatographic removal of CRP.

[0108] Furthermore, a further embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, where the apheresis column is a CRP apheresis column and the regeneration is performed during the removal of CRP from blood.

[0109] Furthermore, a further embodiment of the present invention relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column performing affinity chromatographic removal of CRP, where the regeneration is performed during the removal of CRP from blood. [Ca against CRP] 2+ [Dependent ligand] To perform affinity chromatography removal of CRP from body fluids, such as blood or plasma, column materials containing phosphocholine and / or phosphoethanolamine, or their derivatives, may be used, and the Ca of CRP to the functionalized column material may be used. 2+ It enables dependency coupling.

[0110] For this purpose, phosphocholine, phosphoethanolamine, or their derivatives are immobilized on the column material. This is usually done via an organic linker group, which adsorbs, and more preferably covalently, binds, the phosphocholine, phosphoethanolamine, or their derivatives to the column material. The result is a so-called "functionalized column material" (functionalized substrate material), and the Ca of CRP 2+ Because the chemical group involved in dependent binding is exposed to the outside, CRP in body fluids can also reach this chemical group.

[0111] In other words, as used herein, the term “functionalized column material” refers to a column material for affinity chromatography that is equipped with chemically functionalized groups (ligands). In this case, the chemically functionalized groups may be bound to the column material by adsorption interactions or ionic interactions, but preferably by covalent bonds. It is naturally important that the functionality of the chemically functionalized groups (ligands) is maintained as a result of being bound to the column material in such a way that the functionalized groups are active and exposed. This allows the groups attached to the column material (here, ω-phosphonooxyalkylammonium groups and / or ω-ammonium alkoxy-hydroxy-phosphoryloxy groups) to interact with or bind to the target compound (here, CRP) from the sample (here, a bodily fluid such as blood or plasma).

[0112] When phosphocholine, phosphoethanolamine, or their derivatives bind to the column material, column materials functionalized with ω-phosphonooxyalkylammonium groups (bonding via ammonium groups) and column materials functionalized with ω-ammonium alkoxy-hydroxy-phosphoryloxy groups (bonding via phosphate groups) are distinguished depending on whether the binding occurs via an ammonium group or via a phosphate group through an organic linker.

[0113] Therefore, a preferred embodiment of the present invention is the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, wherein the apheresis column comprises a substrate material functionalized with at least one ω-phosphonooxyalkylammonium group and / or at least one ω-ammonium alkoxy-hydroxy-phosphoryloxy group.

[0114] The bonding with the column material (via an organic linker if necessary) is indicated by dotted lines on the nitrogen atom of the ammonium group or the oxygen atom of the phosphate group in formulas (I) and (II) below.

[0115] As used herein, the term "ω-phosphonooxyalkylammonium group" can be used synonymously with "omega-phosphonooxyalkylammonium" and describes a compound of the following general formula (I).

[0116]

Chem.

[0117]

Chem.

[0118] Thus, one embodiment of the present invention is directed to the use of an alkaline hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, and the apheresis column comprises a substrate material functionalized with at least one ω-phosphonooxyalkylammonium group represented by the following general formula (I).

[0119]

Chem.

[0120] [ka] Here, one or more hydrogen atoms can be substituted with fluorine atoms.

[0121] Preferably, at least one ω-phosphonooxyalkylammonium group corresponds to the group of the following general formula (I).

[0122] [ka] Here, n is either 2 or 3, R 1 and R 2 These are selected independently from -H, -CH3, -C2H5, and -C3H7. Or, R 1 and R 2 These, along with the nitrogen atoms to which they are bonded, can form heterocycles selected from the following structural formulas.

[0123] [ka] Particularly preferably, at least one ω-phosphonooxyalkylammonium group corresponds to the group of the following general formula (I).

[0124] [ka] Here, n is 2, R 1 and R 2 is selected from -H, -CH3, and -C2H5, particularly preferably from -CH3 and -C2H5. Or R 1 and R 2 These, along with the nitrogen atoms to which they are bonded, can form heterocycles selected from the following structural formulas.

[0125] [ka] Suitable compounds that contain the aforementioned ω-phosphonooxyalkylammonium group and are suitable for functionalizing the corresponding column material (substrate material) are, for example, the following compounds.

[0126] 2-[2-(2-aminoethoxy)ethyl-diethyl-ammonio]ethyl hydrogen phosphate, 2-[4-[2-(2-aminoethoxy)ethyl]morpholine-4-ium-4-yl]ethyl hydrogen phosphate, 2-[1-[2-(2-aminoethoxy)ethyl]piperidine-1-ium-1-yl]ethyl hydrogen phosphate, 2-[2-(2-aminoethoxy)ethyl-dimethyl-ammonio]ethyl hydrogen phosphate, 2-[3-aminopropyl-(dimethyl)ammonio]ethyl hydrogen phosphate, 2-[dimethyl(4-sulfanylbutyl)ammonio]ethyl hydrogen phosphate, 2-[4-azidobutyl(dimethyl)ammonium]ethyl hydrogen phosphate, 2-[dimethyl(penta-4-inyl)ammonium]ethyl hydrogen phosphate, 2-[3-(6-aminohexanoyl-amino)propyl-diethyl-ammonium]ethyl hydrogen phosphate, 2-[1-[2-[2-(6-aminohexanoyl-amino)ethoxy]ethyl]piperidine-1-ium-1-yl]ethyl hydrogen phosphate, 2-[4-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]ethyl]morpholine-4-ium-4-yl]ethyl hydrogen phosphate, 2 -[1-[2-[2-[6-(6-aminohexanoylamino)hexanoylamino]ethoxy]ethyl]pyrrolidine-1-ium-1-yl]hydrogen hydrogen phosphate, 2-[2-allyloxyethyl (dimethyl) ammonia]ethyl hydrogen phosphate, 2-[2-allyloxyethyl (diethyl) ammonia]ethyl hydrogen phosphate, 2-[4-(2-allyloxyethyl)morpholine-4-ium-4-yl]ethyl hydrogen phosphate, 2-[1-(2-allyloxyethyl)piperidine-1-ium-1-yl]ethyl hydrogen phosphate, 2-[2-[2-(6-aminohex Xanoylamino)ethoxy]ethyldimethyl-ammonio]hydrogen phosphate, 2-[2-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]-ethyl-dimethyl-ammonio]hydrogen phosphate, 2-[3-azidopropyl(dimethyl)ammonio]hydrogen phosphate, 2-[dimethyl-[2-[2-(prop-2-inoxycarbonylamino)ethoxy]ethyl]ammonio]hydrogen phosphate, 2-[2-[2-(allyloxycarbonylamino)ethoxy]ethyldimethyl-ammonio]hydrogen phosphate,2-[2-[2-[6-(allyloxycarbonylamino)hexanoylamino]ethoxy]ethyldimethyl-ammonio]hydrogen phosphate, 2-[2-(6-aminohexanoylamino)ethyl-dimethyl-ammonio]hydrogen phosphate, 2-[dimethyl-[3-[6-(prop-2-inoxycarbonylamino)hexanoylamino]propyl]ammonio]hydrogen phosphate, and 2-[3-(6-aminohexanoylamino)propyl-dimethyl-ammonio]hydrogen phosphate.

[0127] The term "ω-ammonium alkoxy-hydroxy-phosphoryloxy group" as used herein can be used interchangeably with "omega-ammonium alkoxy-hydroxy-phosphoryloxy group" and describes compounds of the following general formula (II).

[0128] [ka] Here, n is selected from 2 and 3. R 1 , R 2 and R 3 These are -H, -CH3, -C2H5, -C3H7, -C4H9, and -C5H, which are independent of each other. 11 -C6H 13 Selected from R. 1 and R 2 These, along with the nitrogen atoms to which they are bonded, can form heterocycles selected from the following structural formulas.

[0129] [ka] And, R 3 -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 -C6H 13 Selected from, preferably -H, where one or more hydrogen atoms can be substituted with fluorine atoms.

[0130] A suitable "ω-ammonium alkoxy-hydroxy-phosphoryloxy group" is composed of a compound of the following general formula (II).

[0131] [ka] Here, n is selected from 2 and 3. R 1 , R 2 and R 3 These are selected independently from -H, -CH3, -C2H5, and -C3H7. Or, R 1 and R 2 These, along with the nitrogen atoms to which they are bonded, can form heterocycles selected from the following structural formulas.

[0132] [ka] And, R 3 It is -H.

[0133] Within the scope of the present invention, the ω-ammonium alkoxy-hydroxy-phosphoryloxy group is particularly preferred when it is an ω-trialkylammonium alkoxy-hydroxy-phosphoryloxy group.

[0134] Therefore, the ω-ammonium alkoxy-hydroxy-phosphoryloxy group, which is particularly preferred, is composed of a compound of general formula (II).

[0135] [ka] Here, n is 2, R 1 , R 2 and R 3 The ion is selected from -H, -CH3, and -C2H5, with -CH3 and -C2H5 being particularly preferred.

[0136] Furthermore, the ω-ammonium alkoxy-hydroxy-phosphoryloxy group is particularly preferred when it is an ω-trimethylammonium ethoxy-hydroxy-phosphoryloxy group or an ω-trimethylammonium propoxy-hydroxy-phosphoryloxy group.

[0137] Suitable compounds that contain the aforementioned ω-ammonium alkoxy-hydroxy-phosphoryloxy group and are suitable for functionalizing the corresponding column material include, for example, p-aminophenylphosphocholine (APPC), 4-[[hydroxy[2-(trimethylammonio)ethoxy]phosphinyl]oxy]benzenediazonium (p-diazoniumphenylphosphocholine), or p-nitrophenyl-6-(O-phosphocholine)hydroxyhexanoate.

[0138] Therefore, a preferred embodiment relates to the use of an alkali hydroxide solution, preferably a sodium hydroxide solution, for the regeneration of an apheresis column, wherein the apheresis column comprises a substrate material functionalized with at least one ω-ammonium alkoxy-hydroxy-phosphoryloxy group corresponding to the group of the following general formula (II).

[0139] [ka] Here, n is selected from 2 and 3. R 1 , R 2 and R 3 These are -H, -CH3, -C2H5, -C3H7, -C4H9, and -C5H, which are independent of each other. 11 -C6H 13 Selected from R. 1 and R 2 These, along with the nitrogen atoms to which they are bonded, can form heterocycles selected from the following structural formulas.

[0140] [ka] And, R3 -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 -C6H 13 Selected from, preferably -H, where one or more hydrogen atoms can be substituted with fluorine atoms.

[0141] A further aspect of the present invention relates to a method for regenerating an apheresis column for affinity chromatographic removal of CRP, comprising the following steps. (I) An alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the apheresis column to regenerate the apheresis column.

[0142] The alkali hydroxide solution, preferably a sodium hydroxide solution, may be removed from the apheresis column with a neutralizing solution for preparation of the apheresis column for apheresis treatment. Thus, the method according to the present invention may comprise step (II). (II) Introduce the neutralizing solution.

[0143] Therefore, one embodiment of the present invention relates to a method for regenerating an apheresis column for affinity chromatographic removal of CRP, comprising the following steps. (I) An alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the apheresis column to regenerate the apheresis column. (II) Introduce the neutralizing solution.

[0144] Therefore, one embodiment of the present invention relates to a method for regenerating an apheresis column for affinity chromatographic removal of CRP, comprising the following steps. (I) An alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the apheresis column to regenerate the apheresis column. (II') After step (I), discontinue the introduction of an alkali hydroxide solution, preferably a sodium hydroxide solution. (II) Introduce the neutralizing solution.

[0145] Apheresis column regeneration can be performed during apheresis treatment. In such cases, plasma loss can be minimized by removing plasma from a part of the apheresis apparatus, particularly the apheresis column, before introducing an alkali hydroxide solution, preferably a sodium hydroxide solution, for the purpose of making a rinse solution available. Thus, the method according to the present invention may include step (I'). (I') Preferably, wash the apheresis column containing plasma.

[0146] Therefore, one embodiment of the present invention relates to a method for regenerating an apheresis column for affinity chromatographic removal of CRP, and comprises the following steps. (I') Preferably, a wash solution is introduced into an apheresis column containing plasma. (I) An alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the apheresis column to regenerate the apheresis column. (II') After step (I), discontinue the introduction of an alkali hydroxide solution, preferably a sodium hydroxide solution. (II) Introduce the neutralizing solution. [Rinse-off solution] The rinsing solution can, but does not have to, regenerate the apheresis column. In addition to the functions described above, it also plays a role in removing plasma from the apheresis column or in neutralizing the substrate of the apheresis column. Sodium chloride solution, particularly physiological sodium chloride solution or PBS solution (phosphate-buffered saline) can be used as the rinsing solution. Preferably, NaCl solution, and especially preferably physiological NaCl solution, is used as the rinsing solution.

[0147] As used herein, the term “NaCl solution” (sodium chloride solution) refers to an aqueous solution containing sodium chloride (i.e., NaCl, also known as table salt) as its main component. As used herein, the term “main component” means that the molar concentration of sodium chloride in the NaCl solution is higher than the molar concentration of each of the other compounds in the NaCl solution, excluding water. Preferably, the NaCl solution contains 0.1–5 wt%, particularly preferably 0.9 wt%, of sodium chloride. Preferably, the rinse solution is such a NaCl solution. Physiological NaCl solution (PBS solution) is recognized as a sodium chloride solution containing water and 0.9 wt% sodium chloride (NaCl). [Neutralizing solution] As used herein, the term "neutralizing solution" refers to an aqueous solution that adjusts the pH to a range of 6.5 to 7.6, preferably 7.30 to 7.50, and more preferably 7.35 to 7.45.

[0148] In principle, all aqueous solutions permitted for use in the medical field can be considered neutralizing solutions. Preferably, the aqueous solution has a pH of 7 or less, that is, the aqueous solution is neutral pH or may have a pH less than 7. Preferred neutralizing solutions are selected from the group comprising PBS solution, NaCl solution, or citrate solution, or from the group comprising these. Particularly preferred is the citrate solution as the neutralizing solution. Thus, another aspect of the present invention relates to the use of a citrate solution for neutralizing an apheresis column equipped with column material, where the column material is in a basic medium. Therefore, the method according to the present invention may comprise step (II). (II) A neutralizing solution is introduced, which is PBS, NaCl, or a citrate solution, preferably a citrate solution.

[0149] Furthermore, one embodiment of the present invention relates to a method for regenerating an apheresis column for affinity chromatographic removal of CRP, and comprises the following steps. (I) An alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the apheresis column to regenerate the apheresis column. (II') After step (I), discontinue the introduction of an alkali hydroxide solution, preferably a sodium hydroxide solution. (II) Introduce PBS solution, NaCl solution, or citrate solution.

[0150] As used herein, the term "citrate solution" refers to an aqueous solution containing at least one citrate compound.

[0151] As used herein, the term “citrate” refers to the citrate anion, which is a salt of citric acid. Preferably, the citrate solution contains at least one citrate compound selected from the group comprising or consisting of citric acid, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassium hydrogen citrate, tricalcium citrate, lithium dihydrogen citrate, dilithium hydrogen citrate, trilithium citrate, ammonium dihydrogen citrate, diammonium hydrogen citrate, triammonium citrate, tricalcium citrate (calcium citrate), trimagnesium citrate (magnesium citrate), and / or partial esters of citrate.

[0152] A citrate solution comprising citric acid, trisodium citrate, D-glucose, and water is also called "acid-citric acid-dextrose solution (ACD solution)." A preferred modification of the citrate solution used in accordance with the present invention relates to an ACD solution containing 22.9 mM to 38.0 mM citric acid, 44.9 mM to 74.8 mM trisodium citrate, 74.2 mM to 123.6 mM D-glucose, and water. A particularly preferred modification of the citrate solution used in accordance with the present invention relates to an ACD solution containing 38 mM citric acid, 74.8 mM trisodium citrate, 123.6 mM D-glucose, and water. This citrate solution is also called "ACD-A solution."

[0153] A citrate solution consisting of citric acid, trisodium citrate, sodium hydrogen phosphate, D-glucose, and water is also called "citric acid-phosphate-dextrose solution (CPD)." A citrate solution consisting of citric acid, trisodium citrate, sodium hydrogen phosphate, D-glucose, adenine, and water is also called "citric acid-phosphate-dextrose solution containing adenine (CPDA)."

[0154] Preferably, the citrate solution has a concentration of 2-40%, preferably 4%, and a pH in the range of 6.4-7.5. It is suitable for use at a flow rate of 80 ml / min. The effect of using a citrate solution with a PBS solution is to shorten the neutralization time and reduce the required rinse volume. [Device] A further aspect of the present invention relates to an apheresis device (1) for removing CRP from a patient's blood, wherein the apheresis device (1) is configured to be resistant to alkali hydroxide solutions, such as sodium hydroxide solution. Of the components of the apheresis device, only those components that come into contact with alkali hydroxide solutions, that is, components through which alkali hydroxide solutions are stored or flow, need to be resistant to the alkali hydroxide solutions used. For example, the blood component separator and bypass line do not come into contact with alkali hydroxide solutions, so they do not necessarily need to be resistant to the alkali hydroxide solutions used.

[0155] As used herein, the term "resistant" means that no changes occur in product characteristics, such as biocompatibility or performance.

[0156] Chemical resistance typically refers to a material's resistance to exposure to chemicals. A material is considered chemically resistant if, even after prolonged contact with the chemical being tested, its characteristic properties remain unchanged, or are only very slowly eroded. A material is considered partially chemically resistant if its characteristic properties remain unchanged for a limited period of time acceptable for its intended use, or within certain limits of its operating conditions. Conversely, a material that loses its characteristic properties in a very short time, or sooner than permitted by its intended use, is considered chemically unstable. Therefore, as used herein, "resistant" preferably means that the characteristic properties of a material in an apheresis apparatus component in contact with an alkali hydroxide solution, preferably a sodium hydroxide solution, remain unchanged for at least 20 hours of contact. Typically, the acceptable time for the intended use is between 4 and 8 hours.

[0157] Therefore, parts that come into contact with an alkali hydroxide solution, preferably a sodium hydroxide solution, must be made of a material resistant to alkali hydroxide, preferably sodium hydroxide. Suitable materials include, but are not limited to, stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonate (PC). Stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and polyethylene terephthalate (PET) are preferred. In this specification, materials considered resistant to alkali hydroxide, preferably sodium hydroxide, include, but are not limited to, stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonate (PC). Suitable materials resistant to alkali hydroxide, preferably sodium hydroxide, are selected from stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and polyethylene terephthalate (PET).

[0158] In other words, further embodiments of the present invention relate to an apheresis device (1) for extracorporeal removal of CRP from a patient's blood, the apheresis device being connectable to the patient's blood circulation, and the apheresis device (1) being configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions. That is, the mechanical, physical, and chemical properties of the components of the apheresis device in contact with the alkali hydroxide solution do not change within the operating time of the apheresis device in apheresis treatment.

[0159] For regenerating apheresis columns, an alkali hydroxide solution, preferably a sodium hydroxide solution, can be used. While alkali hydroxide solutions, preferably sodium hydroxide solutions, are known for their reactivity, the reactivity is largely determined by the concentration of alkali hydroxide in the alkali hydroxide solution, preferably the concentration of sodium hydroxide in the sodium hydroxide solution. Furthermore, other compounds in the alkali hydroxide solution, preferably sodium hydroxide solution, affect the reactivity of the alkali hydroxide, preferably sodium hydroxide (or dissociated sodium hydroxide).

[0160] Therefore, alkali hydroxide solutions, preferably sodium hydroxide solutions, can corrode materials. For example, strong bases such as alkali hydroxide solutions, preferably sodium hydroxide, can react with glass and dissolve its components. Similarly, there are organic polymer materials that are not resistant to alkali hydroxide solutions, preferably sodium hydroxide, at temperatures above room temperature.

[0161] Embodiments of the present invention relate to an apheresis device (1) for extracorporeal removal of CRP from a patient's blood, wherein the apheresis device is connectable to the patient's blood circulation. Blood is pumped through a portion of the extracorporeal circulation system (2) of the apheresis device (1) to a blood component separator (7), where the blood is separated into plasma and cellular components. Passing through a first outlet of the blood component separator (7), the separated plasma is led through a plasma line (8A) to an apheresis column (4) for affinity chromatographic removal of CRP from the plasma. After the removal of CRP from the patient's plasma, the plasma immediately after this treatment is bound to the cellular components of the blood through a plasma line (8B). Furthermore, the apheresis device (1) according to the present invention is provided with a bypass line (12) that passes from the plasma line (8A) to the plasma line (8B) and bypasses the apheresis column (4). Furthermore, the apheresis apparatus (1) according to the present invention includes at least one regeneration line (14) that flows into the plasma line (8A) behind the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4). The apheresis apparatus (1) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0162] In other words, components of an apheresis apparatus that come into contact with an alkali hydroxide solution are resistant to the alkali hydroxide solution used.

[0163] One embodiment of the present invention relates to an apheresis device (1) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It comprises at least one apheresis column (4) for affinity chromatographic removal of CRP from blood, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4), a plasma line (8B) for plasma after CRP removal from the apheresis column (4) to point (P1), a cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1). An apheresis device (1) comprising at least one connection line (11) connecting at least one fluid container (F) to an arterial line (5) or a blood component separator (7), The bypass line (12) branches off from the plasma line (8A) and flows into the plasma line (8B). The waste line (13) either branches directly from the apheresis column (4) or branches from the plasma line (8B) before the junction of the bypass line (12) in the direction of flow. At least one regeneration line (14) is connected to the plasma line (8A) at or behind the junction of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4). The apheresis apparatus (1) is characterized by being configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0164] Preferably, the apheresis apparatus (1) further comprises a central processing unit (10) that controls the apheresis apparatus (1).

[0165] One embodiment of the present invention relates to an apheresis device (1) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It comprises at least one apheresis column (4) for affinity chromatographic removal of CRP from blood, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4), a plasma line (8B) for plasma after CRP removal from the apheresis column (4) to point (P1), a cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1). An apheresis device (1) comprising at least one connection line (11) connecting at least one liquid container (F1) to an arterial line (5) or a blood component separator (7), The bypass line (12) branches off from the plasma line (8A) and flows into the plasma line (8B). The waste line (13) either branches directly from the apheresis column (4) or branches from the plasma line (8B) before the junction of the bypass line (12) in the direction of flow. At least one regeneration line (14) branches off from at least one liquid container (F1) or at least one connection line (11) and leads to a plasma line (8A) at or behind the junction of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4). At least one second regeneration line (14) branches off from at least one liquid container (F2), and the second regeneration line (14) is not connected to an arterial line (5) or a blood component separator (7), but is connected to a plasma line (8A) at or behind the junction of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4), The apheresis apparatus (1) is characterized by being configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0166] Preferably, the apheresis apparatus (1) further includes a central processing unit that controls the apheresis apparatus (1).

[0167] Therefore, preferably, the apheresis apparatus (1) includes at least two regeneration lines (14', 14'') that independently lead to the plasma line (8A) at or behind the junction of the bypass line (12) in the direction of flow, or that flow directly into the apheresis column (4'). At least one of the regeneration lines (14', 14'') branches off from at least one liquid container (F1) or at least one connection line (11).

[0168] One embodiment of the present invention relates to an apheresis device (1) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It comprises at least one apheresis column (4) for affinity chromatographic removal of CRP from blood, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4), a plasma line (8B) for plasma after CRP removal from the apheresis column (4) to point (P1), a cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1). An apheresis device (1) comprising at least one connection line (11) connecting at least one liquid container (F1) to an arterial line (5) or a blood component separator (7), The bypass line (12) branches off from the plasma line (8A) and flows into the plasma line (8B). The waste line (13) either branches directly from the apheresis column (4) or branches from the plasma line (8B) before the junction of the bypass line (12) in the direction of flow. At least one regeneration line (14) branches off from at least one liquid container (F1) or at least one connection line (11) and leads to a plasma line (8A) at or behind the junction of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4), and at least one regeneration line (14) has an additional connection to at least one liquid container (F2), and the apheresis apparatus (1) is configured to be resistant to alkali hydroxide solution, preferably sodium hydroxide solution.

[0169] Preferably, the apheresis apparatus (1) further includes a central processing unit that controls the apheresis apparatus (1).

[0170] As already stated above, using the term "resistant" means that only the components of the apheresis apparatus that come into contact with the alkali hydroxide solution must be resistant, or only those components must be resistant to the alkali hydroxide solution in which they are used. The remaining components of the apheresis apparatus may, but do not need to be, resistant to the alkali hydroxide solution in which they are used.

[0171] "Tolerant" means that it does not alter biocompatibility in accordance with the DIN EN ISO10993-1 to DIN EN ISO10993-12 series standards. The ISO 10993-1 to ISO 10993-12 series includes ISO 10993-1 "Evaluation and testing in risk management processes", ISO 10993-2 "Requirements for animal protection", ISO 10993-3 "Genotoxicity, carcinogenicity and reproductive toxicity testing", ISO 10993-4 "Selection of blood interaction testing", ISO 10993-5 "In vitro cytotoxicity testing", ISO 10993-6 "Post-implant local effects testing", ISO 10993-7 "Ethylene oxide sterilization residue", ISO 10993-8 "Selection and qualification of reference materials for biological testing", ISO 10993-9 "Framework for identification and quantification of potential degradation products", ISO 10993-10 "Skin sensitization testing", ISO 10993-11 "Systemic toxicity testing", and ISO 10993-12 "Sample preparation and reference materials". This test can be performed using a test extract. For qualitative analysis of the obtained extract, the standard suggests a combination of gas chromatography (GC) or (high-performance) liquid chromatography (LC or HPLC) with mass spectrometry (MS). For further analysis, identification of extracted compounds by ion pair chromatography (IPC) or identification of extractable metal ions by inductively coupled plasma (ICP) is recommended. Cytotoxicity testing, hematological compatibility testing, and extractable compounds are selected from numerous test methods in accordance with DIN EN ISO 10993. Cytocompatibility testing confirms whether the product has toxic / harmful effects on cells. The test is performed by direct and / or indirect contact, and it is possible to reliably identify toxic substances.In vitro blood compatibility testing identifies undesirable material properties at an early stage, before the product could potentially harm a patient. Testing is performed using human blood in simple static or complex dynamic systems. Biomaterials and medical devices can induce nonspecific xenobiotic reactions in the body. Local tissue reaction testing determines parameters for evaluating the compatibility and value of surrogate materials.

[0172] Therefore, the apheresis apparatus according to the present invention is preferably configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions, as described herein, where resistance to alkali hydroxide solutions, preferably sodium hydroxide solutions, exists as long as it does not alter biocompatibility in accordance with the DIN EN ISO 10993-1 to DIN EN ISO 10993-12 series standards.

[0173] Therefore, the apheresis apparatus according to the present invention is preferably configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions, as described herein. Here, resistance to alkali hydroxide solutions, preferably sodium hydroxide solutions, exists if the parts that come into contact with the alkali hydroxide solution, preferably sodium hydroxide solution, are made of a material resistant to alkali hydroxide, preferably sodium hydroxide. The material resistant to alkali hydroxide, preferably sodium hydroxide, is selected from the group consisting of stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and / or polycarbonate (PC), or from the group consisting of these materials, and is preferably selected from the group consisting of stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and / or polyethylene terephthalate (PET), or from the group consisting of these materials.

[0174] Preferably, the plasma line is made of stainless steel, or a polymer selected from the group consisting of polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonates (PC). Particularly preferably, the plasma line is made of stainless steel, or a polymer selected from the group consisting of polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and polyethylene terephthalate (PET), or a polymer selected from the group consisting of these materials.

[0175] Preferably, the liquid container for the regeneration solution is made of stainless steel, or a polymer selected from the group consisting of polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonates (PC). Particularly preferably, the liquid container for the regeneration solution is made of stainless steel, or a polymer selected from the group consisting of polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and polyethylene terephthalate (PET), or a polymer selected from the group consisting of these.

[0176] More preferably, the housing of the apheresis column is made of stainless steel, or a polymer selected from the group consisting of polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), and polycarbonates (PC). Particularly preferably, the housing of the apheresis column is made of stainless steel, or a polymer selected from the group consisting of stainless steel, polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), and polyethylene terephthalate (PET).

[0177] As described above, the apheresis device (1) for removing CRP from blood according to the present invention can be connected to the patient's blood circulation. From the patient's vascular access point (usually a venous access point), blood is pumped through a portion of the extracorporeal circulation system (2) of the present invention to a blood component separator (7). The portion of the extracorporeal circulation system (2) that leads the blood from the patient to the blood component separator (7) leads the blood away from the patient, that is, away from the patient's heart, and is therefore referred to as the "arterial line" (5) by reference to the nomenclature of blood vessels in the human body.

[0178] The patient's blood is supplied to the blood component separator (7) through its inlet, where it is separated into plasma (sometimes simply referred to as "plasma") and cellular components. It should be noted that the separation of plasma and cellular components is not complete, and preferably only 10-90% of the total plasma volume is separated from the cellular components. Passing through the first outlet of the blood component separator (7), the separated plasma is led via the plasma line (8A) to the apheresis column (4) which performs affinity chromatographic removal of CRP from the blood (or plasma). After the removal or reduction of CRP in the patient's plasma, the plasma immediately after this treatment (also referred to as "removed plasma") is led through the plasma line (8B) to point (P1). Passing through the second outlet of the blood component separator (7) and the connecting line (the so-called cell line (9)), the cellular components of the blood proceed to point (P1) near the apheresis column (4). The cellular components are then mixed with the plasma after removal. After mixing the cellular components with the plasma, the blood immediately after processing is returned to the patient through another part of the extracorporeal circulation system (2) of the present invention. In the extracorporeal circulation system (2), the part that guides the processed blood back to the patient from point (P1) of the extracorporeal circulation system (2) is referred to as the "venous line" (6) by reference to the nomenclature of blood vessels in the human body, as it guides the blood toward the patient, that is, toward the patient's heart.

[0179] In another embodiment of the present invention, the cellular components can be separated from the plasma and then returned directly to the patient via a second outlet of the blood component separator and subsequent lines, so that only the processed plasma is delivered to the patient via the venous line.

[0180] To prevent blood coagulation within the extracorporeal circulation system, or to flush or pre-flush the extracorporeal circulation system (e.g., with saline solution), the apheresis apparatus according to the present invention includes at least one line (so-called connection line (11)) that allows connection of at least one liquid container (F), thereby enabling the supply of the liquid (e.g., anticoagulant or saline solution) contained in this at least one liquid container (F) to the extracorporeal circulation system. Here, it is also noted that the connection line (11) connecting at least one fluid container (F) is in a fluid connection with the extracorporeal circulation system, that is, fluid can be introduced from the fluid container into the extracorporeal circulation system via the connection line (11). In a preferred embodiment of the present invention, at least one connection line (11) flows into the extracorporeal circulation system (2), i.e., into the arterial line (5), before the blood component separator (7), or flows directly into the blood component separator (7).

[0181] It will be apparent to those skilled in the art that the liquid container (or multiple liquid containers) (F) itself does not need to be part of the apheresis apparatus according to the present invention, because these are typically disposable items, such as general infusion bags, that are connected to connection lines by an operator (e.g., a doctor or nurse) according to a specific application.

[0182] According to the present invention, it is possible to have a single connection line (11) for connecting one liquid container. However, it is also conceivable that there be a single connection line (11) to which two or three, preferably more, liquid containers can be connected. Similarly, embodiments of the apheresis apparatus according to the present invention are also possible, having two, preferably three, or preferably several connection lines (11', 11'', 11'''', etc.) each for connecting at least one liquid container, wherein it is preferable that these two, preferably three, or preferably several connection lines can flow into the arterial line (5) or directly into the blood component separator (7) independently of each other. "Independent of each other" here means, for example, in one embodiment of the apheresis apparatus according to the present invention having two connection lines (11', 11''), one connection line (11') can flow into the arterial line (5) and the other connection line (11'') can flow directly into the blood component separator (7), but both connection lines (11', 11'') can also flow into the arterial line (5), and both connection lines (11', 11'') can also flow directly into the blood component separator (7).

[0183] According to one embodiment of the present invention, the apheresis apparatus (1) according to the present invention has two connection lines (11', 11'') each connecting to at least one liquid container, and is particularly suitable when the connection lines (11', 11'') flow independently into the arterial line (5) or directly into the blood component separator (7). As a result, both connection lines (11', 11'') flow into the arterial line (5), or both connection lines (11', 11'') flow directly into the blood component separator (7), or particularly preferably, one connection line (11') flows into the arterial line (5) and the other connection line (11'') flows directly into the blood component separator (7). This makes it possible to connect the two connection lines (11', 11'') to different liquid containers. This configuration is particularly suitable when one of the two connection lines (e.g., 11') is connected to a liquid container containing physiological saline solution (e.g., NaCl solution), and the second of the two connection lines (e.g., 11'') is connected to a liquid container containing citrate solution.

[0184] Therefore, the apheresis apparatus (1) is particularly suitable when it has a connection line (11') for connecting a liquid container (F1) and a connection line (11'') for connecting a liquid container (F2), the connection line (11') flows into an arterial line (5) or a blood component separator (7), and the connection line (11'') flows into an arterial line (5) or a blood component separator (7), or into a connection line (11') and finally into an arterial line (5) or a blood component separator (7).

[0185] An important effect of the apheresis apparatus of the present invention is that, although the apheresis column inherently has a limit to its purification capacity, it can be regenerated during operation, that is, without the need to stop blood collection / supply or the blood component separator. For this purpose, there is a bypass line (12, also called a "shunt") that allows the direction of plasma flow to be changed while bypassing the apheresis column (4). This bypass line (12) makes it possible to temporarily disconnect the apheresis column (4) from the plasma flow, and thus, the apheresis column (4) can be regenerated in the apparatus of the present invention without the need to interrupt the flow of blood or plasma. The bypass line branches off from the plasma line (8A), and the point where the bypass line branches off within the plasma line (8A) is referred to as point (P2), which preferably flows into the plasma line (8B), and the point where the bypass line (12) flows into the plasma line (8B) is referred to as point (P6). In one feasible embodiment, the bypass line (12) flows into the cell line (9) rather than the plasma line (8B), and the point in the cell line (9) where the bypass line (12) flows in is referred to as point (P3).

[0186] The regeneration solution required for the regeneration of the apheresis column is supplied to the extracorporeal circulation system (2) via the regeneration line (14). The regeneration line (14) either flows directly into the apheresis column (4), or flows into the plasma line (8A) before the apheresis column (4) (in the direction of flow) but after the branching point of the bypass line, i.e., after point (P2).

[0187] A waste line (13) branches off from the plasma line (8B) to remove the regeneration solution from this system after it has passed through the apheresis column (4) (it is not sent to the patient), and the point where the waste line (13) branches off within the plasma line (8B) is referred to as point (P4). In embodiments in which the bypass line (12) flows into the cell line (9), point (P4) is preferably located in the region from the apheresis column (4) to point (P1). In embodiments in which the bypass line (12) flows into the plasma line (8B), point (P4) is preferably located in the region from the apheresis column (4) to point (P6). It goes without saying that a collection container, for example, can be connected to the waste line (13). As the regeneration solution according to the present invention, an alkali hydroxide solution, preferably a sodium hydroxide solution, is particularly preferred.

[0188] In addition to the regeneration solution, a rinsing solution can also be used. The rinsing solution can be used to regenerate the apheresis column (4), but it is not essential. Its main role is to remove plasma before using the regeneration solution. Plasma is removed from the plasma line (8A) in the region from point P2 to the apheresis column (4), from the apheresis column (4), and from the plasma line (8B) at point P4. This solution is then discarded through the waste line (13) after passing through the apheresis column (4). Preferably, a physiological NaCl solution or PBS solution is used as the rinsing solution. More preferably, when an alkali hydroxide solution, preferably a sodium hydroxide solution, is used as the regeneration solution, a physiological NaCl solution is used as the rinsing solution.

[0189] Preferably, the apheresis device (1) includes at least one regeneration line (14) that flows into the plasma line (8A) at or behind the branching point of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4). Preferably, the apheresis device (1) includes at least one regeneration line (14) that flows into the extracorporeal circulation system (2) in the region from the branching point of the bypass line (12) in the plasma line (8A) to the apheresis column (4). Preferably, the apheresis device (1) includes at least one regeneration line (14) that flows into the extracorporeal circulation system (2) in the region from point (P2) to the apheresis column (4).

[0190] According to one embodiment of the present invention, the apheresis apparatus (1) according to the present invention preferably has at least two connection lines (11), each connecting at least one liquid container (F) to an arterial line (5) or a blood component separator (7).

[0191] Furthermore, each embodiment of the apheresis apparatus (1) is preferable in which the apheresis apparatus (1) has at least two connection lines (11) that connect at least one liquid container (F) to an arterial line (5) or a blood component separator (7), and for each liquid container (F), there is a regeneration line (14) that branches off from the respective liquid container (F) or its connection line (11) and leads to a plasma line (8A) or directly to an apheresis column (4).

[0192] It is also possible for at least two connection lines (11) to merge before their junction, that is, to be integrated into a single line. It is also possible for the regeneration line (14) to merge before its junction, that is, to be integrated into a single line.

[0193] In this application, when it is stated that a feature of the device is that there is a region from a first position to a second position within the device, into which the regeneration line flows, or branches off from this region, this is understood to mean that both the first and second positions, and the interval between them, are closed off by this region. This is illustrated by the example that the statement "the regeneration line (14) flows into the extracorporeal circulation system (2) within the region from point (P2) to the apheresis column (4)" means that the regeneration line (14) flows into the extracorporeal circulation system (2) within the region that includes not only the interval between point (P2) and the apheresis column (4), but also point (P2) itself and the apheresis column (4) itself. This example means that the regeneration line (14) may flow into point (P2), or into the apheresis column (4), or into the interval between point (P2) and the apheresis column (4).

[0194] Point (P1) is a node within the extracorporeal circulation system (2) where the plasma line (8B) merges with the venous line (6). Point (P2) is a node within the extracorporeal circulation system (2) where the bypass line (12) branches off from the plasma line (8A). Point (P3) is a node within the extracorporeal circulation system (2) where the bypass line (12) flows into the cell line (9). Point (P4) is a node within the extracorporeal circulation system (2) where the waste line (13) branches off from the plasma line (8B). Point (P5) is a node within the extracorporeal circulation system (2) where the regeneration line (15) flows into the connection line (11). Point (P6) is a node within the extracorporeal circulation system (2) where the bypass line (12) flows into the plasma line (8B).

[0195] According to a preferred embodiment of the present invention, the connecting line (11) flows into the arterial line (5). According to a further preferred embodiment of the present invention, the connecting line (11) flows directly into the blood component separator (7).

[0196] As described above, the apheresis apparatus according to the present invention is equipped with at least one line (a so-called regeneration line (14)) that enables the supply of a regeneration solution (e.g., an alkali hydroxide solution, preferably a sodium hydroxide solution), a rinsing solution, or a neutralizing solution within the extracorporeal circulation system, preferably immediately before the apheresis column (4), or directly to the apheresis column (4). It is also noted here that the regeneration line (14), to which at least one liquid container (F) is connected, is fluidly connected to the extracorporeal circulation system, meaning that the liquid from the liquid container can be introduced into the extracorporeal circulation system via the regeneration line.

[0197] According to a preferred embodiment of the present invention, the regeneration line (14) flows into the plasma line (8A) behind point (P2), that is, between point (P2) and the apheresis column (4). According to a further preferred embodiment of the present invention, the regeneration line (14) flows into the plasma line (8A) at point (P2). According to a further preferred embodiment of the present invention, the regeneration line (14) flows directly into the apheresis column (4).

[0198] It will be apparent to those skilled in the art that the liquid container (F) connected to the regeneration line does not need to be part of the apheresis apparatus according to the present invention. This is because these are typically disposable items, such as general infusion bags, that are connected to the connection line by an operator (e.g., a doctor or nurse) according to a specific application.

[0199] According to the present invention, it is possible to have a separate regeneration line (14) for connecting a single liquid container (F). Here, for example, it is conceivable that an infusion bag containing a single liquid container, such as an alkali hydroxide solution, preferably a sodium hydroxide solution, can be connected to the regeneration line (14). However, it is also conceivable that the end of the regeneration line (14) to which a liquid container can be connected is spatially close to the end of the connection line (11) to which a liquid container can be connected. For example, in the case of an infusion bag containing an NaCl solution or a citrate solution, a single liquid container (having at least two connecting parts or corresponding adapters) can be connected to both the connection line (11) and the regeneration line (14).

[0200] According to the present invention, it is possible for a single regeneration line (14) to exist, and one or two regeneration lines are particularly preferred. Furthermore, embodiments of the apheresis apparatus according to the present invention are possible that have two or more regeneration lines (14', 14'', 14''', etc.), in which case these two or more regeneration lines can flow into the extracorporeal circulation system (2) independently of each other within the region from the branch of the bypass line (12) in the plasma line (8A) (i.e., from point P2) to the apheresis column (4). "Independent of each other" here means, for example, in an embodiment of the apheresis apparatus according to the present invention having two regeneration lines (14', 14''), one regeneration line (14') flows into the plasma line (8A) located between the point (P2) and the apheresis column (4), and the other regeneration line (14'') flows directly into the apheresis column (4). However, it is also possible for both regeneration lines (14', 14'') to flow into the plasma line (8A) located between the point (P2) and the apheresis column (4). Furthermore, it is also possible for one regeneration line (14') to flow into the other regeneration line (14''). However, if there are two or more regeneration lines (14', 14'', 14''', etc.), it is particularly preferable that all regeneration lines (14', 14'', 14''', etc.) flow into the extracorporeal circulation system (2) at the same point within the region from point (P2) to the apheresis column (4), and it is even more preferable that all regeneration lines (14', 14'', 14''', etc.) flow into the extracorporeal circulation system (2) at point (P2).

[0201] According to the present invention, if the connection line (11) and the regeneration line (14) use the same liquid source, not only can space be saved, but the effort required for operating and maintaining the apheresis apparatus according to the present invention is minimized, making it particularly effective. In this way, existing apheresis systems can be improved or complemented without the need to connect separate, large-scale additional equipment. Therefore, in a preferred embodiment of the present invention, the regeneration line (14) branches off from the connection line (11), and the point in the connection line (11) where the regeneration line (14) branches off is referred to as point (P5).

[0202] Therefore, according to some embodiments of the present invention, it is preferable that at least one regeneration line (14) leading to a plasma line (8A) or directly to an apheresis column (4) begins at a point (P5) in at least one connection line (11).

[0203] In embodiments where two or more connection lines (11', 11'', 11'''', etc.) exist and one regeneration line (14) is connected to several connection lines (11', 11'', 11'''', etc.), the naming convention for branching points (P5', P5'', P5'''', etc.) is based on the naming convention for connection lines (11', 11'', 11'''', etc.). For example, in the case of one regeneration line (14) that flows into or connects to two existing connection lines (11', 11''), the point where the regeneration line (14) flows into the connection line (11') is called point (P5'), and the point where the regeneration line (14) flows into the connection line (11'') is called point (P5'').

[0204] A suitable apheresis apparatus (1) is one in which each has two connection lines (11', 11'') that connect one liquid container (F1, F2) to an arterial line (5) or a blood component separator (7), and two regeneration lines (14', 14'') branch off from the two liquid containers (F1, F2) or the two connection lines (11', 11'') to a plasma line (8A) or directly to an apheresis column (4).

[0205] Embodiments in which a regeneration line (14) leading to a plasma line (8A) or directly to an apheresis column (4) and starting from a point (P5) within at least one connection line (11) also have at least one additional connection to a liquid container (see Figure 5). This additional connection can preferably be connected to an infusion bag containing an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0206] In a preferred embodiment, the apheresis apparatus (I) further comprises at least one regeneration line (14) that branches off from at least one liquid container (F1) or at least one connection line (11) and then leads to a plasma line (8A) at or behind the branching point of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4), the at least one regeneration line (14) having an additional connection for at least one liquid container (F2). This additional connection can preferably be connected to an infusion bag containing an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0207] In a preferred embodiment, the apheresis apparatus (I) further comprises at least one second regeneration line (14) branching from at least one liquid container (F2), the second regeneration line (14) not connected to the arterial line (5) or the blood component separator (7), but leading to the plasma line (8A) at or behind the branching point of the bypass line (12) in the direction of flow, or flowing directly into the apheresis column (4). At least one regeneration line (14) has an additional connection for at least one liquid container (F2). Preferably, an infusion bag containing an alkali hydroxide solution, preferably a sodium hydroxide solution, can be connected to this second regeneration line (14).

[0208] In embodiments where there are more connection lines than regeneration lines, each regeneration line is connected to one connection line, provided that each regeneration line has established a connection with at least one connection line, and the remaining connection lines (multiple connection lines) are connected only to arterial lines or blood component separators, or more connection lines can be aggregated into a regeneration line, meaning several connection lines can be connected to a single regeneration line. Combinations of these configurations are also possible.

[0209] There are various possibilities for adjusting the flow rate in the section of the connection line (11) behind point (P5) and in the regeneration line (14). This can be achieved, for example, by separately controllable pumps located in the section of the connection line (11) behind point (P5) and in the regeneration line (14). Another possibility is a pump located before point (P5) in the connection line (11), where the flow rate distribution behind point (P5) is either fixed by the respective diameters of the regeneration line (14) and the connection line (11), or adjustable by appropriate means (clamps, valves) (e.g., by changing the diameter of each line). Naturally, flow rate adjustment is particularly important when a solution (e.g., citrate solution) must be supplied to the system via the connection line (11) (e.g., for anticoagulation of blood) and simultaneously flowed into the apheresis column via the regeneration line (14) (e.g., as a neutralizing solution). For example, by using such a mechanism, even if the solution is branched during the step of neutralizing the apheresis column after regeneration using an alkali hydroxide solution, preferably a sodium hydroxide solution, via the regeneration line (14), the supply of the solution via the connection line (11) can be kept constant (for example, to maintain constant anticoagulation).

[0210] Compared to other systems, in the case of this apheresis apparatus (1), the sufficient number of pumps is a maximum of 8, preferably 7, more preferably 6, and most preferably 5.

[0211] In an embodiment of the present invention having several connection lines (11', 11'', 11'''', etc.) and several regeneration lines (14', 14'', 14'''', etc.), each connection line is connected to one of the regeneration lines and can flow into the plasma line (8A) or directly into the apheresis column (4) after point (P2). Here, each regeneration line can flow into the plasma line (8A) or directly into the apheresis column (4) at a point after point (P2) independently of the other regeneration lines. However, it is preferable that all regeneration lines flow into the plasma line (8A) or directly into the apheresis column (4) at the same point after point (P2), more preferably directly into the apheresis column (4), and most preferably at point (P2). One such exemplary embodiment may be described with reference to Figure 4. Here, the apheresis device (1) has a first connection line (11'), which first leads to the arterial line (5), from which the first regeneration line (14') branches off at point (P5'). The apheresis device (1) also has a second connection line (11''), which first leads directly to the blood component separator (7), from which the second regeneration line (14'') branches off at point (P5''). In this embodiment, both regeneration lines (14',14'') flow into the extracorporeal circulation system (2) at point (P2).

[0212] Therefore, an apheresis apparatus (1) is preferred, each having two connection lines (11', 11'') that connect at least one liquid container (F) to an arterial line (5) or a blood component separator (7), and at least one regeneration line (14) leading to a plasma line (8A) or directly to an apheresis column (4) connected to the connection line (11') at point (P5') and to the connection line (11'') at point (P5'').

[0213] Therefore, each apheresis device (1) has two connection lines (11', 11'') that connect at least one liquid container (F1, F2) to an arterial line (5) or a blood component separator (7), and at least one regeneration line (14) that leads to a plasma line (8A) or directly to an apheresis column (4) is connected to the connection line (11') at point (P5') and to the connection line (11'') at point (P5''), and the regeneration line (14') is An embodiment of the apheresis apparatus (1) is particularly preferred in which a liquid container (F1) or a connection line (11') branching from the liquid container (F1) leads to an apheresis column (4) or a plasma line (8A), and a regeneration line (14'') leads from the liquid container (F2) or a connection line (11'') branching from the liquid container (F2) to the apheresis column (4) or a plasma line (8A), or into the regeneration line (14'). Therefore, the apheresis apparatus (1) is particularly preferable if it has a connection line (11') for connecting a liquid container (F1) and a connection line (11'') for connecting a liquid container (F2), the connection line (11') flows into an arterial line (5) or a blood component separator (7), the connection line (11'') flows into an arterial line (5) or a blood component separator (7), or flows into the connection line (11') and ultimately flows back into the arterial line (5) or a blood component separator (7), the regeneration line (14') is connected from the liquid container (F1) or the connection line (11') to an apheresis column (4) or a plasma line (8A), and the regeneration line (14'') is connected from the liquid container (F2) or the connection line (11'') to the apheresis column (4) or a plasma line (8A), or into the regeneration line (14').

[0214] Therefore, the embodiment of the apheresis apparatus (1) is particularly preferred when the apheresis apparatus (1) has a connection line (11') that connects a liquid container (F1) to an arterial line (5) or a blood component separator (7), and a connection line (11'') that connects a liquid container (F2) to an arterial line (5) or a blood component separator (7), and a regeneration line (14') that branches off from the liquid container (F1) or the connection line (11') and flows into the plasma line (8A) behind the branch of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4), and the regeneration line (14'') that branches off from the liquid container (F2) or the connection line (11'') and leads to the plasma line (8A) or the regeneration line (14') behind the branch of the bypass line (12) in the direction of flow, or leads directly to the apheresis column (4).

[0215] In one embodiment, an apheresis apparatus (1) is preferred, each having two connection lines (11', 11'') that connect at least one liquid container to an arterial line (5) or a blood component separator (7), and at least one regeneration line (14) leading to a plasma line (8A) or a direct apheresis column (4) establishing a connection to the connection line (11') at point (P5') and to the connection line (11'') at point (P5''). This is understood as the regeneration line (14) being a connecting element between the connection lines (11', 11'') on the one hand, and the plasma line (8A) or apheresis column (4) on the other hand. Thus, liquid from one of the liquid containers (F) connected to one of the two connection lines (11', 11'') can also flow through the regeneration line (14) to point (P2) and into the plasma line (8A) or the direct apheresis column (4).

[0216] Embodiments having two (or more) connection lines are ideally suited for regenerating the apheresis column (4) and subsequently introducing plasma into the apheresis column (4) using different regeneration solutions. For example, such a device is ideally suited for first introducing a NaCl solution to drain the plasma contained in the apheresis column, then introducing an alkali hydroxide solution, preferably a sodium hydroxide solution, to efficiently and rapidly regenerate the adsorbent, and finally introducing another NaCl solution to drain the alkali hydroxide solution, preferably a sodium hydroxide solution, contained in the apheresis column before introducing plasma back into the apheresis column.

[0217] In an embodiment of the apheresis apparatus according to the present invention, in which a bypass line (12) leads to a point (P6) in a plasma line (8B), it is preferable that point (P6) is located before point (P1) (in the direction of flow) (see Figures 1-2).

[0218] According to a preferred embodiment of the present invention, the connecting line flows into the arterial line. According to a further preferred embodiment of the present invention, the connecting line flows directly into the blood component separator.

[0219] According to a preferred embodiment of the present invention, the regeneration line (14) flows into the plasma line (8A) behind point (P2), that is, between point (P2) and the apheresis column (4). According to a further preferred embodiment of the present invention, the regeneration line (14) flows directly into the apheresis column (4).

[0220] To reduce dead space in the system, according to the present invention, it is particularly preferable that at least one regeneration line (14) flows into the extracorporeal circulation system (2) at a point (P2) in the apheresis device (1) according to the present invention. In embodiments in which two or more regeneration lines (14', 14'', 14''', etc.) are present, it is particularly preferable that all present regeneration lines (14', 14'', 14''', etc.) flow into the extracorporeal circulation system (2) at a point (P2) or into the plasma line (8A) at a point (P2).

[0221] Accordingly, the present invention relates to an apheresis device (1) according to the present invention, wherein a bypass line (12) passes from a point (P2) in the plasma line (8A) to a point (P6) in the plasma line (8B), a waste line (13) passes from a point (P4) in the plasma line (8B), and at least one regeneration line (14) flows into the plasma line (8A) at point (P2).

[0222] To further reduce the dead space in the system, it is even more preferable that, in addition to the regeneration line (14) flowing into the plasma line (8A) at point (P2) and the bypass line (12) branching off from the plasma line (8A), the point where the waste line (13) branches off within the plasma line (8B) is the same point where the bypass line (12) flows in. In other words, it is preferable that the point where the bypass line (12) flows into the plasma line (8B) (P6) coincides with the point where the waste line (13) branches off from the plasma line (8B) (P4), i.e., P4 = P6 (see also Figure 2).

[0223] Therefore, the present invention relates to an apheresis device (1) according to the present invention, wherein a bypass line (12) passes from point (P2) in the plasma line (8A) to point (P6) in the plasma line (8B), a waste line (13) passes from point (P4) in the plasma line (8B), and at least one regeneration line (14) flows into the plasma line (8A) at point (P2), and point (P6) and point (P4) are the same.

[0224] The apparatus according to the present invention incorporates a blood component separator that separates the patient's blood supplied (via an arterial line) into plasma and cellular components, and then sends each component to the next via corresponding lines, namely the plasma line and the cellular line. Here, as already described, it should be considered that the separation of plasma and cellular components by the blood component separator used is not complete, and preferably only 10-90% of the total plasma volume is separated from the cellular components. When a centrifugal blood component separator is used, preferably 70-90%, more preferably 80-87% of the total plasma volume is separated from the cellular components. When a membrane separation blood component separator is used, preferably 10-30%, more preferably 13-25%, and even more preferably 15-20% of the total plasma volume is separated from the cellular components.

[0225] The types of blood component separators that can be used in connection with the present invention include centrifugal blood component separators and membrane separation blood component separators, such as membrane separation blood component separators having a semipermeable membrane and membrane separation blood component separators having a rotary membrane.

[0226] Therefore, the present invention also relates to an apheresis device for removing CRP from blood extracorporeally, wherein the blood component separator (7) is either a centrifugal blood component separator or a membrane separation blood component separator.

[0227] In this application, when the position of one or more components of the apheresis apparatus according to the present invention relative to another component of the apheresis apparatus according to the present invention is described using the terms “before” or “after” (or “before in the direction of flow” and “after in the direction of flow”), this refers to the normal direction of blood or plasma flow within the apheresis apparatus according to the present invention. Thus, “before” a component of the apparatus according to the present invention means a direction opposite to the normal direction of blood or plasma flow, and “after” a component of the apparatus according to the present invention means a direction following the normal direction of blood or plasma flow. Preferably, the direction of flow within the apheresis apparatus is not reversed and is not reversed by means of generating or regulating the flow.

[0228] According to the present invention, the apheresis apparatus for removing CRP from blood extracorporeally comprises an apheresis column (4) for affinity chromatographic removal of CRP from blood or plasma, and its function is to bind CRP present in the patient's blood or plasma as it passes through the apheresis column (4). [pump] According to the present invention, the apheresis device for removing CRP from blood extracorporeally is provided with means for generating and regulating the flow of blood (or plasma) within the extracorporeal circulation system. For this purpose, one or more pumps or pump systems are typically used, which allows control over the flow of blood (or plasma or regenerative solution or anticoagulant solution) passing through the extracorporeal circulation system and the components of the device according to the present invention that are fluidly connected thereto.

[0229] According to the present invention, the preferred direction of flow within the extracorporeal circulation system and the components of the apparatus according to the present invention fluidly connected thereto is such that the blood flows from the access point on the patient surface where blood enters the apparatus according to the present invention, through the arterial line of the extracorporeal circulation system, to the venous line of the extracorporeal circulation system, and to the access point on the patient surface where the processed blood is returned to the patient.

[0230] The means for generating and regulating the flow according to the present invention, used in an extracorporeal circulation system, is preferably a pump such as a peristaltic pump (also called a hose pump), a piston pump, an air pump, a hydraulic pump, or another type of pump known to those skilled in the art. Therefore, in this specification, the terms “means for generating and regulating the flow” and “pump” may be used synonymously.

[0231] According to the present invention, it is preferable that the means for generating and regulating the flow of blood (or plasma, or regenerative solutions or anticoagulant solutions) used in the extracorporeal circulation system does not come into direct physical contact with the blood (or plasma, or regenerative solutions or anticoagulant solutions) within the apparatus according to the present invention. This is particularly effective in terms of hygiene, as it prevents the contamination of complex mechanical components such as pumps by blood, and naturally, also prevents the blood from being contaminated by the flow generating means used.

[0232] Therefore, in a particularly preferred embodiment of the present invention, the means for generating and regulating flow within the extracorporeal circulation system is one or more peristaltic pumps.

[0233] Means for generating and adjusting flow within an extracorporeal circulation system, that is, the exact position of one or more pumps is not essential to the present invention. Embodiments of the present invention using only one pump are also possible, where the pump is located in the arterial line region of the apheresis device according to the present invention for extracorporeal removal of CRP from blood, that is, in front of the blood component separator. According to the present invention, when several means for generating and adjusting flow, that is, several pumps, are provided within the extracorporeal circulation system, it is preferable that these can be controlled and adjusted independently of each other (for example, by a CPU, that is, for example, a central processing unit). Depending on the specific application, various flow rates may be desired or required within the extracorporeal circulation system. Also, during the execution of a specific application, different flow rates may be desired in various components of the device according to the present invention.

[0234] According to the present invention, several means for generating and adjusting flow (that is, pumps) can also be installed in the apheresis device according to the present invention. Therefore, the means for generating and adjusting flow can be located within the arterial line (5), and / or within the plasma line (8A), and / or within the plasma line (8B), and / or within the venous line (6), and / or within the bypass line (12), and / or within the cell line (9), and / or within the connection line (11), and / or within the connection lines (11’, 11’’, 11’’’, etc.), and / or within the regeneration line (14) or the regeneration lines (14’, 14’’, 14’’’, etc.). As described above, according to an embodiment of the present invention where the regeneration line (l4) branches from the connection line (11) at point (P5), it is preferable that the means for generating and adjusting flow (of the inorganic salt solution) is provided in front of point (P5) within the connection line (11).

[0235] According to a further embodiment of the present invention where the regeneration line (14) branches from the connection line (11) at point (P5), it is preferable that the means for generating and adjusting flow is provided behind point (P5) within the connection line (11), and that the means for generating and adjusting flow is provided within the regeneration line (14).

[0236] Furthermore, the apheresis device (1) preferably has at least one particle filter provided behind the apheresis column (4) in the plasma line (8B) or the venous line (6).

[0237] Furthermore, the apheresis device (1) preferably has at least one air bubble trap provided behind the apheresis column (4) in the plasma line (8B) or the venous line (6).

[0238] When there is a centrifuge as the blood component separator (7), the apheresis device (1) preferably has at least one plasma reservoir provided behind the centrifuge (7) and in front of the apheresis column (4) in the plasma line (8A).

[0239] In a further embodiment, the apheresis device for extracorporeal removal of CRP from blood or plasma according to the present invention may comprise one or more pressure sensors having a function of measuring or monitoring pressure at specific parts of the device according to the present invention. This not only has the function of monitoring and adjusting the operating parameters of the apheresis device according to the present invention, but is also effective in that when a malfunction occurs (for example, when the tubes or filters of the device are clogged), harmful results to the patient can be avoided by stopping the operation. The exact operating mode and mounting position within the device according to the present invention are part of the prior art and are known to those skilled in the art. In a preferred embodiment of the present invention, at least one pressure sensor is arranged in the arterial line of the apheresis device according to the present invention, and at least one pressure sensor is arranged in the venous line of the apheresis device according to the present invention. In a more preferred embodiment of the present invention, such a pressure sensor is incorporated into the means for generating and adjusting flow within the extracorporeal circulation system used in the apheresis device according to the present invention.

[0240] The suitable pressure or pressure range for the NaOH solution is -200 to 200 mbar (differential pressure before and after the adsorbent), with a maximum of 300 mbar.

[0241] At nodes in the extracorporeal circulation system, i.e., points where several lines converge or diverge, means are preferably provided to control the direction of flow within the system, thereby regulating the flow of a solution (e.g., blood, plasma, or regeneration solution). These means may be valves, multiway valves, clamps, or valves of the form of stop valves, check valves, pressure valves, directional control valves, or other types of valves known to those skilled in the art, which open the flow in one direction and block the flow in another. Preferably, such flow regulating means (e.g., valves) are located at points (P1), and / or (P2), and / or (P3), and / or (P4), and / or (P5), and / or (P6). Furthermore, more complex flow regulation can be achieved, for example, by connecting two or more valves in series at one point.

[0242] Furthermore, it is particularly preferable that the flow adjustment means (e.g., valves) be electronically controllable, meaning their position can be controlled by a central processing unit.

[0243] Therefore, the present invention relates to an apheresis device for removing CRP from blood from the body, wherein electronically controlled valves are provided at points (P1), (P2), (P4), (P5), (P6), (P7), and (P8).

[0244] The valves are not located precisely at the branching points (P1, P2, P4, P5, P6, P7, P8), but rather within the upstream and / or downstream lines, thereby controlling the flow of solution within the extracorporeal circulation system, as is also the case in this invention. For this purpose, hose clamps can also be used. It is particularly preferable that these valves or hose clamps are electronically controlled.

[0245] A further advantage of the present invention, related to the fact that apheresis and apheresis column regeneration are performed within a single device, is that the entire device can be controlled by a single central processing unit (CPU). Therefore, during a single apheresis operation, separate programs—for example, the normal operation of passing plasma through the apheresis column and the regeneration operation of flushing the apheresis column with a regeneration solution while the plasma is bypassed through a bypass line—can be controlled by a single processing unit or software on that unit. This facilitates the automation of many processes, resulting in less room for operator error. In contrast, conventional devices require the combination of separate, complex systems (a primary system for separating blood into plasma and cellular components, and a secondary system for apheresis and regeneration), each of which must be controlled separately.

[0246] Therefore, the present invention relates to an apheresis device for extracorporeal removal of CRP from blood, which controls the entire device using only one central processing unit (10).

[0247] Further aspects of the present invention relate to an apheresis apparatus (II) for extracorporeal removal of CRP from a patient's blood, wherein the apheresis apparatus (II) comprises at least two apheresis columns, and the apheresis apparatus (II) is configured to be resistant to an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0248] In other words, further aspects of the present invention relate to an apheresis device (II) for extracorporeal removal of CRP from a patient's blood, wherein the apheresis device comprises at least two apheresis columns, the apheresis device is connectable to the patient's blood circulation, and the apheresis device (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0249] A further aspect of the present invention relates to an apheresis apparatus, wherein a second apheresis column (4'') is connected to a bypass line, or the bypass line comprises a second apheresis column. Preferably, the second apheresis column (4'') is contained within the bypass line. Thus, as described herein, an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention may include a second apheresis column (4''), the second apheresis column (4'') being contained within the bypass line. The apheresis column (4'') is contained within the bypass line if a portion of the bypass line (12') of the bypass line (12) flows into the second apheresis column (4'') and another portion of the bypass line (12'') of the bypass line (12) leads away from the outlet of the apheresis column (4'').

[0250] Therefore, a further aspect of the present invention is an apheresis device (II) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) to the blood component separator (7), a plasma line (8A) from the blood component separator (7) to the apheresis column (4'), a plasma line (8B) for plasma after CRP removal from the apheresis column (4') to point (P1), a cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1). an apheresis apparatus (II) comprising at least one connection line (11) connecting at least one fluid container (F) to an arterial line (5) or a blood component separator (7), The bypass line (12) branches off from the plasma line (8A) and flows into the plasma line (8B), and the bypass line (12) is equipped with a second apheresis column (4''). The waste line (13) either branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line (12) in the direction of flow. At least one regeneration line (14) leads to the plasma line (8A) behind the branch of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4'). The apheresis apparatus (II) is characterized in that the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4',4'') can only operate alternately to remove CRP, i.e., they cannot be used simultaneously, and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0251] Preferably, the apheresis apparatus (II) further comprises a central processing unit that controls the apheresis apparatus (II).

[0252] Therefore, a further aspect of the present invention is an apheresis device (II) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) up to the blood component separator (7), a plasma line (8A) from the blood component separator (7) to the apheresis column (4'), a plasma line (8B) for the plasma after CRP removal from the apheresis column (4') to the point (P1), a cell line (9) for the separated cell components from the blood component separator (7) to the point (P1), and a venous line (6) starting from the point (P1). An apheresis device (II) comprising at least one connection line (11) connecting at least one fluid container (F1) to the arterial line (5) or the blood component separator (7). The bypass line (12) branches from the plasma line (8A) and flows into the plasma line (8B), and the bypass line (12) includes a second apheresis column (4''). The waste line (13) branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line (12) in the flow direction. At least one regeneration line (14) branches from at least one liquid container (F1) or at least one connection line (11) and leads to the plasma line (8A) at or behind the junction point of the bypass line (12) in the flow direction, or directly flows into the apheresis column (4'). At least the second regeneration line (14) branches from at least one liquid container (F2), the second regeneration line (14) is not connected to either the arterial line (5) or the blood component separator (7), and leads to the plasma line (8A) at or behind the branching point of the bypass line (12) in the flow direction, or directly flows into the apheresis column (4'). The second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4', 4'') can only operate alternately for CRP removal, that is, they cannot be used simultaneously. The apheresis device (II) is configured to be resistant to an alkaline hydroxide solution, preferably a sodium hydroxide solution. This is the apheresis device (II) characterized by this.

[0253] Preferably, the apheresis apparatus (II) further comprises a central processing unit that controls the apheresis apparatus (II).

[0254] Therefore, preferably, the apheresis apparatus (II) comprises at least two regeneration lines (14', 14'') that independently lead to the plasma line (8A) at or behind the branching point of the bypass line (12) in the direction of flow, or that flow directly into the apheresis column (4'), with at least one of the regeneration lines (14', 14'') branching from at least one liquid container (F1) or at least one connection line (11).

[0255] Therefore, a further aspect of the present invention is an apheresis device (II) for removing CRP from blood outside the body, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) to the blood component separator (7), a plasma line (8A) from the blood component separator (7) to the apheresis column (4'), a plasma line (8B) for plasma after CRP removal from the apheresis column (4') to point (P1), a cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1). an apheresis apparatus (II) comprising at least one connection line (11) connecting at least one fluid container (F1) to an arterial line (5) or a blood component separator (7), The bypass line (12) branches off from the plasma line (8A) and flows into the plasma line (8B), and the bypass line (12) is equipped with a second apheresis column (4''). The waste line (13) either branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line (12) in the direction of flow. At least one regeneration line (14) branches off from at least one liquid container (F1) or at least one connection line (11) and leads to a plasma line (8A) at or behind the branching point of the bypass line (12) in the direction of flow, or flows directly into the apheresis column (4'), and at least one regeneration line (14) has at least one additional connection to a liquid container (F2), The apheresis apparatus (II) is characterized in that the second apheresis column (4'') is connected in parallel with the first apheresis column (4'), and both apheresis columns (4',4'') can only operate alternately to remove CRP, i.e., they cannot be used simultaneously, and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0256] Preferably, the apheresis apparatus (II) further comprises a central processing unit (10) that controls the apheresis apparatus (II).

[0257] The above-described embodiment of the apheresis device (1) according to the present invention will be replaced by the apheresis device (II) according to the present invention. The bypass line (12) of the apheresis device (1) will be used as a plasma line in the apheresis device (II).

[0258] By using the apheresis apparatus (II) according to the present invention, it is possible to remove CRP from blood more efficiently in the same processing time compared to using conventional apparatuses. By using two parallel-connected apheresis columns that can only be used alternately for CRP removal, the apheresis apparatus according to the present invention allows for the removal of CRP from blood using one apheresis column, while the second apheresis column can be replaced with another apheresis column or regenerated during the ongoing apheresis operation. This makes it possible to achieve high clinical processing capacity using the apheresis apparatus. Furthermore, the use of the apheresis apparatus according to the present invention is not limited by dead space. Normally, apheresis columns are not only large but also connected in series, so their use in apheresis is severely limited due to their large dead space. In addition, the volume of the apheresis apparatus, and therefore the volume and number of apheresis columns connected in series, are limited by the flow rate of human blood. Furthermore, even when using an apheresis apparatus with apheresis columns connected in parallel and used simultaneously, the large dead space makes it impossible to efficiently remove CRP from blood without risking the patient.

[0259] As described herein, the apheresis apparatus (II) according to the present invention is characterized in that the second apheresis column is connected in parallel to the first apheresis column (4'). Here, "parallel" means that various circulations exist side by side within the extracorporeal circulation system (2), that is, for example, the first apheresis column (4') having a plasma line (8A) for separated plasma and a plasma line (8B) for plasma after CRP removal corresponds to the first circulation system of the extracorporeal circulation system (2), and the second apheresis column (4'') having a bypass line portion (12') of the bypass line (12) and a bypass line portion (12'') of the bypass line (12) corresponds to the second circulation system of the extracorporeal circulation system (2). "Parallel" also means that the two apheresis columns are not connected in series, that is, one is behind the other and they are not connected so that the outflow from the first apheresis column is introduced into the second apheresis column. Since the apheresis columns are connected in parallel, their capacities are not added together.

[0260] What should be distinguished from this is the series connection of apheresis columns, which is not in accordance with the present invention. "Series" means that several apheresis columns are in only one circulation of the extracorporeal circulation system (2), that is, for example, the first apheresis column (4') and the second apheresis column (4'') together with the plasma line (8A) and the plasma line (8B) form only one circulation of the extracorporeal circulation system (2), i.e., they are connected or arranged in series.

[0261] According to the present invention, these two apheresis columns (4',4''), which are connected or arranged in parallel with each other, can only operate alternately. "Alternately" means that the separated plasma passes through either apheresis column (4') or apheresis column (4''), but not both apheresis columns (4',4'') simultaneously. Here, "alternately" operation means CRP removal as a therapeutic action. For CRP removal, both apheresis columns (4' and 4'') cannot be used simultaneously. Naturally, one of the two apheresis columns can be used for CRP removal while the other is being regenerated at the same time. Only the simultaneous operation of both apheresis columns performing therapeutic action to remove CRP is excluded.

[0262] Therefore, the following situations are possible: Plasma is passed through one apheresis column to remove CRP. Simultaneously, the second apheresis column is ready for use and the plasma flow can be switched to this second apheresis column as soon as the capacity of the first apheresis column is exhausted or as soon as another problem occurs with the first apheresis column. Alternatively, the second apheresis column has already been used for CRP removal and must be replaced or regenerated. Alternatively, the second apheresis column is regenerated while the first apheresis column is removing CRP.

[0263] Therefore, in each embodiment of the present invention, the apheresis apparatus (II) having two apheresis columns is designed such that the apheresis columns can only operate alternately.

[0264] Therefore, according to one embodiment of the apheresis apparatus (II) according to the present invention, at the same time, plasma can only pass through either the first apheresis column (4') or the second apheresis column (4''). Hence, in a further embodiment of the apparatus according to the present invention, the apheresis apparatus is designed so that plasma can pass through either the first apheresis column (4') or the second apheresis column (4'') at the same time.

[0265] During the alternating operation of the two apheresis columns (4', 4''), plasma does not pass through either apheresis column (4') or apheresis column (4''). As a result, one of the two apheresis columns can be replaced from the apheresis device while it is in operation. Here, "replacement" means either replacing one of the two apheresis columns with a new apheresis column or regenerating one of the two apheresis columns. Regeneration of one of the two apheresis columns can be carried out, for example, by washing it with an alkali hydroxide solution, preferably a sodium hydroxide solution. It is preferable to use an alkali hydroxide solution, preferably a sodium hydroxide solution, for regenerating apheresis columns. Here, "in operation" means that the removal of CRP from the blood is continuing.

[0266] Accordingly, as described herein, one embodiment of the apheresis apparatus (II) of the present invention relates to an apheresis apparatus in which the first apheresis column (4') is replaceable during the operation of the second apheresis column (4''), and the second apheresis column (4'') is replaceable during the operation of the first apheresis column (4').

[0267] Furthermore, an embodiment is conceivable in which the first apheresis column (4') is regenerative during the operation of the second apheresis column (4''), and the second apheresis column (4'') is regenerative during the operation of the first apheresis column (4').

[0268] Therefore, in one embodiment of the present invention, the apheresis apparatus (II) is designed such that the first apheresis column (4') is replaceable or regenerative during the operation of the second apheresis column (4''), and the second apheresis column (4'') is replaceable or regenerative during the operation of the first apheresis column (4').

[0269] A preferred embodiment is an apheresis apparatus (II) for extracorporeal removal of CRP from blood, in which a second apheresis column (4'') is connected in parallel to a first apheresis column (4'), both apheresis columns (4',4'') can only operate alternately at the same time, the first apheresis column (4') is replaceable or regenerative during operation of the second apheresis column (4''), and the second apheresis column (4'') is replaceable or regenerative during operation of the first apheresis column (4'), and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0270] Furthermore, a preferred embodiment includes an apheresis device (II) for extracorporeal removal of CRP from blood, in which the second apheresis column (4'') is connected in parallel to the first apheresis column (4'), both apheresis columns (4',4'') cannot be used simultaneously for CRP removal, one of the apheresis columns (4',4'') can be regenerated simultaneously with the CRP removal by the other apheresis column, and the apheresis device (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0271] Therefore, according to one embodiment of the present invention, the apheresis apparatus (II) is configured as follows: The first apheresis column (4') is replaceable during the operation of the second apheresis column (4''), the apheresis column is regenerative in itself, the second apheresis column (4'') is configured to be replaceable during the operation of the first apheresis column (4'), and the apheresis column (4'') is configured to be regenerative.

[0272] A second apheresis column (4'') connected in parallel to the first apheresis column (4') can be incorporated into a bypass line; that is, the bypass line (12) consists of a bypass line portion (12') and a bypass line portion (12''), with the second apheresis column (4'') located between the two bypass line portions. Therefore, an apheresis apparatus (II) is preferred, characterized in that the bypass line portion (12') of the bypass line (12) branches off from the plasma line (8A) and flows into the second apheresis column (4'), and the bypass line portion (12'') of the bypass line (12'') flows into the plasma line (8B) which starts from the apheresis column (4'').

[0273] Furthermore, a preferred embodiment is an apheresis apparatus (II) for extracorporeal removal of CRP from blood, in which the second apheresis column (4'') is connected in parallel to the first apheresis column (4'), and both apheresis columns (4',4'') cannot be used simultaneously for CRP removal (i.e., they can only be operated alternately), and the apheresis apparatus (1) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0274] According to one embodiment of the present invention, the apheresis apparatus (II) according to the present invention has two connection lines (11', 11'') each connected to at least one liquid container (F), and it is particularly preferable that the connection lines (11', 11'') independently flow into an arterial line (5) or directly into a blood component separator (7). As a result, both connection lines (11', 11'') flow into the arterial line (5), or both connection lines (11', 11'') flow directly into the blood component separator (7), or particularly preferably, one connection line (11') flows into the arterial line (5) and the other connection line (11'') flows directly into the blood component separator (7). This makes it possible to connect the two connection lines (11', 11'') to separate liquid containers.

[0275] According to a further embodiment of the present invention, the apheresis apparatus (II) has a waste line (13') which branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction with the bypass line portion (12'') of the bypass line in the direction of flow, and a waste line (13'') which branches directly from the apheresis column (4'') or branches from the bypass line portion (12'') before the junction with the plasma line (8B) in the direction of flow.

[0276] Therefore, the present invention also relates to an apheresis device (II) for extracorporeal removal of CRP from blood, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4'), and a plasma line (8B) for plasma after CRP removal from the apheresis column (4') to a point (P1). A cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1), an apheresis apparatus (II) comprising at least one connection line (11) connecting at least one fluid container (F) to an arterial line (5) or a blood component separator (7), The bypass line portion (12') of the bypass line (12) branches off from the plasma line (8A) and flows into the second apheresis column (4'), while the bypass line portion (12'') of the bypass line (12) flows into the plasma line (8B) which starts from the apheresis column (4''). The waste line (13') either branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line portion (12'') of the bypass line (12) in the direction of flow, and the waste line (13'') either branches directly from the apheresis column (4'') or branches from the bypass line portion (12'') before the junction with the plasma line (8B) in the direction of flow, At least one regeneration line (14) flows into the plasma line (8A), or into the bypass line portion (12') of the bypass line (12) at or behind the branch point of the bypass line portion (12') in the direction of flow, or directly into the apheresis column (4') or apheresis column (4''), The present invention relates to an apheresis apparatus (II) characterized in that a second apheresis column (4'') is connected in parallel with a first apheresis column (4'), both apheresis columns (4',4'') cannot be used simultaneously for removal, i.e., they can only be operated alternately, and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0277] According to a further embodiment of the present invention, the apheresis apparatus (II) further has at least one regeneration line (14) branching from at least one liquid container (F) or at least one connection line (11) and leading to a plasma line (8A) or to a bypass line portion (12') of a bypass line (12), or flowing directly into the apheresis column (4') or directly into the apheresis column (4''). According to a further embodiment of the present invention, the apheresis apparatus (II) further has at least one regeneration line (14) flowing into a bypass line portion (12') and the apheresis column (4') in a region from a point (P2), or flowing into a plasma line (8A) and the apheresis column (4'') in a region from a point (P2), or flowing directly into the apheresis column (4'), or leading directly to the apheresis column (4'').

[0278] In a particularly preferred embodiment of the present invention, the apheresis apparatus (II) comprises a waste line (13') that branches directly from the apheresis column (4') or from the plasma line (8B) prior to the junction of the bypass line portion (12'') of the bypass line (12) in the direction of flow, and at least one regeneration line (14) that branches from at least one liquid container (F) or at least one connection line (11) and leads to the bypass line portion (12') or the plasma line (8A), or flows directly into the apheresis column (4') or directly into the apheresis column (4'').

[0279] In a particularly preferred embodiment of the present invention, the apheresis apparatus (II) comprises: a waste line (13') that branches directly from the apheresis column (4') or from the plasma line (8B) prior to the junction of the bypass line portion (12'') of the bypass line in the direction of flow; a waste line (13'') that branches directly from the apheresis column (4'') or from the bypass line portion (12'') of the bypass line (12) prior to the junction of the bypass line portion (12') of the bypass line in the direction of flow; and at least one regeneration line (14) that branches from at least one liquid container (F) or at least one connection line (11) and leads to the plasma line (8A) or the bypass line portion (12') of the bypass line (12), or flows directly into the apheresis column (4') or directly into the apheresis column (4'').

[0280] Furthermore, an embodiment of the apheresis device (II) according to the present invention is possible in which at least one regeneration line (14) leads to point (P7), from point (P7) line (15') leads to point (P2) or flows into plasma line (8A), and from point (P7) line (15'') leads into plasma line (8A) (see Figure 7).

[0281] If at least one regeneration line (14) for the rinse solution flows into the plasma line (8A) between point (P2) and the apheresis column (4'), or if at least one regeneration line (14) flows into the bypass line portion (12') of the bypass line (12) between point (P2) and the apheresis column (4''), then the rinse solution can be used for either the apheresis column (4') only or the apheresis column (4''). Thus, the regeneration line (14) is either selective for the apheresis column (4') or selective for the apheresis column (4'').

[0282] Similarly, embodiments of the apheresis apparatus (II) according to the present invention are possible, having two, three, or more regeneration lines (14', 14'', 14''', etc.), where these two, three, or more regeneration lines can independently flow into the plasma line (8A) (i.e., from point (P2) to the apheresis column (4')), or into the bypass line portion (12') (i.e., from point (P2) to the apheresis column (4'')), or into the apheresis column (4'), or into the apheresis column (4''). Here, "independently of each other" means, firstly, in an embodiment of the apheresis apparatus according to the present invention having two regeneration lines (14', 14''), one regeneration line (14') flows into the plasma line (8A) between the point (P2) and the apheresis column (4'), and the other regeneration line (14'') flows directly into the apheresis column (4''), but both regeneration lines (14', 14'') can also flow into the plasma line (8A) between the point (P2) and the apheresis column (4'). Another possibility is that one regeneration line (14') flows into the extracorporeal circulation system (2) at the point (P2), and the other regeneration line (14'') flows into the bypass line portion (12') of the bypass line (12) between the point (P2) and the apheresis column (4''). It is also possible for one regeneration line (14') to flow into the extracorporeal circulation system at point (P2), and the other regeneration line (14'') to flow into the apheresis column (4''). It is also possible for one regeneration line (14') to flow into the other regeneration line (14''). However, when there are two or more regeneration lines (14', 14'', 14''', etc.), it is preferable for all of the regeneration lines (14', 14'', 14''', etc.) to flow into the extracorporeal circulation system (2) at point (P2), and the apheresis device (II) is configured to be resistant to alkali hydroxide solution, preferably sodium hydroxide solution.

[0283] It is even more preferable that one regeneration line (14') flows into the bypass line portion (12') of the bypass line (12) located between point (P2) and the apheresis column (4'), and the other regeneration line (14'') flows into the bypass line portion (12') of the bypass line (12) located between point P2 and the apheresis column (4''). It is even more preferable that one regeneration line (14') flows into the apheresis column (4'), and the other regeneration line (14'') flows into the apheresis column (4''). Here, the regeneration line (14') is selective for the first apheresis column (4'), and the regeneration line is selective for the second apheresis column (4'').

[0284] Accordingly, according to a particularly preferred embodiment of the present invention, the apheresis apparatus (II) further comprises a regeneration line (14') for a wash solution selective to the first apheresis column (4') and / or a regeneration line (14'') for a wash solution selective to the second apheresis column (4'').

[0285] As described above, the regeneration solution required for the regeneration of the apheresis column can be supplied into the extracorporeal circulation system (2) via the regeneration line (14), thereby allowing the use of a regeneration solution (e.g., an alkali hydroxide solution, preferably a sodium hydroxide solution) in addition to the rinsing solution. The rinse solution can be used, but is not required, to regenerate the first apheresis column (4') and / or apheresis column (4''). In addition to the functions described above, it also serves to drain plasma from the plasma line (8A) in the region from point (P2) to apheresis column (4'), and from the plasma line (8B) from apheresis column (4') to point (P8), or from the bypass line portion (12') of the bypass line (12) in the region from point (P2) to apheresis column (4''), and from the bypass line portion (12'') of the bypass line (12) from apheresis column (4'') to point (P8) before using the regeneration solution. This rinse solution is discarded via the waste line (13',13'') after passing through one of the two apheresis columns (4',4'').

[0286] Therefore, it is conceivable that apheresis columns (4',4'') connected in parallel can not only operate alternately but also regenerate alternately.

[0287] As described herein, in the apheresis apparatus (II) according to the present invention, the first apheresis column (4') may be replaceable or regenerative during the operation of the second apheresis column (4''), and the second apheresis column (4'') may be replaceable or regenerative during the operation of the first apheresis column (4').

[0288] In other words, a preferred apheresis apparatus (II) is one in which the second apheresis column (4'') is connected in parallel to the first apheresis column (4'), both apheresis columns (4',4'') can only operate alternately, the first apheresis column (4') is replaceable or regenerative during the operation of the second apheresis column (4''), the second apheresis column (4'') is replaceable or regenerative during the operation of the first apheresis column (4'), and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0289] Furthermore, an embodiment of the present invention is conceivable in which the apheresis apparatus has a regeneration line (14) for each liquid container (F), the regeneration line (14) branches off from each liquid container (F) or its connecting line (11), and in each case leads to a plasma line (8A) or the bypass line portion (12') of a bypass line (12), or directly to an apheresis column (4'), or directly to an apheresis column (4'').

[0290] A particularly preferred embodiment of the present patent invention relates to an apheresis device (II) for removing CRP from blood, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4'), and a plasma line (8B) for plasma after CRP removal from the apheresis column (4') to a point (P1). A cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1), an apheresis apparatus (II) comprising at least one connection line (11) connecting at least one fluid container (F) to an arterial line (5) or a blood component separator (7), The bypass line portion (12') of bypass line (12) branches off from the plasma line (8A) and flows into the second apheresis column (4'), and the bypass line portion (12'') of bypass line (12'') flows into the plasma line (8B) which starts from the apheresis column (4''). The waste line (13') either branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line portion (12') of the bypass line (12) in the direction of flow, and the waste line (13'') either branches directly from the apheresis column (4'') or branches from the bypass line portion (12'') of the bypass line (12) before the junction of the bypass line portion (12') of the bypass line (12) in the direction of flow. Each liquid container (F) contains a regeneration line (14), and the regeneration line (14) branches off from each liquid container (F) or from its connecting line (11) and flows into the plasma line (8A) or the bypass line portion (12') of the bypass line (12) behind the branch of the bypass line portion (12') in the direction of flow, or flows directly into the apheresis column (4') or directly into the apheresis column (4''). The present invention relates to an apheresis apparatus (II) characterized in that a second apheresis column (4'') is connected in parallel to a first apheresis column (4'), both apheresis columns (4',4'') cannot be used simultaneously for CRP removal, and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0291] Furthermore, an embodiment of the apheresis device (II) is preferred in which each apheresis device (II) has at least two connection lines (11) that connect at least one liquid container (F) to an arterial line (5) or a blood component separator (7), and for each liquid container (F), there is a regeneration line (14) that branches off from each liquid container (F) or its connection line (11) and leads to a plasma line (8A), or to the bypass line portion of a bypass line (12), or directly to an apheresis column (4'), or directly to an apheresis column (4'').

[0292] According to some embodiments of the present invention, it is preferable that at least one regeneration line (14) leading to a plasma line (8A) or to the bypass line portion (12') of a bypass line (12), or flowing directly into an apheresis column (4') or directly into an apheresis column (4''), starts from a point (P5) in at least one connection line (11).

[0293] A suitable apheresis apparatus (II) is one in which each has two connection lines (11', 11'') that connect one liquid container (F1, F2) to an arterial line (5) or a blood component separator (7), and two regeneration lines (14', 14'') branch off from the two liquid containers (F1, F2) or the two connection lines (11', 11'') to a plasma line (8A), or to the bypass line portion (12') of a bypass line (12), or directly to an apheresis column (4'), or directly to an apheresis column (4'').

[0294] Particularly preferred is an embodiment in which a regeneration line (14), which leads to a plasma line (8A), or to the bypass line portion (12') of a bypass line (12), or directly to an apheresis column (4'), or directly to an apheresis column (4''), and starts from a point (P5) in at least one connection line (11), has at least one additional connection to a liquid container (Figure 10). For example, an infusion bag containing an alkali hydroxide solution, preferably a sodium hydroxide solution, can be connected to this additional connection.

[0295] In an embodiment of the present invention having multiple connection lines (11', 11'', 11'''', etc.) and multiple regeneration lines (14', 14'', 14'''', etc.), each connection line communicates with its respective regeneration line and can then flow into a plasma line (8A), or into the bypass line portion (12') of a bypass line (12), or directly into an apheresis column (4'), or directly into an apheresis column (4'') after point (P2). Here, each regeneration line can flow into a plasma line (8A), or into the bypass line portion (12') of a bypass line (12), or directly into an apheresis column (4'), or directly into an apheresis column (4'') independently of other regeneration lines. However, it is preferable that all regeneration lines flow directly into the apheresis column (4'; 4''), preferably at point (P2) in the extracorporeal circulation system (2). Such exemplary embodiments will be described with reference to Figure 10. In this specification, the apheresis device (II) has a first connection line (11'), which first leads to an arterial line (5), from which a first regeneration line (14') branches off at point (P5'). The apheresis device (II) also has a second connection line (11''), which first leads directly to a blood component separator (7), from which a second regeneration line (14'') branches off at point (P5''). In this embodiment, both regeneration lines flow into the extracorporeal circulation system (2) at point (P2).

[0296] Therefore, an apheresis apparatus (II) is preferred, which has two connection lines (11', 11'') each connecting at least one liquid container (F) to an arterial line (5) or a blood component separator (7), and at least one regeneration line (14) leading to a plasma line (8A), or to the bypass line portion (12') of a bypass line (12), or directly to an apheresis column (4'), or directly to an apheresis column (4''), connected to the connection line (11') at point (P5') and to the connection line (11'') at point (P5'').

[0297] Therefore, the apheresis apparatus (II) is equipped with two connection lines (11', 11'') each connecting a liquid container (F1, F2) to an arterial line (5) or a blood component separator (7), and at least one regeneration line (14) leading to a plasma line (8A), or the bypass line portion (12') of the bypass line (12), or directly to the apheresis column (4'), or directly to the apheresis column (4''), is connected to the connection line (11') at point (P5') and to the connection line (11'') at point (P5''), and the regeneration line (14') is connected from the liquid container (F1), or the liquid container A particularly preferred embodiment of the apheresis apparatus is one in which a connection line (11') starting from the container (F1) leads to the apheresis column (4'), or the apheresis column (4''), or the plasma line (8A'), or the plasma line (8A''), and a regeneration line (14'') leads from the liquid container (F2), or from a connection line (11'') starting from the liquid container (F2), to the apheresis column (4'), or the apheresis column (4''), or the plasma line (8A), or the bypass line portion (12') of the bypass line (12), or to the regeneration line (14').

[0298] Therefore, the apheresis device (II) has a connection line (11') for connecting liquid container (F1) and a connection line (11'') for connecting liquid container (F2), the connection line (11') flows into the arterial line (5) or blood component separator (7), the connection line (11'') flows into the arterial line (5) or blood component separator (7) or connection line (11'), and finally flows back into the arterial line (5) or blood component separator (7), and the regeneration line (14') flows into the liquid container (F1) or connection line ( It is particularly preferable that the line from 11') leads to the apheresis column (4'), or to the apheresis column (4''), or to the plasma line (8A), or to the plasma line (8A''), and the regeneration line (14'') leads from the liquid container (F2) or the connection line (11'') to the apheresis column (4'), or to the apheresis column (4''), or to the plasma line (8A'), or to the bypass line portion (12') of the bypass line portion (12'), or to the regeneration line (14').

[0299] Therefore, the apheresis device (II) has a connection line (11') that connects the liquid container (F1) to the arterial line (5) or the blood component separator (7), and a connection line (11'') that connects the liquid container (F2) to the arterial line (5) or the blood component separator (7), and the regeneration line (14') branches off from the liquid container (F1) or the connection line (11') to the plasma line (8A), or to the bypass line portion (12') of the bypass line (12), or directly Embodiments of the apheresis apparatus (II) are particularly preferred, in which the liquid flows into the apheresis column (4') or directly into the apheresis column (4''), and the regeneration line (14'') branches off from the liquid container (F2) or the connection line (11'') and flows into the plasma line (8A), or the bypass line portion (12') of the bypass line (12), or the regeneration line (14'), or directly into the apheresis column (4'), or directly into the apheresis column (4'').

[0300] Therefore, the present invention also relates to an apheresis device (II) according to the present invention, wherein the plasma line (8A) and the bypass line portion (12') of the bypass line (12) are branched at point (P2), the plasma line (8B) and the bypass line portion (12'') of the bypass line (12) are integrated at point (P6), the waste line (13') branches off from the plasma line (8B) at point (P4), the waste line (13'') branches off from the bypass line portion (12'') of the bypass line (12) at point (P8), and at least one regeneration line (14) flows into the extracorporeal circulation system (2) at point (P2).

[0301] A preferred embodiment of the present patent invention relates to an apheresis device (II) for removing CRP from blood, The extracorporeal circulation system of blood (2), A means (3) for generating and regulating blood flow within the extracorporeal circulation system (2), A blood component separator (7) that separates blood into plasma and cellular components, It is equipped with two apheresis columns (4',4'') for affinity chromatographic removal of CRP from plasma, The extracorporeal circulation system (2) includes an arterial line (5) to a blood component separator (7), a plasma line (8A) from the blood component separator (7) to an apheresis column (4'), and a plasma line (8B) for plasma after CRP removal from the apheresis column (4') to a point (P1). A cell line (9) for separated cellular components from the blood component separator (7) to point (P1), and a venous line (6) starting from point (P1), an apheresis apparatus (II) comprising at least one connection line (11) connecting at least one fluid container (F) to an arterial line (5) or a blood component separator (7), The bypass line portion (12') of bypass line (12) branches off from the plasma line (8A) and flows into the second apheresis column (4'), and the bypass line portion (12'') of bypass line (12'') flows into the plasma line (8B) which starts from the apheresis column (4''). The waste line (13') either branches directly from the apheresis column (4') or branches from the plasma line (8B) before the junction of the bypass line portion (12') of the bypass line (12) in the direction of flow, the waste line (13'') either branches directly from the apheresis column (14'') or branches from the bypass line portion (12'') of the bypass line (12) before the junction of the bypass line portion (12') of the bypass line (12) in the direction of flow, the plasma line (8A) and the bypass line portion (12') of the bypass line (12) branch at point (P2), the plasma line (8B) and the bypass line portion (12'') of the bypass line (12) merge at point (P6), At least one regeneration line (14) is connected to the plasma line (8A) behind the bypass line portion (12') of the bypass line (12) in the direction of flow, or to the bypass line portion (12') of the bypass line (12), or flows directly into the apheresis column (4') or directly into the apheresis column (4''), The waste line (13') branches off from the plasma line (8B) at point (P4), and the waste line (13'') branches off from the bypass line portion (12'') of the bypass line (12) at point (P8). At least one regeneration line (14) flows into the extracorporeal circulation system (2) at point (P2), The present invention relates to an apheresis apparatus (II) characterized in that a second apheresis column (4'') is connected in parallel to a first apheresis column (4'), both apheresis columns (4',4'') cannot be used simultaneously for CRP removal, i.e., they can only be operated alternately, and the apheresis apparatus (II) is configured to be resistant to alkali hydroxide solutions, preferably sodium hydroxide solutions.

[0302] To further reduce the dead space in the system, it is preferable not only when the regeneration line (14) flows into the extracorporeal circulation system at the point (P2) where the plasma line (8A) and the bypass line portion (12') of the bypass line (12) diverge, but also when the waste line (13', 13'') branches from the same point (P6) where the plasma line (8B) and the bypass line portion (12'') of the bypass line (12) merge. In other words, it is preferable when the point (P6) where the plasma line (8B) and the bypass line portion (12'') of the bypass line (12) merge, the point (P8) where the waste line (13'') branches, and the point (P4) where the waste line (13') branches coincide, that is, when P8 = P4 = P6 (see Figure 8).

[0303] Accordingly, the present invention also relates to an apheresis device (II) according to the present invention, wherein the plasma line (8B) and the bypass line portion (12'') of the bypass line (12) are integrated at point (P6), the waste line (13'') branches off from the bypass line portion (12'') of the bypass line (12) at point (P8), the waste line (13') branches off from the plasma line (8B) at point (P4), and at least one regeneration line (14) flows into the extracorporeal circulation system (2) at point (P2), and points (P6), (P4), and (P8) are the same.

[0304] In accordance with the present invention, one embodiment of the apheresis apparatus (II) for extracorporeal removal of CRP from blood according to the present invention comprises two apheresis columns (4',4'') for affinity chromatographic removal of CRP from blood or plasma, the function of which the apheresis columns (4',4'') is to bind CRP present in the patient's blood or plasma and passing through the apheresis column (4') or the apheresis column (4''). [method] A further aspect of the present invention also relates to a method for regenerating an apheresis column (4) that performs affinity chromatographic removal of CRP within an apheresis apparatus (1), the method which enables regeneration in operation and is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) The introduction of the neutralizing solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby introducing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0305] Furthermore, a further aspect of the present invention relates to a method for regenerating an apheresis column (4) that performs affinity chromatographic removal of CRP within an apheresis apparatus (1), the method which enables regeneration during operation and comprises the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) Stop introducing the neutralizing solution.

[0306] Furthermore, a further aspect of the present invention relates to a method for regenerating an apheresis column (4) that performs affinity chromatographic removal of CRP within an apheresis apparatus (1), the method which enables regeneration during operation and comprises the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) The introduction of the neutralizing solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby introducing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13).

[0307] Furthermore, a further aspect of the present invention relates to a method for regenerating an apheresis column (4) that performs affinity chromatographic removal of CRP within an apheresis apparatus (1), the method which enables regeneration during operation and comprises the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) The introduction of the neutralizing solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby introducing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0308] The phrase “stopping the introduction of separated plasma” in step (A) may, depending on the embodiment of the present invention, be understood to mean preventing further plasma flow to the plasma line (8A), or to the bypass line portion (12') of the bypass line (12), or to the apheresis column (4') or apheresis column (4'') using a hose clamp, control element, valve and / or hose pump.

[0309] The phrase “stopping the introduction of the regeneration solution” in step (D) may, depending on the embodiment of the present invention, be understood to mean using a hose clamp, control element, valve and / or peristaltic pump to prevent further flow of the regeneration solution into the plasma line (8A) or into the apheresis column (4). Here, in embodiments where only one regeneration solution is used, this should be understood as stopping the introduction of that same solution. In embodiments where several regeneration solutions are introduced consecutively, this means stopping the introduction of the last used regeneration solution, thereby stopping the introduction of any further regeneration solutions.

[0310] The phrase “close the waste line (13)” in step (E) may, depending on the embodiment of the present invention, be understood to mean using a hose clamp, control element, valve and / or hose pump to prevent further flow of the liquid coming out of the apheresis column (4). Here, in embodiments where only one regeneration solution is used, it should be understood to mean stopping the introduction of that same solution. In embodiments where several regeneration solutions are introduced in succession, it should be understood to mean stopping the introduction of the last used regeneration solution, thereby stopping the introduction of any further regeneration solutions.

[0311] By "discharging the flow of liquid coming out of the apheresis column (4)" in step (E), the separated plasma then passes through the apheresis column (4) and returns to the plasma line (8B), from which it further passes through the venous line (6). In some embodiments of the present invention, a hose clamp, a control element, a valve and / or a hose pump may be used to change the direction of the flow of liquid coming out of the apheresis column (4).

[0312] Furthermore, the present invention relates to a method for regenerating an apheresis column (4) that performs affinity chromatographic removal of CRP within an apheresis apparatus (1). As described herein, the method enables regeneration in operation by switching from apheresis mode to regeneration mode, in which plasma separated from blood using a blood component separator (7) is guided to the apheresis column (4) via a plasma line (8A), and the liquid flow from the apheresis column (4) is guided to a venous line (6) via a plasma line (8B), and the regeneration mode is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) The introduction of the neutralizing solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby introducing the separated plasma from the plasma line (8A) to the apheresis column (4). (E) Close the waste line (13).

[0313] A step (E) is preferred in which the waste line (13) is closed and the system switches to apheresis mode. A step (E) is even more preferred in which the waste line (13) is closed and the flow of liquid from the apheresis column (4) is sent to the venous line (6), thereby switching the system back to apheresis mode.

[0314] Regarding the two methods described above, the regeneration solution is preferably an alkali hydroxide solution, and more preferably a sodium hydroxide solution.

[0315] Furthermore, step (C) is preferably initiated after a total volume X of regeneration solution (or multiple regeneration solutions) has been introduced into the plasma line (8A) or directly into the apheresis column (4), where X corresponds to at least 75% of the volume of the apparatus between the point where the regeneration line (14) flows into the extracorporeal circulation system (2) behind the branch of the bypass line (12) in the direction of flow, and the point where the waste line (13) begins from the extracorporeal circulation system (2). Here, the regeneration solution is, for example, an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0316] Alternatively, step (E) is preferably initiated after volume Y of plasma has been introduced into the plasma line (8A) or directly into the apheresis column (4), where Y is at least 90% of the volume of the apparatus between the point where the regeneration line (14) flows into the extracorporeal circulation system (2) behind the branch of the bypass line (12) in the direction of flow, and the point where the waste line (13) begins from the extracorporeal circulation system (2).

[0317] As used herein, “operating” means that it is not necessary to stop the blood collection and supply and the operation of the blood component separator in order to perform the method for regenerating the apheresis column (4) according to the present invention. In other words, while the method for regenerating the apheresis column (4) according to the present invention is being performed, the continuously collected plasma is mixed with cellular components via the bypass line (12), bypasses the apheresis column (4), and is supplied to the patient. During regeneration, the apheresis column is thus disconnected from the blood collection and supply or blood circulation. While the plasma is being redirected through the bypass line (12), the apheresis column (4) is being regenerated, usually with reduced volume. This ensures that the continuously withdrawn blood is returned to the patient without interruption, thus not burdening the patient's circulation.

[0318] Therefore, as used herein, “in operation” does not mean that continuous plasma collection must be interrupted in order to carry out the method for regenerating the apheresis column (4) of the present invention. Furthermore, it does not mean that CRP removal is performed during the regeneration of the apheresis column.

[0319] Therefore, in both the method described above and the method broadly disclosed herein, the introduction of the regeneration solution preferably involves the introduction of one regeneration solution or the sequential introduction of several regeneration solutions.

[0320] It is quite obvious to those skilled in the art that the initial flushing of the adsorbent or the entire system must have already been performed before carrying out the method according to the present invention. This relates to pre-filling the entire tubing system. For this reason, under certain circumstances, there may be further connections in the system, which would allow the entire system to flow. After the patient has been disconnected from the tubing system, the adsorbent may be stored so that it can be used again for further treatment of the same patient.

[0321] In other words, the present invention also relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP in an apheresis apparatus (1) according to the present invention, the method enabling regeneration in operation and characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12). (B) At least one regeneration solution is introduced from a liquid container into the plasma line (8A) via the regeneration line (14), or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) The flow of liquid coming out of the apheresis column (4) is redirected from the plasma line (8B) to the waste line (13). (D) Stop introducing the regeneration solution. (E) Begin introducing the neutralizing solution. (F) The separated plasma is transferred from the plasma line (8A) to the apheresis column (4), and the introduction of the neutralization solution is stopped. (G) Close the waste line (13).

[0322] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0323] As used herein, the term “conversion” refers to changing the direction of the flow of the relevant fluid. During processing mode, separated plasma flows through the plasma line (8A) to the apheresis column (4). After exiting the apheresis column (4), the decontaminated plasma flows through the plasma line (8B) to the venous line (6).

[0324] By "reversing" the direction of the flow of the separated plasma in step (A), the separated plasma no longer flows through the apheresis column (4) and is redirected to the bypass line (12), thereby bypassing the apheresis column (4).

[0325] The term “introduction” as used herein in relation to step (B) may be understood, depending on the embodiment of the present invention, to mean supplying at least one regeneration solution to a plasma line (8A) or to an apheresis column (4) (using or operating a hose clamp, control element, valve and / or hose pump).

[0326] By "reversing" the direction of the liquid flow coming out of the apheresis column (4) in step (C), the liquid coming out thereafter no longer flows into the plasma line (8B) but directly into the waste line (13). According to the present invention, in order to minimize the volume of regeneration solution required for the regeneration of the apheresis column (4), it is preferable that the waste line (13) branches off directly from, immediately after, or behind the apheresis column (4). In the spirit of the present invention, the waste line (13) can also branch off from the plasma line (8B), thereby eliminating the need to branch off directly from the apheresis column.

[0327] By "reversing" the direction of the flow of the separated plasma in step (D), the separated plasma thereafter returns through the apheresis column (4) and does not flow into the bypass line (12). In a particular embodiment, the bypass line (12) is provided with a pump, and after the reversal in step (D), the plasma present in the bypass line (12) is pumped out to the plasma line (8B) and then to the venous line (6). Here, preferably, the plasma present in the bypass line is discharged from the regeneration line (14) with an NaCl solution. Preferably, this solution is a 0.9% NaCl solution. A separate liquid container can be connected to the bypass line (12), and it is conceivable that this container can supply the NaCl solution for discharge.

[0328] Therefore, a method for regenerating the apheresis column (4) that performs affinity chromatographic removal of CRP within the apheresis apparatus (1) is particularly preferred, and this method is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (E) Stop introducing the regeneration solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) The introduction of the rinse solution is stopped, thereby halting the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), and thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13).

[0329] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0330] Alternatively, a method for regenerating the apheresis column (4) that performs affinity chromatographic removal of CRP within the apheresis apparatus (1) is particularly preferred, and this method is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the introduction of the separated plasma from the plasma line (8A) into the apheresis column (4). (B) Start introducing the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E) Stop introducing the regeneration solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Close the waste disposal line (13). (G) The introduction of the rinse solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0331] A preferred step (F) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0332] In both of the methods described above, a flushing solution is used in addition to the regeneration solution. The flushing solution is preferably physiologically suitable and, firstly, serves to drain plasma from point P2 through the plasma line (8A), from the apheresis column (4), and from the plasma line (8B) to point P4. The flushing solution has little to no function in regenerating the apheresis column (4). The regeneration solution is introduced to regenerate the apheresis column (4) only when the plasma has been almost completely drained from the portion of the apheresis apparatus (1) that should be flowed through with the regeneration solution. After regeneration has occurred, the flushing solution is first passed through the portion of the apheresis apparatus (1) that was flowed through with the regeneration solution (i.e., from point P2 through the apheresis column (4) to point P4 in the direction of flow) until the regeneration solution is completely drained through the waste line (13). Only after this is done should the bypass line (12) be closed and the plasma be passed back through the apheresis column (4). In the two methods described above, steps (C) and (D) are interchangeable; that is, they can be performed in any order, simultaneously, or combined into a single step. However, it is preferable to perform step (D) before step (C).

[0333] In this method, the rinsing solution is preferably a physiological NaCl solution or a PBS solution, and the regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0334] Therefore, a method for regenerating the apheresis column (4) that performs affinity chromatographic removal of CRP within the apheresis apparatus (1) is particularly preferred, and this method is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (E) Stop introducing the regeneration solution and proceed to introduce the neutralizing solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop introducing the neutralizing solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (G) The introduction of the rinse solution is stopped, and the transfer of the separated plasma from the plasma line (8A) to the bypass line (12) is stopped, thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (H) Close the waste line (13).

[0335] A preferred step (H) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0336] Alternatively, a method for regenerating the apheresis column (4) that performs affinity chromatographic removal of CRP within the apheresis apparatus (1) is particularly preferred, and this method is characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E) Stop introducing the regeneration solution and proceed to introduce the neutralizing solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop introducing the neutralizing solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (G) Close the waste line (13). (H) The introduction of the rinse solution is stopped, thereby halting the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), and thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0337] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0338] In the two methods described above, steps (C) and (D) are interchangeable; that is, they can be performed in any order, simultaneously, or combined into a single step. However, it is preferable to perform step (D) before step (C).

[0339] A preferred embodiment of the method according to the present invention allows the method to be carried out more efficiently without plasma loss. Since the separated plasma is converted simultaneously and the flushing solution is introduced into the apheresis column (4) in parallel, there is no plasma loss, or significant loss. Furthermore, an effect of the preferred embodiment is that mixing of the regeneration solution and plasma can be completely avoided. This ensures that the regeneration solution does not enter the patient's body, while at the same time, the patient does not experience plasma loss.

[0340] This is ensured by performing steps (B) through (E) in the correct order. Plasma dilution will occur, but if any, it will only occur when passing through the rinsing solution. On the other hand, mixing of plasma with the regeneration solution is completely avoided.

[0341] The volume of the rinsing solution in step (B) is preferably 3 to 4 times the volume of the substrate in the apheresis column (4).

[0342] At a minimum, the volume of the rinse solution used in step (B) is equivalent to the sum of the volume of the plasma line (8A) from point P2 to the apheresis column (4), the volume of the substrate in the apheresis column (4), and the volume of the plasma line (8B) from the apheresis column (4) to point P4.

[0343] The volume of the regeneration solution in step (C) is preferably 2 to 100 times the volume of the substrate in the apheresis column (4).

[0344] The volume of the rinsing solution in step (E) is preferably 2 to 4 times the volume of the substrate in the apheresis column (4).

[0345] At a minimum, the volume of the rinse solution in step (E) corresponds to the sum of the volume of the plasma line (8A) from point P2 to the apheresis column (4), the volume of the substrate in the apheresis column (4), and the volume of the plasma line (8B) from the apheresis column (4) to point P4.

[0346] According to this more preferred embodiment, plasma dilution is largely prevented, and mixing with the regeneration solution is completely avoided. Users do not encounter anything that is too complex when using the apheresis device (1). In another embodiment, each step of the method can be operated manually without the user finding it too complex, or even being excessively complex.

[0347] In this specification, "apheresis column substrate volume" refers to the volume of the solid phase inside the column, which consists of a substrate material and a compound that binds to it and specifically binds CRP. To distinguish this, there is the "apheresis column dead space," that is, the space inside the column where the mobile phase (e.g., plasma) can be used. The "apheresis column dead space" is the difference between the volume enclosed by the apheresis column housing and the volume occupied by the expanded substrate (i.e., the "apheresis column substrate volume").

[0348] A further aspect of the present invention relates to a method for regenerating an apheresis column (4') that performs affinity chromatographic removal of CRP while the second apheresis column (4'') is operating in an apheresis apparatus (II), and comprises the following steps. (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing the regeneration solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). At least one regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) The flow of liquid coming out of the apheresis column (4'') is redirected from the bypass line portion (12'') of the bypass line (12) to the waste line (13''). (D) Start introducing the neutralization solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E) Stop introducing the neutralizing solution. (F) Start introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12), and stop introducing the separated plasma into the apheresis column (4') via the plasma line (8A). (G) Close the waste line (13'') and begin diverting the flow of liquid from the apheresis column (4') from the plasma line (8B) to the waste line (13').

[0349] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass portion (12') of the bypass line (12).

[0350] A preferred step (F) is to initiate the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12) to direct the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4') via the plasma line (8A).

[0351] The term "operating" as used here means that it is not necessary to stop the blood collection and supply, or the operation of the blood component separator, in order to regenerate the apheresis column (4') or the method for regenerating the apheresis column (4'') according to the present invention. As a result, the continuously extracted blood is returned to the patient without interruption, so there is no burden on the circulation within the patient's body.

[0352] In other words, in one embodiment, the present invention relates to a method for regenerating an apheresis column (4') that performs affinity chromatographic removal of CRP during ongoing operation of a second apheresis column (4'') in an apheresis apparatus (II), comprising the following steps: (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) At least one regeneration solution is introduced into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). At least one regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (C) The flow of liquid coming out of the apheresis column (4'') is redirected from the bypass line (12'') of the bypass line (12) to the waste line (13''). (D) Start introducing the neutralization solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E) Stop introducing the neutralizing solution. (F) The separated plasma is introduced into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12), and the introduction of the separated plasma into the apheresis column (4') via the plasma line (8A) is stopped. (G) Close the waste line (13'') to redirect the flow of liquid from the apheresis column (4') from the plasma line (8B) to the waste line (13').

[0353] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A) to remove CRP, and then directing the plasma to the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass portion (12') of the bypass line (12).

[0354] A preferred step (F) is to introduce the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12) to remove CRP, thereby directing the plasma to the venous line (6) and stopping the introduction of the separated plasma into the apheresis column (4') via the plasma line (8A).

[0355] Furthermore, the present invention relates to a method for regenerating two apheresis columns (4',4'') that perform affinity chromatographic removal of CRP within an apheresis apparatus (II), the method enabling regeneration during operation and characterized by the following steps. (A) The process begins by passing a plasma stream through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing the rinse solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') via the bypass line portion (12'') of the bypass line (12). (D) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (E) Stop introducing the regeneration solution and proceed to introduce the rinse solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (F) The rinse solution is introduced into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (G) Close the waste line (13''). (H) Start switching the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (J) Stop introducing the regeneration solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0356] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0357] A preferred step (G) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0358] In the two methods described above, a flushing solution is used in addition to the regeneration solution. The flushing solution is preferably physiologically acceptable and, firstly, serves to drain plasma from point P2 to the plasma line (8A) or the bypass line portion (12') of the bypass line (12), from the apheresis column (4') or apheresis column (4''), from the bypass line portion (12'') of the bypass line (12) up to point P3, and from the plasma line (8B) up to point P4. The flushing solution has little to no effect on regenerating the apheresis column (4') or apheresis column (4''). Therefore, by using the flushing solution, plasma loss is minimized or completely prevented. The regeneration solution is introduced to regenerate the apheresis column (4') or apheresis column (4'') only when the plasma has been almost completely drained from the portion of the apheresis device (II) that should be flushed with the regeneration solution. After regeneration is performed, the rinse solution is first passed through the portion of the apheresis apparatus (II) that was previously run over by the regeneration solution (i.e., from point P2 through the apheresis column (4'') to point P8, or through the apheresis column (4') to point P4) until the regeneration solution is completely discharged through the waste line (13',13'').

[0359] In this method, the rinsing solution is preferably saline solution, physiological saline solution, PBS solution (phosphate-buffered saline), or a combination of saline solution and PBS solution used continuously or simultaneously, and the regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0360] Furthermore, the present invention relates to a method for regenerating two apheresis columns (4',4'') that perform affinity chromatographic removal of CRP within an apheresis apparatus (II), the method enabling regeneration during operation and characterized by the following steps. (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing the rinse solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') via the bypass line portion (12'') of the bypass line (12). (D) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). The regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution. (E) Stop introducing the regeneration solution and proceed to introduce the neutralizing solution either through at least one regeneration line (14) into the bypass line portion (12') of the bypass line (12) or directly into the apheresis column (4''). (F) Stop introducing the neutralizing solution and proceed to introduce the neutralizing solution either through at least one regeneration line (14) to the bypass line portion (12') of the bypass line (12) or directly into the apheresis column (4''). (G) The rinse solution is introduced into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (H) Close the waste line (13''). (I) Start diverting the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce the regeneration solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (J) Stop introducing the regeneration solution and proceed to introduce the rinse solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0361] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0362] A preferred step (H) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0363] In both of the methods described above, steps (C) and (D) are interchangeable; that is, they can be performed in any order, simultaneously, or combined into a single step. However, it is preferable to perform step (D) before step (C).

[0364] A preferred embodiment of the method according to the present invention allows the method to be carried out more efficiently without plasma loss. Since the separated plasma is converted simultaneously and the flushing solution is introduced into the apheresis column (4'') in parallel, there is no plasma loss, or significant loss. Furthermore, an effect of the preferred embodiment is that mixing of the regeneration solution and plasma can be completely avoided. This ensures that the regeneration solution does not enter the patient's body, while at the same time, the patient does not experience plasma loss.

[0365] This is ensured by performing steps (B) through (E) in the correct order. Plasma dilution will occur, but if any, it will only occur when passing through the rinsing solution. On the other hand, mixing of plasma with the regeneration solution is completely avoided.

[0366] The volume of the rinsing solution in step (B) is preferably 3 to 4 times the volume of the substrate in the apheresis column (4''). At a minimum, the volume of the rinsing solution in step (B) is equivalent to the sum of the volume of the bypass line portion (12') of the bypass line (12) from point P2 to the apheresis column (4''), the volume of the substrate in the apheresis column (4''), and the volume of the bypass line portion (12') of the bypass line (12) from the apheresis column (4'') to point (P3).

[0367] The volume of the rinsing solution in step (F) is preferably 3 to 4 times the volume of the substrate in the apheresis column (4'). At a minimum, the volume of the rinsing solution in step (B) is equivalent to the sum of the volume of the plasma line (8A') from point (P2) to the apheresis column (4'), the volume of the substrate in the apheresis column (4'), and the volume of the plasma line (8B) from the apheresis column to point (P4).

[0368] The volume of the regeneration solution in step (D) is preferably 2 to 100 times the volume of the substrate in the apheresis column (4'').

[0369] The volume of the regeneration solution in step (I) is preferably 2 to 100 times the volume of the substrate in the apheresis column (4').

[0370] The volume of the rinsing solution in step (E) is preferably 2 to 4 times the volume of the substrate in the apheresis column (4'').

[0371] At a minimum, the volume of the rinse solution in step (E) corresponds to the sum of the volume of the bypass line portion (12') of the bypass line (12) from point P2 to the apheresis column (4''), the volume of the substrate in the apheresis column (4''), and the volume of the bypass line portion (12') of the bypass line (12) from the apheresis column (4') to point P3.

[0372] The volume of the rinsing solution in step (J) is preferably 2 to 4 times the volume of the substrate in the apheresis column (4').

[0373] At a minimum, the volume of the rinse solution in step (E) corresponds to the sum of the volume of the plasma line (8A) from point P2 to the apheresis column (4'), the volume of the substrate in the apheresis column (4'), and the volume of the plasma line (8B) from the apheresis column (4') to point P4.

[0374] In a preferred specific embodiment, the rinsing solution is saline solution, physiological saline solution, PBS solution (phosphate-buffered saline), or a combination of saline solution and PBS solution used sequentially or simultaneously, and the regeneration solution is an alkali hydroxide solution, preferably a sodium hydroxide solution.

[0375] Furthermore, a preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13).

[0376] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0377] Alternatively, a preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Close the waste disposal line (13). (G) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0378] A preferred step (F) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0379] Alternatively, a preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (G) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (H) Close the waste line (13).

[0380] A preferred step (H) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0381] Alternatively, a preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (G) Close the waste line (13). (H) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0382] A preferred step (G) is to close the waste line (13) and direct the flow of liquid coming out of the apheresis column (4) towards the venous line (6).

[0383] In the four methods described above, steps (C) and (D) are interchangeable; that is, they can be performed in any order, simultaneously, or combined into a single step.

[0384] Preferably, the regeneration method according to the present invention is carried out by first using a rinsing solution such as saline or physiological saline to drain the plasma from the apheresis column (4) and sending it back into the patient's body to a point where almost only saline is returned. Only after this, saline is introduced into the waste line (13), and a regeneration solution such as an alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the plasma line (8A) behind the bypass line (12) that drains saline in the direction of flow to regenerate the apheresis column (4), and then completely introduced into the waste line (13) for disposal. After regenerating the apheresis column (4) with several volumes of regeneration solution for the apheresis column, a rinsing solution such as saline or physiological saline is introduced again until the regeneration solution is completely drained from the apheresis device (1) and then disposed of. Only after this are the waste line (13) closed and the flushing solution returned to the patient, and the bypass line (12) closed and the plasma reintroduced into the apheresis column (4) through the plasma line (8A), but these steps are performed simultaneously or continuously. The order of each step can be changed.

[0385] A more preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps. (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E1) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E2) Stop introducing saline solution and proceed to introduce PBS solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E3) Stop introducing the PBS solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13).

[0386] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0387] Another preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP in an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E1) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E2) Stop introducing saline solution and proceed to introduce PBS solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E3) Stop introducing the PBS solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Close the waste disposal line (13). (G) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0388] A preferred step (F) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0389] Another preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP within an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E1) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E2) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E3) Stop introducing saline solution and proceed to introduce PBS solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E4) Stop introducing the PBS solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4). (G) Close the waste line (13).

[0390] A preferred step (G) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0391] Another preferred particular embodiment relates to a method for regenerating an apheresis column (4) for affinity chromatographic removal of CRP in an apheresis apparatus (1), the method characterized by the following steps: (A) The separated plasma is switched from the plasma line (8A) to the bypass line (12), thereby stopping the flow of the separated plasma from the plasma line (8A) to the apheresis column (4). (B) Start introducing saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (C) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (D) Start diverting the flow of liquid coming out of the apheresis column (4) from the plasma line (8B) to the waste line (13). (E1) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E2) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E3) Stop introducing saline solution and proceed to introduce PBS solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (E4) Stop introducing the PBS solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4). (F) Close the waste disposal line (13). (G) Stop the introduction of saline solution to stop the transfer of the separated plasma from the plasma line (8A) to the bypass line (12), thereby directing the separated plasma from the plasma line (8A) to the apheresis column (4).

[0392] A preferred step (F) is to close the waste line (13) and send the liquid flow from the apheresis column (4) to the venous line (6).

[0393] In the four methods described above, steps (C) and (D) are interchangeable; that is, they can be performed in any order, simultaneously, or combined into a single step.

[0394] Therefore, the present invention relates to a method for regenerating two apheresis columns (4',4'') that perform affinity chromatographic removal of CRP in an apheresis apparatus (II), the method enables regeneration during operation and is characterized by the following steps. (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') via the bypass line portion (12'') of the bypass line (12). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (F) Start introducing saline solution into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (G) Close the waste line (13''). (H) Start switching the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (J) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0395] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and then directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0396] A preferred step (G) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0397] Therefore, the present invention relates to a method for regenerating two apheresis columns (4',4'') that perform affinity chromatographic removal of CRP in an apheresis apparatus (II), the method enables regeneration during operation and is characterized by the following steps. (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') via the bypass line portion (12'') of the bypass line (12). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (F) Start introducing saline solution into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (G) Close the waste line (13''). (H) Start switching the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (13) or directly into the apheresis column (4'). (J) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (K) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0398] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0399] A preferred step (G) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0400] Preferably, the regeneration method according to the present invention is carried out by first using a rinsing solution such as saline or physiological saline to drain the plasma from the apheresis column (4'') until almost only saline solution has passed through. Only after this, preferably, saline solution is introduced into the waste line (13''), and a regeneration solution such as an alkali hydroxide solution, preferably a sodium hydroxide solution, is introduced into the bypass line portion (12') of the bypass line (12) at point P2 in the direction of flow where saline solution is drained, to regenerate the apheresis column (4''), which is then completely introduced into the waste line (13'') and discarded. After regenerating the apheresis column (4'') with several volumes of regeneration solution for the apheresis column, a rinsing solution such as saline or physiological saline solution is introduced again until the regeneration solution is completely drained from the apheresis apparatus (II) and then discarded. Only after this are the plasma line (8A) closed and the flushing solution returned to the patient, and the bypass line (12) closed and the plasma reintroduced into the apheresis column (4'') through the bypass line portion (12') of the bypass line (12), but these steps are performed simultaneously or continuously.

[0401] A more preferred particular embodiment relates to a method for regenerating two apheresis columns (4',4'') for affinity chromatographic removal of CRP within an apheresis apparatus (II), the method enabling regeneration in operation and characterized by the following steps. (A) The process begins by passing a plasma stream through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') via the bypass line portion (12'') of the bypass line (12). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E1) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E2) Stop introducing saline solution and proceed to introduce PBS solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E3) Stop introducing the PBS solution and proceed to introduce saline into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (F) Start introducing saline solution into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (G) Close the waste line (13''). (H) Start switching the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (J) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0402] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and then directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0403] A preferred step (G) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0404] A more preferred particular embodiment relates to a method for regenerating two apheresis columns (4',4'') for affinity chromatographic removal of CRP within an apheresis apparatus (II), the method enabling regeneration in operation and characterized by the following steps. (A) The process begins by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), and finally stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (B) Start introducing saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (C) Start introducing the liquid flow from the apheresis column (4'') into the waste line (13'') from the bypass line portion (12') of the bypass line (12). (D) Stop introducing saline solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E1) Stop introducing the alkali hydroxide solution, preferably sodium hydroxide solution, and proceed to introduce saline solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E2) Stop introducing saline solution and proceed to introduce PBS solution into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (E3) Stop introducing the PBS solution and proceed to introduce saline into the bypass line portion (12') of the bypass line (12) via at least one regeneration line (14), or directly into the apheresis column (4''). (F) Start introducing saline solution into the plasma line (8A) via the apheresis column (4'), thereby introducing the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12). (G) Close the waste line (13''). (H) Start switching the flow of liquid coming out of the apheresis column (4') from the plasma line (8B) to the waste line (13'). (I) Stop introducing the rinse solution and proceed to introduce an alkali hydroxide solution, preferably a sodium hydroxide solution, into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (J) Stop introducing the alkali hydroxide solution, preferably the sodium hydroxide solution, and proceed to introduce the citrate solution into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4'). (K) Stop introducing the citrate solution and proceed to introduce saline into the plasma line (8A) via at least one regeneration line (14) or directly into the apheresis column (4').

[0405] A preferred step (A) is to begin by passing the plasma flow through the apheresis column (4''), then introducing the separated plasma into the apheresis column (4') via the plasma line (8A), directing the plasma after CRP removal towards the venous line (6), thereby stopping the introduction of the separated plasma into the apheresis column (4'') via the bypass line portion (12') of the bypass line (12).

[0406] A preferred step (G) is to close the waste line (13'') and send the liquid flow from the apheresis column (4'') to the venous line (6).

[0407] In all of the above methods, the components of the apheresis apparatus into which the alkali hydroxide solution is introduced are resistant to the alkali hydroxide solution used, particularly the sodium hydroxide solution used. [Brief explanation of the drawing]

[0408] [Figure 1]Figure 1 is a schematic diagram of an embodiment of an apheresis apparatus (1) for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4) for affinity chromatographic removal of CRP from the blood. From here, a plasma line (8B) leads to a node (P1). Another line, a cell line (9), leads from the blood component separator (7) to the node (P1). A venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) for connecting a liquid container (F1), which flows into the arterial line (5) or directly into the blood component separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at node (P2) and flows into the plasma line (8B) at node (P6). The waste line (13) branches off from the plasma line (8B) at node (P4). The regeneration line (14), which connects to the liquid container (F2), flows into the plasma line (8A) in the region between node (P2) and the apheresis column (4). Alternatively, the regeneration line (14) can lead directly to the apheresis column (4) (not shown). [Figure 2]Figure 2 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow, and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4) for affinity chromatographic removal of CRP from the blood. From here, a plasma line (8B) leads to a node (P1). Another line, a cell line (9), leads from the blood component separator (7) to the node (P1). A venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connecting line (11) that either flows into the arterial line (5) or directly into the blood component separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at node (P2) and flows into the plasma line (8B) at node (P6). The waste line (13) branches off from the plasma line (8B) at node (P6). The regeneration line (14) also flows into the plasma line (8A) at node (P2). [Figure 3]Figure 3 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow, and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4) for affinity chromatographic removal of CRP from the blood. From here, a plasma line (8B) leads to a node (P1). Another line, a cell line (9), leads from the blood component separator (7) to the node (P1). A venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) that either flows into the arterial line (5) or leads directly to the blood component separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at node (P2) and flows into the cell line (9) at node (P3). The waste line (13) branches off from the plasma line (8B) at node (P1). The regeneration line (14) branches off from the connection line (11) at point (P5) and flows into the plasma line (8A) at node (P2). [Figure 4]Figure 4 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4) for affinity chromatographic removal of CRP from the blood. From here, a plasma line (8B) leads to a node (P1). Another line, a cell line (9), leads from the blood component separator (7) to the node (P1). A venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11') that flows into the arterial line (5) but could also flow directly into the blood component separator (7), and similarly, there is a connection line (11'') that flows into the blood component separator (7) but could also flow into the arterial line (5). The bypass line (12) branches off from the plasma line (8A) at node (P2) and flows into the plasma line (8B) at node (P6). The waste line (13) branches off from the plasma line (8B) at node (P6). Also, both the first regeneration line (14'), which separates from the connection line (11') at point (P5'), and the second regeneration line (14''), which separates from the connection line (11'') at point (P5''), flow into the plasma line (8A) at node (P2). [Figure 5]Figure 5 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow, and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4) for affinity chromatographic removal of CRP from the blood. From here, a plasma line (8B) leads to a node (P1). Another line, a cell line (9), leads from the blood component separator (7) to the node (P1). A venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) for connecting a liquid container (F1), which flows into the arterial line (5) or directly into the blood component separator (7) (dotted line). The bypass line (12) branches off from the plasma line (8A) at node (P2) and flows into the plasma line (8B) at node (P6). The waste line (13) branches off from the plasma line (8B) at node (P6). The regeneration line (14) branches off from the connection line (11) at point (P5) and flows into the plasma line (8A) at node (P2). For clarity, the central processing unit, which is part of the apheresis apparatus according to the present invention, is not shown in the diagram. The regeneration line (14) has an additional connection to a liquid container (F2), and since this connection is located behind the blood component separator (7) in the direction of flow, the liquid from this additional liquid container (F2) cannot be supplied to the blood component separator (7), nor can it be supplied into the arterial line (5) located in front of the blood component separator (7), but can only be supplied to the plasma line (8A) located behind the blood component separator (7) in the direction of flow, or directly to the apheresis column (4). [Figure 6]Figure 6 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4') for affinity chromatographic removal of CRP. The bypass line portion (12') of a bypass line (12) branching from the plasma line (8A) leads to an apheresis column (4'') for affinity chromatographic removal of CRP from blood. From the apheresis column (4''), the bypass line portion (12') of the bypass line (12) for plasma after CRP removal leads to a node (P1), and from the apheresis column (4'), a plasma line (8B) for plasma after CRP removal leads to a node (P1). Another line, the cell line (9), leads from the blood component separator (7) to the node (P1). The venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) for connecting the liquid container (F1), which either flows into the arterial line (5) or goes directly to the blood component separator (7) (dotted line). The bypass line portion (12') of the bypass line (12) and the plasma line (8A) branch off at the node (P2), and the bypass line portion (12'') of the bypass line (12) and the plasma line (8B) merge at the node (P6). The waste line (13'') branches off from the bypass line portion (12') of the bypass line (12) at the node (P8), and the waste line (13') branches off from the plasma line (8B) at the node (P4). Furthermore, the regeneration line (14) connected to the liquid container (F2) flows into the extracorporeal circulation system (2) at node (P2). [Figure 7]Figure 7 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4') for affinity chromatographic removal of CRP. The bypass line portion (12') of a bypass line (12) branching from the plasma line (8A) leads to an apheresis column (4'') for affinity chromatographic removal of CRP from blood. From the apheresis column (4''), the bypass line portion (12') of the bypass line (12) for plasma after CRP removal leads to a node (P1), and from the apheresis column (4'), a plasma line (8B) for plasma after CRP removal leads to a node (P1). Another line, the cell line (9), leads from the blood component separator (7) to the node (P1). The venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) for connecting the liquid container (F1), which either flows into the arterial line (5) or goes directly to the blood component separator (7) (dotted line). The bypass line portion (12') of the bypass line (12) and the plasma line (8A) branch off at the node (P2), and the bypass line portion (12'') of the bypass line (12) and the plasma line (8B) merge at the node (P6). The waste line (13'') branches off from the bypass line portion (12') of the bypass line (12) at the node (P8), and the waste line (13') branches off from the plasma line (8B) at the node (P4). Additionally, the regeneration line (14) leads to node (P7) and connects to the liquid container (F2). Two lines (15', 15'') branch at node (P7). Line (15') flows into the extracorporeal circulation system (2) at node (P2), and line (15'') flows into the region between node (P2) and the apheresis column (4''). [Figure 8]Figure 8 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4') for affinity chromatographic removal of CRP. The bypass line portion (12') of a bypass line (12) branching from the plasma line (8A) leads to an apheresis column (4'') for affinity chromatographic removal of CRP from blood. From the apheresis column (4''), the bypass line portion (12') of the bypass line (12) for plasma after CRP removal leads to a node (P1), and from the apheresis column (4'), a plasma line (8B) for plasma after CRP removal leads to a node (P1). Another line, the cell line (9), leads from the blood component separator (7) to the node (P1). The venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) that connects to the liquid container (F1), which either flows into the arterial line (5) or directly to the blood component separator (7) (dotted line). The bypass line portion (12') of the bypass line (12) and the plasma line (8A) branch off at the node (P2), and at the node (P6), the bypass line portion (12'') of the bypass line (12) and the plasma line (8B'') merge. The waste line (13) branches off from the extracorporeal circulation system (2) at the node (P6). Also, the regeneration line (14) that connects to the liquid container (F2) flows into the extracorporeal circulation system (2) at the node (P2). [Figure 9]Figure 9 is a schematic diagram of an embodiment of an apheresis apparatus for extracorporeal removal of CRP from blood according to the present invention. An arterial line (5) has means (3) (e.g., a peristaltic pump) for generating and regulating blood flow and leads the patient's blood to a blood component separator (7, e.g., a centrifugal blood component separator). From here, a plasma line (8A) leads to an apheresis column (4') for affinity chromatographic removal of CRP. The bypass line portion (12') of a bypass line (12) branching from the plasma line (8A) leads to an apheresis column (4'') for affinity chromatographic removal of CRP from blood. From the apheresis column (4''), the bypass line portion (12') of the bypass line (12) for plasma after CRP removal leads to a node (P1), and from the apheresis column (4'), a plasma line (8B) for plasma after CRP removal leads to a node (P1). Another line, the cell line (9), leads from the blood component separator (7) to the node (P1). The venous line (6) returns the processed blood to the patient and also branches off from the node (P1). Furthermore, there is a connection line (11) for connecting the liquid container (F1), which either flows into the arterial line (5) or goes directly to the blood component separator (7) (dotted line). The bypass line portion (12') of the bypass line (12) and the plasma line (8A) branch off at the node (P2), and at the node (P6), the bypass line portion (12'') of the bypass line (12) and the plasma line (8B'') merge. The waste line (13) branches off from the extracorporeal circulation system (2) at the node (P6). The waste line (13) branches off from the extracorporeal circulation system (2) at the node (P6). Furthermore, the regeneration line (14) connected to the liquid container (F2) flows into the extracorporeal circulation system (2) at node (P2). [Figure 10]Figure 10 is a schematic diagram of an embodimen...

Claims

1. The use of an alkali hydroxide solution for regenerating an apheresis column, wherein the apheresis column is for selectively removing CRP from blood or plasma by affinity chromatography. The apheresis column comprises a substrate for removing CRP by affinity chromatography, and the substrate comprises a substrate material to which a ligand having the property of specifically binding to CRP is bound. The ligand bound to the substrate material is selected from phosphocholine or phosphoethanolamine, or The apheresis column comprises a substrate material functionalized with at least one ω-phosphonooxyalkylammonium group and / or at least one ω-ammonium alkoxy-hydroxy-phosphoryloxy group, CRP binds to the substrate of the apheresis column with a higher affinity than other substances present in the blood. The alkali hydroxide solution is a lithium hydroxide solution, a sodium hydroxide solution, a potassium hydroxide solution, or a mixture of these solutions. The concentration of alkali hydroxide in the alkali hydroxide solution is in the range of 0.01 mol / l to 1 mol / l. Use of an alkali hydroxide solution.

2. The use of the alkali hydroxide solution according to claim 1, wherein the alkali hydroxide solution is a sodium hydroxide solution.

3. The use of the alkali hydroxide solution according to claim 1 or 2, wherein the alkali hydroxide concentration of the alkali hydroxide solution is in the range of 0.04 mol / l to 0.4 mol / l.

4. The use of the alkali hydroxide solution according to any one of claims 1 to 3, wherein the alkali hydroxide solution has a pH in the range of 12 to 14.

5. Use of the alkali hydroxide solution according to any one of claims 1 to 4, wherein the alkali hydroxide solution has a pH in the range of 12 to 13.

7.

6. The use of the alkali hydroxide solution according to any one of claims 1 to 5, wherein the regeneration is performed during apheresis treatment in which CRP is removed from the body from blood or plasma, and the apheresis column is not connected to an extracorporeal circulation system during the regeneration.

7. The use of the alkali hydroxide solution according to any one of claims 1 to 6, wherein the patient's plasma is passed through the apheresis column before the regeneration is performed.

8. The use of the alkali hydroxide solution according to any one of claims 1 to 7, wherein the apheresis column contains CRP.

9. The use of the alkali hydroxide solution according to any one of claims 1 to 8, wherein the CRP bound to the apheresis column is eluted.

10. The use of the alkali hydroxide solution according to any one of claims 1 to 9, wherein the bound CRP is eluted and the apheresis column is simultaneously restored to a state ready for therapeutic use.

11. The apheresis column is saturated with CRP, using the alkali hydroxide solution according to any one of claims 1 to 10.

12. The use of an alkali hydroxide solution according to any one of claims 1 to 11, wherein the apheresis column comprises a substrate material functionalized with at least one ω-phosphonooxyalkylammonium group and / or at least one ω-ammonium alkoxy-hydroxyphosphoryloxy group.

13. The aforementioned at least one ω-phosphonooxyalkylammonium group corresponds to a group represented by the following general formula (I): 【Chemistry 1】 Here, n is selected from 2 and 3. R １ and R ２ are, independently of each other, -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ selected from, and R １ and R ２ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the following structural formulas, 【Chemistry 2】 Alternatively, the use of the alkali hydroxide solution according to claim 12, wherein one or more hydrogen atoms of R1 and R2 are substituted with one or more fluorine atoms.

14. The aforementioned at least one ω-ammonium alkoxy-hydroxyphosphoryloxy group corresponds to a group represented by the following general formula (II): 【Transformation 3】 Here, n is selected from 2 and 3. R １ , R ２ and R ３ These are -H and -CH, which are independent of each other. ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ Selected from, and also R １ and R ２ Together with the nitrogen atoms to which they are bonded, they form a heterocycle selected from the following structural formulas. 【Chemistry 4】 R ３ is -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ Use of the alkali hydroxide solution according to claim 12, wherein selected from, or one or more hydrogen atoms of R1, R2, and R3 are substituted with one or more fluorine atoms.

15. The use of the alkali hydroxide solution according to any one of claims 1 to 14, wherein the apheresis column contains agarose.

16. The use of the alkali hydroxide solution according to any one of claims 1 to 15, wherein the apheresis column contains DNA and / or RNA.

17. A method for regenerating an apheresis column for selectively removing CRP from blood or plasma by affinity chromatography, (I) The process includes a step of introducing an alkali hydroxide solution into the apheresis column to regenerate the apheresis column, The apheresis column comprises a substrate for removing CRP by affinity chromatography, and the substrate comprises a substrate material to which a ligand having the property of specifically binding to CRP is bound. The ligand bound to the substrate material is selected from phosphocholine or phosphoethanolamine, or The apheresis column comprises a substrate material functionalized with at least one ω-phosphonooxyalkylammonium group and / or at least one ω-ammonium alkoxy-hydroxy-phosphoryloxy group, CRP binds to the substrate of the apheresis column with a higher affinity than other substances present in the blood. The alkali hydroxide solution is a lithium hydroxide solution, a sodium hydroxide solution, a potassium hydroxide solution, or a mixture of these solutions. The concentration of alkali hydroxide in the alkali hydroxide solution is in the range of 0.01 mol / l to 1 mol / l. method.

18. A method for regenerating an apheresis column for affinity chromatographic removal of CRP, (I) Introduce an alkali hydroxide solution into the apheresis column to regenerate the apheresis column. (II) Introduce the neutralizing solution. The method according to claim 17, comprising the steps.

19. A method for regenerating an apheresis column for affinity chromatographic removal of CRP, (I') Introduce the rinse solution into the apheresis column. (I) An alkali hydroxide solution is introduced into the apheresis column to regenerate the apheresis column. (II') After step (I), the introduction of the alkali hydroxide solution is stopped. (II) Introduce the neutralizing solution. The method according to claim 17 or 18, comprising the steps.

20. A method for regenerating an apheresis column for affinity chromatographic removal of CRP, wherein the alkali hydroxide solution is a sodium hydroxide solution, according to any one of claims 17 to 19.

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