JP2009240609A - Liquid component collection device and body fluid component collection method using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid component collection device which simplifies operation to prevent false operation, does not require addition of a flow path switch member even when used by adding the kind of liquid, and suppresses complication of the operation. <P>SOLUTION: The liquid component collection device is provided with: a suction part for selectively sucking a specific target component in the liquid; a flow path switch mechanism for linking to a downstream side of the suction part and switching flow exits in two directions; a liquid waste collection part which is joined to one of the flow exits of the flow path switch mechanism to collect liquid waste; and a component collection part which is joined to the other flow exit of the flow path switch mechanism and collects the target component sucked by the suction part. In the liquid component collection device, a plurality of liquid dischargers for discharging a plurality of liquids respectively to an upstream side of the suction part and a flow path opening/closing mechanism which is selectively removaly/attachably joined to one of the plurality of liquid dischargers and opens/closes a flow path of the discharged liquids. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a device for recovering a specific component in a liquid, particularly a body fluid, a liquid component recovery device and a liquid component recovery system capable of preventing an erroneous operation by simplifying the operation, and a body fluid using this system The present invention relates to a component recovery method.

  Various components are contained in body fluids typified by blood, among which many medically useful substances such as fibrinolytic components exist. For example, as a method for treating diabetic retinopathy, a method of collecting plasminogen from the patient's own blood, converting it into plasmin and administering it to the patient is known as “plasmin therapy”.

  As a method for recovering a specific target component from blood, a method using affinity chromatography has become the mainstream. Generally, the blood component recovery method by affinity chromatography is generally performed by (1) adsorbing the objective sentence to the adsorbent by bringing the blood into contact with the specific adsorbent, and (2) washing the adsorbent with the cleaning liquid. This includes the steps of removing components other than the target component from the adsorbent, and (3) separating and recovering the target component from the adsorbent using the eluate. In this specification, whole blood, plasma, serum and the like are collectively referred to as “blood”.

  As an apparatus for recovering blood components by this affinity chromatography method, for example, a plurality of discharge mechanisms such as syringes for discharging blood, washing liquid, and eluate, respectively, on the upstream side of the adsorption part for adsorbing target components, Arranged through multiple three-way stopcocks, and arranged the waste liquid recovery unit and the target component recovery unit via the three-way stopcocks downstream of the adsorption unit, and switch these multiple three-way stopcocks according to the required procedure Thus, a method for recovering a target component has been proposed (Patent Document 1).

  However, when the above-described apparatus is used, since the necessary flow path switching must be performed by operating a plurality of three-way stopcocks according to the procedure, the operation becomes complicated. In addition, since a plurality of three-way cocks having the same function are sequentially operated, the three-way cocks to be operated are easily confused, and as a result, erroneous operations are likely to occur. In the above apparatus, three types of liquid ejectors are arranged on the upstream side of the adsorption unit. However, for the purpose of changing the target component to be recovered and the recovery method, or performing higher-accuracy recovery, When increasing the types of liquids to be used, it is necessary to further add a flow path switching mechanism such as a stopcock to the apparatus. As a result, not only the operation is further complicated, but also the apparatus is increased in size and cost.

JP 2006-160731 A

  According to the present invention, in order to solve such a problem, the operation is simplified to prevent an erroneous operation. Further, even when the liquid type is added and used, it is not necessary to add a flow path switching member. An object of the present invention is to provide a liquid component recovery apparatus and a liquid component recovery system in which complication of operation is suppressed. Furthermore, it aims at providing the bodily fluid component collection | recovery method which can collect | recover specific target components from a bodily fluid efficiently by simple operation using such a liquid component collection | recovery system.

  In order to achieve the above-described object, the liquid component recovery apparatus according to the present invention is selectively attached to or detached from any one of a plurality of liquid ejectors for ejecting liquid, each corresponding to a plurality of liquids having different functions. A flow path opening / closing mechanism that opens and closes the flow path of the discharged liquid and a downstream side of the flow path opening / closing mechanism to selectively select a specific target component in the liquid discharged from the liquid discharger. An adsorbing part that adsorbs to the adsorbing part, a flow path switching mechanism that communicates with the downstream side of the adsorbing part and that switches the outlet in at least two directions, and is detachably connected to one outlet of the channel switching mechanism. A waste liquid recovery unit that recovers the waste liquid, and a component recovery unit that is detachably connected to the other outlet of the flow path switching mechanism and recovers the target component adsorbed by the adsorption unit.

  According to this configuration, a plurality of simple and difficult to confuse operations such as connection and removal of the liquid ejector and the channel opening / closing mechanism, opening / closing of the channel opening / closing mechanism, and channel switching of the channel switching mechanism are performed. The target component in the liquid can be recovered using liquids having different functions. Therefore, operation is greatly simplified as compared with an apparatus including a plurality of flow path switching mechanisms, and erroneous operation can be effectively prevented. Furthermore, when it is necessary to add the type of liquid to be used, it is only necessary to add a liquid discharger as necessary, and there is no need to add other parts such as a flow path switching mechanism. The complexity can be minimized, and the increase in size and cost of the apparatus can be suppressed.

  As one embodiment of the liquid component recovery apparatus according to the present invention, for example, the adsorption unit may be a body fluid component adsorption unit that selectively adsorbs a target component in the body fluid. In this case, the target component to be recovered may be plasminogen, and the adsorption part may be composed of an adsorbent obtained by immobilizing L-lysine on a hard porous resin. With such a configuration, plasminogen used for plasmin therapy, which is a treatment method for diabetic retinopathy, can be efficiently recovered. The body fluid here is a fluid derived from a living body, and includes, for example, blood, umbilical cord blood, lymph fluid, bone marrow, urine, saliva, tears, sweat, and the like.

  When the present invention is applied to a device that collects a specific component in a body fluid as described above, the body fluid is being collected or processed in the middle of the channel between the channel switching mechanism and the component recovery unit. It is desirable to have a sterilization mechanism for removing bacteria mixed in the inside. Further, the component recovery unit, the sterilization mechanism, and the air needle forming the gas vent hole of the target component recovery device may be supplied in a sterilized state, and the adsorption member is sterilized in a wet state. Alternatively, it may be sterilized in a state where a liquid is filled between the channel opening / closing mechanism and the channel switching mechanism. By setting it as such a structure, the objective component which has higher safety | security can be collect | recovered.

Furthermore, a liquid component recovery system according to the present invention includes a plurality of liquid ejectors for discharging a liquid respectively corresponding to a plurality of liquids having different functions, and any one of the liquid component recovery devices described above, The path opening / closing mechanism includes a liquid component recovery device that is selectively and detachably connected to any one of the plurality of liquid ejectors. According to this liquid component recovery system, by a combination of simple and difficult to confuse operations such as connection and removal of the liquid discharger and the channel opening / closing mechanism, opening / closing of the channel opening / closing mechanism, and channel switching of the channel switching mechanism. The target component in the liquid can be recovered using liquids having a plurality of different functions. Therefore, operation is greatly simplified as compared with an apparatus including a plurality of flow path switching mechanisms, and erroneous operation can be effectively prevented. Furthermore, when it is necessary to add the type of liquid to be used, it is only necessary to add a liquid discharger as necessary, and there is no need to add other parts such as a flow path switching mechanism. The complexity can be minimized, and the increase in size and cost of the apparatus can be suppressed.
As described above, in the present invention, the volume from the channel opening / closing mechanism to the channel switching mechanism can be reduced, so that the time required for component recovery can be shortened and the amount of liquid required for component recovery can be reduced. It becomes. In particular, when this system is used to recover a target component in a body fluid, it is possible to reduce the burden on the patient who collects the body fluid necessary for the component recovery.
In addition, when a liquid ejector filled with aseptic liquid having a plurality of different functions is used, it is not necessary to adjust the concentration of the liquid before use, so that the operability is further improved and errors in concentration can be reduced. .

  As one embodiment of the liquid component recovery system according to the present invention, for example, the plurality of liquid dischargers discharge at least one cleaning liquid discharger for discharging a cleaning liquid for cleaning a flow path, and a body fluid discharger for discharging body fluid. And an elution liquid discharger that discharges the elution liquid, and the adsorption unit may be a body fluid component adsorption unit that selectively adsorbs a target component in the body fluid discharged from the body fluid discharger.

  When the liquid component recovery system according to the present invention recovers the target component in the body fluid as described above and includes a cleaning liquid discharger, the liquid component recovery system is for cleaning the flow path before the body fluid is discharged. A first cleaning liquid discharger that discharges the cleaning liquid and a second cleaning liquid discharger that discharges the cleaning liquid for cleaning the flow path after the body fluid is discharged may be included. By providing two types of cleaning liquid ejectors in this way, different types of cleaning liquids can be used according to the purpose of cleaning, and the recovery efficiency and recovery accuracy of target components can be improved. Moreover, even if the number of cleaning liquid ejectors is increased in this way, as described above, the complexity of operation, the increase in size of the apparatus, and the increase in cost can be minimized.

  In particular, when the target component to be recovered is plasminogen, the eluate is, for example, a tranexamic acid solution, so that plasminogen used in plasmin therapy, which is a treatment for diabetic retinopathy, is used. Can be efficiently recovered. A suitable concentration of tranexamic acid is 0.4 mM (mol / L) to 400 mM, more preferably 4 to 40 mM.

  In order to achieve the other object described above, the bodily fluid component recovery method according to the present invention is configured such that the flow path opening / closing mechanism is connected to the waste liquid recovery section while the flow path switching mechanism is connected to the waste liquid recovery section. A first cleaning step of connecting to the first cleaning liquid discharger, opening the flow path by a flow path opening and closing mechanism, discharging the first cleaning liquid from the first cleaning liquid discharger, and cleaning the flow path including at least the adsorbing portion; Close the flow path opening / closing mechanism and connect to the body fluid discharger instead of the first cleaning liquid discharger, open the flow path by the flow path opening / closing mechanism, discharge body fluid from the body fluid discharger, and remove a specific body fluid component An adsorbing step for adsorbing to the adsorbing part, and closing the flow path opening / closing mechanism to connect to the second cleaning liquid discharger instead of the body fluid discharger, opening the flow path by the flow path opening / closing mechanism, and discharging the second cleaning liquid Discharge the second cleaning liquid from the vessel A second cleaning step for cleaning the flow path including the adsorbing portion; and an eluent discharger connecting step for closing the flow path opening / closing mechanism and connecting to the eluate discharger instead of the second cleaning liquid discharger; A flow path switching step for switching the outlet of the flow path switching mechanism to the component recovery unit side, and a body fluid for discharging the eluate from the eluate discharger and recovering the body fluid component adsorbed on the adsorption unit And a component recovery step.

  The body fluid component recovery method may further include a third washing step of discharging a predetermined amount of eluate from the eluate discharger after the eluate discharger connection step and before the flow path switching step. May be included.

  According to this method, a plurality of simple and difficult to confuse operations such as connection and removal of the liquid ejector and the channel opening / closing mechanism, opening / closing of the channel opening / closing mechanism, and channel switching of the channel switching mechanism are performed. The target component in the liquid can be recovered using liquids having different functions. Therefore, compared with a method using an apparatus including a plurality of flow path switching mechanisms, the operation is greatly simplified, and erroneous operations can be effectively prevented.

  Thus, according to the liquid component recovery apparatus and the liquid component recovery system according to the present invention, the operation is greatly simplified and can be prevented from being erroneously operated. It is not necessary to add a flow path switching member, and operation complexity is suppressed. Furthermore, since the volume from the channel opening / closing mechanism to the channel switching mechanism can be reduced, the amount of body fluid used and the recovery time can be reduced. For example, when it is used for collecting plasmin, it is particularly useful because a small amount of blood is used. Moreover, according to the bodily fluid component collection | recovery method concerning this invention, a specific target component can be efficiently collect | recovered by simple operation from bodily fluid using said liquid component collection | recovery apparatus.

  Hereinafter, embodiments according to the present invention will be described with reference to the drawings. However, the present invention is not limited to the embodiments.

FIG. 1 is a schematic diagram showing a configuration of a liquid component recovery system according to an embodiment of the present invention. This liquid component recovery system is configured as a body fluid component recovery system 1 for recovering plasminogen as a target component E from blood B by affinity chromatography, and discharges a liquid used for recovery of plasminogen. Liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S, a flow path opening / closing mechanism 5 for opening / closing a liquid flow path, an adsorption portion 7 for selectively adsorbing plasminogen as a target component E, and a flow path in two directions And a liquid component recovery device 14 having a component recovery unit 13 for recovering plasminogen as the target component E.

The liquid discharge mechanism 3 includes a plurality (here, four) of liquid dischargers 3C ₁ , 3B, 3C ₂ , 3S and a syringe pump 23 that is a common drive unit that drives the liquid dischargers 3C ₁ , 3B, 3C ₂ , 3S. The flow path opening / closing mechanism 5 is detachably connected only to any one of the liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S selected according to the recovery procedure. The flow path opening / closing mechanism 5 and the suction portion 7 disposed on the downstream side thereof are communicated with each other through an introduction passage 15 formed by a tubular communication tube. A flow path switching mechanism 9 is connected to the downstream side of the adsorption unit 7. A waste liquid recovery part 11 is connected to a waste liquid outlet 9a, which is one of two outlets of the flow path switching mechanism 9, via a waste liquid outlet passage 17 formed by a communication tube. A component recovery unit 13 is connected to the outlet 9b via a sterilization mechanism 19.

In the present embodiment, in order to recover plasminogen, as a liquid in addition to blood B, the cleaning liquid C for cleaning the flow path of the apparatus and the plasminogen adsorbed by the adsorption unit 7 are separated from the adsorption unit. The eluate S for this purpose is used. The cleaning liquid C is used twice before and after the blood B is discharged. Therefore, specifically, the plurality of liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S include a first cleaning liquid ejector 3C ₁ that ejects the cleaning liquid C before blood ejection and a body fluid ejector 3B that ejects blood B. When includes a second cleaning liquid dispenser 3C ₂ that discharges a cleaning liquid C after blood discharge, the eluate dispenser 3S for discharging the eluate S.

Any liquid ejector 3C ₁ , 3B, 3C ₂ , 3S may be used as long as it is safe for a living body and can store and discharge liquid. In this embodiment, the syringe 21 is used. Is mounted on the syringe pump 23 and used. When the syringe 21 is used together with the syringe pump 23, there is an advantage that the liquid discharge speed can be accurately controlled. In addition to the syringe, for example, a container made of a soft resin such as polyethylene, polypropylene, polyurethane, or polyvinyl chloride may be used. Specifically, for example, a soft resin bag used as a blood collection bag, a blood component separation bag or a blood transfusion bag, a soft resin bottle used as a reagent bottle, or a soft resin tube-like container, It can be used as the liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S. The capacity and size of the liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S can be appropriately set according to the required amount of each liquid, use conditions, and the like.

  The cleaning liquid C may be any liquid that is safe for a living body and that can clean the inside of the apparatus, and in particular, can flow body fluid components other than the target component present in the adsorption unit 7 out of the adsorption unit. Any type may be used. In the present embodiment, physiological saline is used as the cleaning liquid C, but various other buffer solutions such as a phosphate buffer containing sodium chloride can be used.

In the present embodiment, the first and the cleaning liquid dispenser 3C ₁ and a second cleaning liquid dispenser 3C _2, is used as a cleaning solution C was filled with physiological saline of the same composition, the target component E to recover Depending on the type, the purpose of cleaning, and the like, different types of saline solutions or different types of cleaning liquids C may be used. Further, when the same type and composition of cleaning liquid C is used before and after blood B is discharged, one cleaning liquid discharger 3 may be used twice before and after blood discharge. It is possible to omit the cleaning before discharging the blood B.

  In this embodiment, plasma is used as the blood B. However, the blood B is not limited thereto, and whole blood collected from a human body or serum collected from whole blood may be used. Furthermore, instead of blood B, a fluid containing a recoverable component such as umbilical cord blood, lymph fluid, bone marrow, urine, saliva, tears, sweat and the like may be used. If it is necessary to quickly collect the desired blood components after collecting whole blood from the human body, untreated blood (whole blood) can be used as it is from the viewpoint of pretreatment operations such as centrifugation. It is preferable to apply to the component recovery system 1.

  As the eluent S, any kind of eluent may be used as long as it is safe for a living body and can elute the body fluid component adsorbed by the adsorption unit 7. In the present embodiment, a tranexamic acid solution is used as the eluent S that can elute plasminogen adsorbed on the adsorbing unit 7, but other body fluids adsorbed by the adsorbing unit 7 are also used. Those suitable for eluting the components can be appropriately selected and used. For example, when plasminogen is adsorbed to the adsorbing part 7 as a blood component, a phosphate buffer containing ε-aminocaproic acid and sodium chloride can be used.

  In this embodiment, a three-way cock 31 shown in FIG. 2 is used as the flow path opening / closing mechanism 5. FIGS. 2A and 2B are a plan view and a front view, respectively, showing a state where the flow path is closed, and FIG. 2C is a plan view showing a state where the flow path is opened. The three-way stopcock 31 is generally used, and has two main branch pipes 33a and 33b arranged on the outer periphery of the cylindrical body portion 32 in a straight line and opposite to each other, and these A sub-branch pipe 33c disposed substantially orthogonal to the main branch pipes 33a and 33b is provided, and a substantially T-shaped passage 35a formed at a position corresponding to each branch pipe is provided inside the trunk portion 32. The valve body 35 which has is inserted so that rotation is possible. The valve body 35 is provided with a lever 37. By rotating the valve body 35 in the body portion 32 via the lever 37, the two main branch pipes 33a and 33b and the inside of the valve body 35 are provided. The liquid flow path formed by the T-shaped passage 35a is opened and closed. In the present embodiment, one main branch pipe 33a serves as a liquid inflow port, and the other main branch pipe 33b serves as an outflow port. Further, the sub branch pipe 33c has a cap 39 attached to the tip thereof in a liquid-tight state, and functions as a gas vent hole when discharging the liquid.

The upstream end of the outer peripheral surface of the main branch pipe 33a serving as an inflow port is provided with a thread groove, and the liquid ejectors 3C ₁ , 3B, 3C ₂ and 3S, which are syringes, are provided on the inner peripheral surface of the connecting portion. By screwing, the liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S and the flow path opening / closing mechanism 5 are connected to each other. On the other hand, a cylindrical connecting portion 33e is provided as a female connecting member on the outside of the main branch pipe 33b serving as an outlet, and a thread groove is formed on the downstream side of the inner peripheral surface thereof.

  As the adsorption part 7, as shown in a side view in FIG. 3, a cylindrical column 41 filled with an adsorbent 43 is used. The column 41 includes a cylindrical column main body 45 and an inflow side cap 47 and an outflow side cap 49 that are threadedly engaged with the outer periphery of both ends of the column main body 45 to form an inlet and an outlet of the adsorption unit 7, respectively. Has been. The column may have a mechanism that prevents the adsorbent from flowing out. For example, a mesh that prevents the adsorbent particles and debris from flowing out may be installed at least at the end on the outlet side of the column. In particular, when the column volume is small, it is preferable to fuse the mesh to at least one of the inlet / outlet port and the cap of the column.

  Any material may be used as the material of the column 41 as long as it is safe for a living body, but in this embodiment, a polycarbonate resin is used. In addition, the shape and size of the column can be appropriately selected according to the purpose of use and the use environment.

  The substance forming the adsorbent 43 is appropriately selected according to the type of the target component E to be collected from the blood B, the usage environment, and the like. When plasminogen is recovered as the target component E, a carrier containing a hydrophilic organic polymer compound and a ligand having affinity for plasminogen as a fibrinolytic component is preferably used. . In the present embodiment, a hard porous resin, more specifically, a polymethacryl methacrylate (PMMA) porous resin in which L-lysine is immobilized is used as the adsorbent 43.

  The adsorbent adsorbs a desired target component from the body fluid. The type of adsorbent can be appropriately selected according to the type of target component to be collected. Examples of the adsorbent include an adsorbent composed of a ligand having affinity for a fibrinolytic component and a carrier made of a rigid porous resin containing a hydrophilic organic polymer compound.

  The hydrophilic organic polymer compound is excellent in compatibility with water, body fluid, blood and the like. Therefore, an adsorbent composed of a carrier containing a hydrophilic organic polymer compound causes adhesion of blood components and plasma proteins, coagulation, hemolysis, activation of the blood coagulation system, activation of the fibrinolysis system, etc. Therefore, it is preferably used in the body fluid component recovery system of the present invention.

  The hydrophilic organic polymer compound contained in the carrier may contain a crosslinked structure in the molecular structure. The concept of the hydrophilic organic polymer compound includes, for example, an organic polymer compound that swells with water, an organic polymer compound that easily wets in water, and the like. When the main structure of the hydrophilic organic polymer compound is composed of a chain organic polymer compound, for example, dialdehydes such as glutaraldehyde, diisocyanates such as tolylene diisocyanate; phthalic anhydride, maleic anhydride, etc. Acid anhydrides; polyfunctional epoxy compounds such as ethylene glycol glycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether; forming a crosslinked structure using a crosslinking agent such as epichlorohydrin Is preferred.

  Examples of the functional group that the hydrophilic organic polymer compound has to contribute to hydrophilic expression and ligand fixation include groups having dissociation properties such as a carboxyl group, a sulfonic acid group, and a quaternary ammonium group, a hydroxyl group, an acrylamide group, Nonionic hydrophilic groups such as ether groups are exemplified. The number of functional groups in the hydrophilic organic polymer compound is preferably large in order to adsorb and recover more components of interest, but on the other hand, as the number of functional groups increases, the number of functional groups increases depending on the immobilized ligand. There is a tendency to cause specific adsorption. Therefore, the number of the functional groups per 1 g of the hydrophilic organic polymer compound is preferably 50 μmol or more, more preferably 50 to 1000 μmol, and still more preferably 170 to 500 μmol.

  Examples of hydrophilic organic polymer compounds include hydrophilic (meth) acrylate-based polymers obtained by polymerizing (meth) acrylates such as glycidyl (meth) acrylate, ethylene glycol di (meth) acrylate, and hydroxyethyl (meth) acrylate. Molecular compound; polyvinyl alcohol polymer compound using vinyl acetate or the like as a raw material for polymerization; polyethylene glycol polymer compound obtained by polymerizing ethylene glycol such as ethylene glycol or diethylene glycol; in the presence of the polyvinyl alcohol polymer compound Hydroxyl-containing hydrophilic (meth) acrylate obtained by polymerizing (meth) acrylates such as glycidyl (meth) acrylate, ethylene glycol di (meth) acrylate, and hydroxyethyl (meth) acrylate Such as over preparative based copolymer.

  More specifically, examples of the hydrophilic (meth) acrylate polymer compound include glycidyl (meth) acrylate-ethylene glycol di (meth) acrylate copolymer, polyethylene glycol (meth) acrylate, polyhydroxyethyl (meta ) Acrylate and the like. Examples of the polyvinyl alcohol polymer compound include polyvinyl alcohol and ethylene-vinyl alcohol copolymer. Examples of polyethylene glycol-based polymer compounds include polyethylene glycol (the number of oxyethylene units is preferably in the range of 3 to 500 because blood components tend to hardly enter the pores in the particles if the number is too large. And a number within the range of 3 to 200, more preferably a number within the range of 3 to 100), polydiethylene glycol and the like. Examples of the hydroxyl group-containing hydrophilic (meth) acrylate-based copolymer include a copolymer obtained by polymerizing glycidyl (meth) acrylate and ethylene glycol di (meth) acrylate in the presence of polyvinyl alcohol, Examples thereof include a copolymer obtained by polymerizing glycidyl (meth) acrylate and ethylene glycol di (meth) acrylate in the presence of polyvinyl acetate.

Further, as the hydrophilic organic polymer compound, in addition to the above, the formula: HO—C _m H _2m —OH (where m is an integer of 3 to 6, and the alkylene group (C _m H _2m ) is straight 2 may be a chain or a branched chain, and the carbon atom to which the hydroxyl group is bonded may be any of primary, secondary and tertiary). Trihydric alcohols such as glycerin, trimethylolethane and trimethylolpropane; tetrahydric alcohols such as pentaerythritol, ditrimethylolethane, ditrimethylolpropane, erythritol and threitol; pentahydric alcohols such as ribitol, arabinitol and xylitol; Hexavalent alcohols such as dulcitol, glucitol, sorbitol, mannitol, altitol, iditol Include polyalcohol polymer compound obtained by polymerizing a polyhydric alcohol such Lumpur. Examples of the polyhydric alcohol polymer compound include polyglycerin, polyerythritol, polysorbitol and the like. The hydrophilic organic polymer compound also includes a polymer compound obtained by polymerizing monosaccharides, disaccharides (such as maltitol and lactitol).

  Among the hydrophilic organic polymer compounds for adsorbents that constitute the adsorbing part in the body fluid component recovery system of the present invention, glycidyl (meth) acrylate, ethylene glycol di (meth) acrylate, hydroxyethyl (meth) acrylate and the like ( Hydrophilic (meth) acrylate polymer compound obtained by polymerizing meth) acrylates; polyvinyl alcohol polymer compound using vinyl acetate or the like as a raw material for polymerization; in the presence of the polyvinyl alcohol polymer compound A hydroxyl group-containing hydrophilic (meth) acrylate copolymer obtained by polymerizing (meth) acrylates such as glycidyl (meth) acrylate, ethylene glycol di (meth) acrylate, and hydroxyethyl (meth) acrylate, More preferred.

  It goes without saying that the hydrophilic organic polymer compound exemplified above may form a crosslinked structure by using a crosslinking agent in combination. Moreover, a hydrophilic organic polymer compound is used individually or in mixture of 2 or more types in manufacture of an adsorbent.

  The term “(meth) acrylate” used in the present specification is a general term for “acrylate” and “methacrylate”.

  As a polymerization method for obtaining the hydrophilic organic polymer compound, a known method can be employed, and examples thereof include a solution polymerization method, a suspension polymerization method, and an emulsion polymerization method. It is not limited.

  The weight average molecular weight of the hydrophilic organic polymer compound is not necessarily limited, but is generally preferably 1,000 to 1,000,000, and preferably 3,000 to 800,000 from the viewpoint of preventing structural destruction under high pressure or high flow rate. More preferred.

  The carrier for the adsorbent contains a hydrophilic organic polymer compound as a constituent material. The entire carrier may be substantially composed only of the hydrophilic organic polymer compound, but the surface of the substrate made of a substance other than the hydrophilic organic polymer compound is coated with the hydrophilic organic polymer compound. It may be a thing, and it may be comprised from the mixture of substances other than a hydrophilic organic polymer compound and a hydrophilic organic polymer compound.

  As the carrier for the adsorbent, for example, those having an arbitrary particle shape such as spherical particles and crushed particles are used. In order to enhance the adsorptivity, since it is preferable that the contact area with the substance to be adsorbed (body fluid component) is large, spherical particles are particularly preferable among the above-mentioned forms. The carrier includes non-porous gel type and porous porous type, and any of them can be used in the present invention. From the viewpoint of enhancing the adsorptivity with the adsorbed substance, the porous type is used. Are more preferred.

  The average particle size of the carrier particles is not necessarily limited, but generally, from the viewpoint of increasing the specific surface area to increase the adsorptivity and reducing the resistance when high-viscosity plasma or whole blood passes, Is preferably 170 μm or more, more preferably 170 to 1000 μm, and even more preferably 300 to 900 μm. The average particle size is, for example, the particle size distribution of the particles having the largest number of particles in the particle size distribution measured with a precision particle distribution measuring apparatus (trade name: Coulter Multisizer II, manufactured by Beckman Coulter, Inc.). I can grasp it.

  It should be noted that if the carrier is deformed due to resistance during passage of fluid such as body fluid, there is a possibility that the passage of fluid may be hindered. Therefore, it is preferable that the carrier has strength that does not cause deformation.

  Examples of the ligand used for the adsorbent include biological substances such as basic amino acids and antibodies; groups derived from organic compounds such as diethylaminoethyl group and trimethylaminomethyl group; inorganic compounds such as silica and silicic acid. It is done. In these, a biological substance is preferable and a basic amino acid is more preferable. Examples of basic amino acids include L-lysine, arginine, and histidine, and L-lysine is particularly preferable.

  The adsorbent can be obtained, for example, by binding a carrier and a ligand (or an organic compound that gives a ligand) according to a known method. The bond between the carrier and the ligand is preferably a bond based on the chemical bond or physical force between the hydrophilic organic polymer compound constituting the carrier and the ligand, and the bond between the carrier and the ligand is strong. Therefore, a chemical bond between the hydrophilic organic polymer compound constituting the carrier and the ligand is particularly preferable.

  The method of chemically binding the ligand to the hydrophilic organic polymer compound is not necessarily limited. For example, the reactive group present in the hydrophilic organic polymer compound is left as it is or chemically modified. Later, a method of chemically reacting with a reactive group present in the ligand molecule may be mentioned. When the reactive group present in the hydrophilic organic polymer compound is a hydroxyl group, the chemical modification of the hydroxyl group includes epoxidation using epichlorohydrin, carboxylation using succinic anhydride, and N-hydroxysuccinimide. The amidation used can be employed.

  The amount of the ligand bound to the hydrophilic organic polymer compound is preferably 50 μmol or more, more preferably 170 μmol or more, per 1 g of the hydrophilic organic polymer compound, from the viewpoint of adsorbing and recovering a desired target component more. On the other hand, non-specific adsorption tends to occur as the amount of ligand increases, so from the viewpoint of preventing non-specific adsorption, the amount of ligand bound to the hydrophilic organic polymer compound is high in hydrophilic organic polymer. The amount is preferably 1000 μmol or less, more preferably 500 μmol or less, per 1 g of the molecular compound. In general, the amount of the ligand bound to the hydrophilic organic polymer compound is preferably 50 μmol or more, more preferably 50 to 1000 μmol, more preferably 170 to 500 μmol, per 1 g of the hydrophilic organic polymer compound. Is more preferable.

  The amount of the ligand in the adsorbent can be confirmed by a known method. When the ligand is lysine, for example, the amount of nitrogen atom contained in the adsorbent of a constant weight is quantified by the semi-micro Kjeldahl method described in the 14th revised Japanese Pharmacopoeia, and lysine is determined from the quantified amount of nitrogen atom. The amount can be calculated.

  The communication tube forming the introduction passage 15 may be made of any material as long as it is safe for a living body, but γ-ray sterilization, high-pressure steam sterilization, EOG sterilization, electron beam sterilization, etc. It is preferably a safe and flexible material that can withstand a known sterilization method. In this embodiment, a polyethylene resin is used.

  As the flow path switching mechanism 9, a three-way cock 51 shown in FIG. 4 is used. 4A shows a state where the flow path is switched to the waste liquid recovery unit 11 side, and FIG. 4B shows a state where the flow path is switched to the component recovery unit 13 side. The three-way stopcock 51 has substantially the same structure as the three-way stopcock 31 of FIG. 2 used as the flow path opening / closing mechanism 5 in the present embodiment, but a female type is formed on the outer sides of the two main branch pipes 51a and 51b. Is provided. The valve body 55 has a T-shaped passage 55a inside. On the other hand, a screw groove serving as a male connection portion is formed on the outer peripheral surface of the end portion of the sub branch pipe 51c. In the three-way stopcock 51, one main branch pipe 51a serves as an inflow port through which blood components and the like flow in, the other main branch pipe 51b serves as a component outflow port 9b communicating with the component recovery unit 13, and the sub branch pipe 51b serves as an inlet. The waste liquid outlet 9 a communicates with the waste liquid recovery unit 11.

  As will be described in detail later, the waste liquid collecting unit 11 collects the cleaning liquid C, the components that have not been adsorbed by the blood B adsorbing part 7 and, if necessary, a part of the eluate as the waste liquid W. As the waste liquid recovery unit 11, a container made of any material may be used as long as the waste liquid W can be stored. In the present embodiment, a resin bag is used. The capacity, size, shape, and the like of the waste liquid recovery unit 11 are appropriately selected according to the recovery amount of the waste liquid W, usage conditions, and the like. In addition, the communication tube that forms the waste liquid lead-out path 17 that communicates the flow path switching mechanism 9 and the waste liquid recovery unit 11 is formed as a separate member and connected to the waste liquid recovery unit 11 by a method such as screwing. However, it may be formed integrally with the waste liquid recovery unit 11.

  Any sterilization mechanism 19 may be used as long as it has a necessary sterilization function and can pass the target component E to be recovered. In the present embodiment, the sterilization filter is used. Is used. As shown in FIG. 1, the sterilization filter 19 includes a main body portion 19a including a sterilization filter formed in a disk shape and a filter case that houses the sterilization filter, a connection portion between the flow path switching mechanism 9 and a target component. A sterilization filter inflow portion 19b that also serves as an inflow port of the sterilization filter, and a sterilization filter outflow portion 19c that guides the target component sterilized by the main body portion 19a toward the component recovery portion 13. An introduction needle 61 for introducing the target component E into the component recovery unit 13 is attached to the sterilization filter outflow portion 19c. The introduction needle 61 is generally used as an injection needle.

  As the component recovery unit 13 that recovers the target component E, a vial 71 is used. The vial 71 includes a vial main body 73 that is a bottle-shaped glass container and a cap 75 that covers the opening of the vial main body 73. In the present embodiment, plasminogen as the target component E is sterilized by passing through the main body portion 19a of the sterilization filter 19, and after passing through the sterilization filter outflow portion, in order to avoid contact with air as much as possible. As shown in FIG. 1, it is introduced into the vial 71 through an introduction needle 61 that penetrates the cap 75. Therefore, as the cap 75, it is preferable to use a cap whose material or shape is selected so that the introduction needle 61 can penetrate. The material of the vial body 73 is not limited to glass and may be a resin that is generally used.

  An air needle 77 that functions as a degassing hole when introducing the target component E into the vial 71 is installed in the vicinity of the place where the introduction needle 61 penetrates the cap 75 of the vial 71. . The air needle 77 is a dedicated injection needle (air needle) provided with a filter for sterilization. In order to ensure safety, the component recovery unit 13, the sterilization mechanism 19 and the air needle 77 are preferably supplied in a sterilized state, and the waste liquid recovery unit 11 is also supplied in a sterilized state. Is more preferable. Furthermore, the adsorbent 43 may be sterilized in a wet state, or may be sterilized in a state where a liquid is filled between the channel opening / closing mechanism 5 and the channel switching mechanism 7.

  Next, a method for recovering plasminogen as a target component from blood B using the body fluid component recovery system 1 will be described.

  First, the lever 57 of the three-way stopcock 51 which is the flow path switching mechanism 9 shown in FIG. 4 is operated so that the outlet is switched to the waste liquid outlet 9a side. That is, the three-way cock 51 is set in the state shown in FIG. At this time, the three-way cock 31 which is the flow path opening / closing mechanism 5 keeps the flow path closed as shown in FIGS. 2 (a) and 2 (b).

Next, the flow path opening / closing mechanism 5 is connected to the first cleaning liquid discharger 3C ₁ filled with physiological saline, which is the cleaning liquid C, and a small amount of cleaning liquid is flowed as necessary to cause air in the flow path opening / closing mechanism 5 to flow. After discharging from the sub branch pipe 33c, the lever 37 of the three-way cock 31 that is the flow path opening / closing mechanism 5 is operated to open the flow path as shown in FIG. In this state, the syringe pump 23 is operated to discharge a predetermined amount of the cleaning liquid C. The discharged cleaning liquid C is washed through the communicating flow path to clean the flow path opening / closing mechanism 5, the adsorbing section 7, etc. (first cleaning step), and then recovered as the waste liquid W in the waste liquid recovery section 11.

  Subsequently, after the flow path of the flow path opening / closing mechanism 5 is closed, the flow path opening / closing mechanism 5 is removed from the first washing liquid discharger 3C1 and connected to the body fluid discharger 3B filled with blood B. Thereafter, the flow path opening / closing mechanism 5 is opened as in the first washing step, and the syringe pump 23 is operated to discharge a predetermined amount of blood B. The discharged blood B flows into the adsorbing unit 7 through the communicating channel, and the target component plasminogen is adsorbed to the adsorbent 43 in the adsorbing unit 7 (adsorption step). The blood component that has not been adsorbed by the adsorbing unit 7 is collected in the waste liquid collecting unit 11 as the waste liquid W.

Then, after closing the flow path of the flow path opening and closing mechanism 5, remove the flow path opening and closing mechanism 5 from the body fluid dispenser 3B, connected to the second cleaning liquid dispenser 3C ₂ of the cleaning liquid C filled. Thereafter, the flow path opening / closing mechanism 5 is opened as in the first cleaning step, and the syringe pump 23 is operated to discharge a predetermined amount of the cleaning liquid C. The discharged cleaning liquid C cleans the components that have not been adsorbed by the internal adsorption unit 7 such as the channel opening / closing mechanism 5 and the adsorption unit 7 through the communicating channel (second cleaning step). Is recovered in the waste liquid recovery unit 11. Note that the second cleaning liquid discharge device 3C ₂ may reuse the first cleaning liquid dispenser 3C ₁ used in the first washing step.

Next, after closing the flow path of the flow path opening / closing mechanism 5, the flow path opening / closing mechanism 5 is removed from the second cleaning liquid discharger 3 </ _b > C ₂ , and the eluate discharger 3 </ _b > S filled with the tranexamic acid solution that is the eluate S is disposed. Connect (eluent dispenser connection step). A small amount of the eluate S is discharged from the eluent discharger 3S, and the eluate having a low concentration of the target component E is discarded as the waste liquid W in the waste liquid recovery unit 11 (third cleaning step). The discharge amount of the eluate S in the third washing step can be appropriately set as necessary, but is approximately equal to the internal volume between the flow path opening / closing mechanism 5 and the column and the flow path switching mechanism 9, preferably 0 to 50 mL, more preferably 0.5 to 5 mL.

  Next, the lever 57 of the three-way cock 51 of the three-way cock 51 that is the channel switching mechanism 9 is operated to switch the outlet to the component outlet 9b side as shown in FIG. Step).

  Next, similarly to the first washing step, the flow path of the flow path opening / closing mechanism 5 is opened, and the syringe pump 23 is operated to discharge a predetermined amount of the eluate S. The discharged eluate S flows into the adsorbing unit 7, plasminogen adsorbed on the adsorbent 43 is separated from the adsorbent, and collected in the vial 71 which is the component recovery unit 13 through the sterilization mechanism 19. (Body fluid component recovery step).

  Furthermore, the plasminogen collected in the vial 71 is mixed with a predetermined amount of urokinase and activated to obtain plasmin for use in the treatment of posterior vitreous detachment in ophthalmology.

Note that the third cleaning step may be omitted. In the body fluid component recovery method according to the present embodiment, the flow channel opening / closing mechanism 5 and the liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S are connected and disconnected, the flow channel opening / closing mechanism 5 is opened / closed, and the flow channel Each operation of switching the flow path of the switching mechanism 9 is performed manually, but may be performed automatically using an external device. In this case, an automatic switching mechanism for each liquid ejector 3C ₁ , 3B, 3C ₂ , 3S may be added.

According to the body fluid component recovery system 1 according to the above-described embodiment, the connection and removal of the plurality of liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S and the flow path opening / closing mechanism 5, the opening / closing of the flow path opening / closing mechanism 5, and the flow The target component can be recovered using liquids having a plurality of different functions by a combination of simple operations that are not easily confused with each other, such as flow path switching of the path switching mechanism 9. Therefore, compared with the case where an apparatus having a plurality of flow path switching mechanisms is used, the operation is greatly simplified and erroneous operation can be prevented. In the present embodiment, four liquid ejectors 3C ₁ , 3B, 3C ₂ , 3S are used. However, when a larger number of types of liquid need to be used, that is, a larger number of liquid ejectors are used. Even when necessary, as a component of the liquid component recovery system, only a liquid discharger needs to be added according to the number of types of required liquid, and a flow path opening / closing mechanism 5 and a flow path switching mechanism 9 need to be added. There is no. Thereby, the enlargement of an apparatus and the increase in cost are suppressed. Further, in the operation, the target component can be obtained only by a combination of the operations of connecting / disconnecting the plurality of liquid ejectors and the flow path opening / closing mechanism 5, opening / closing the flow path opening / closing mechanism 5, and flow path switching of the flow path switching mechanism 9. Can be recovered. Therefore, compared with the case where the flow path opening / closing mechanism 5 and the flow path switching mechanism 9 are added, it is possible to greatly suppress the complexity of the operation due to the addition of the liquid type.

  Further, since the volume between the channel opening / closing mechanism 5 and the channel switching mechanism 9 can be reduced (specifically, 10 mL or less, preferably 5 mL or less, more preferably 2 mL or less), the amount of body fluid to be used is reduced, and Collection time can be shortened. For example, when used for plasmin recovery, it is particularly useful because a small amount of blood is used.

Further, in the body fluid component recovery system 1, since the sterilization mechanism 19 is provided between the adsorption unit 7 and the component recovery unit 13, the flow path opening / closing mechanism 5 and the plurality of liquid ejectors 3C ₁ , 3B, 3C ₂ Even if it is necessary to repeat the connection and removal with 3S sequentially, the safety of the target component to the living body can be ensured.

1 is a schematic configuration diagram illustrating a liquid component recovery device and a liquid component recovery system according to an embodiment of the present invention. (A) is a top view which shows the state which closed the flow path of the flow-path opening-and-closing mechanism used for the component collection | recovery apparatus of FIG. 1, (b) is the front view, (c) is the flow path of the flow-path opening and closing mechanism. It is a top view which shows the open state. It is a side view which shows the adsorption | suction part used for the component collection | recovery apparatus of FIG. It is a top view which shows the flow-path switching mechanism used for the component collection | recovery apparatus of FIG. 1, (a) is a state in which the flow path is connecting to the waste liquid collection | recovery part side, (b) is a flow path to the component collection | recovery part side. Indicates a state in which is communicated.

Explanation of symbols

1 body fluid component recovery system _{3C 1, 3B, 3C 2,} 3S liquid dispenser 5 passage opening and closing mechanism 7 adsorption unit 9 flow path switching mechanism 9a waste outlet 9b component outlet 11 the waste liquid recovery unit 13 component recovery unit 14 the liquid component recovery Equipment E Target component W Waste liquid

Claims (14)

A flow path opening / closing mechanism for opening / closing a flow path of the discharged liquid, which is selectively attachable to and detachable from any one of a plurality of liquid discharge apparatuses for discharging the liquid, each corresponding to a liquid having a plurality of different functions;
An adsorbing portion that communicates with the downstream side of the flow path opening / closing mechanism and selectively adsorbs a specific target component in the liquid ejected from the liquid ejector;
A flow path switching mechanism that communicates with the downstream side of the adsorption portion and switches the outlet in at least two directions;
A waste liquid recovery unit that is detachably connected to one outlet of the flow path switching mechanism and recovers waste liquid;
A liquid component recovery apparatus comprising: a component recovery unit that is detachably connected to the other outlet of the flow path switching mechanism and recovers a target component adsorbed by the adsorption unit.   2. The liquid component recovery apparatus according to claim 1, wherein the adsorption unit is a body fluid component adsorption unit that selectively adsorbs a target component in the body fluid.   3. The liquid component recovery apparatus according to claim 2, wherein the target component to be recovered is plasminogen, and the adsorbing portion is composed of an adsorbent in which L-lysine is immobilized on a hard porous resin.   4. The liquid component according to claim 2, further comprising a sterilization mechanism for removing bacteria in the body fluid in the middle of the flow path between the flow path switching mechanism and the component recovery unit. Recovery device.   5. The liquid component recovery apparatus according to claim 4, wherein the component recovery unit, the sterilization mechanism, and an air needle that forms a gas vent hole of the component recovery unit are supplied in a sterilized state.   6. The liquid component recovery apparatus according to claim 5, further comprising a sterilized state of the waste liquid recovery unit.   The liquid component recovery apparatus according to any one of claims 3 to 6, wherein the adsorbent is sterilized in a wet state.   8. The liquid component recovery apparatus according to claim 1, wherein the liquid component is sterilized in a state in which a liquid is filled between the flow path opening / closing mechanism and the flow path switching mechanism. A plurality of liquid ejectors for ejecting liquid, each corresponding to a plurality of liquids having different functions;
9. The liquid component recovery apparatus according to claim 1, wherein the flow path opening / closing mechanism is selectively and detachably connected to any one of the plurality of liquid ejectors. 10. A liquid component recovery system comprising a liquid component recovery device. The plurality of liquid ejectors according to claim 9,
At least one cleaning liquid discharger for discharging a cleaning liquid for cleaning the flow path;
A body fluid discharger for discharging body fluid;
An eluent dispenser for discharging the eluate,
The liquid component recovery system, wherein the adsorption unit is a body fluid component adsorption unit that selectively adsorbs a target component in the body fluid discharged from the body fluid discharger.   11. The first cleaning liquid discharger for discharging a cleaning liquid for cleaning a flow path before body fluid is discharged, and the second cleaning liquid for discharging a cleaning liquid for cleaning the flow path after body fluid is discharged A liquid component recovery system including a discharger.   12. The liquid component recovery system according to claim 10 or 11, wherein the target component to be recovered is plasminogen and the eluate is a tranexamic acid solution. A body fluid component recovery method using the liquid component recovery system according to any one of claims 9 to 12,
With the outlet of the flow path switching mechanism connected to the waste liquid recovery unit, the flow path opening / closing mechanism is connected to the first cleaning liquid discharger, the flow path opening / closing mechanism opens the flow path, and the first cleaning liquid A first cleaning step of discharging the first cleaning liquid from the discharger to clean at least the flow path including the adsorption part;
Close the flow path opening / closing mechanism and connect to the body fluid discharger instead of the first cleaning liquid discharger, open the flow path by the flow path opening / closing mechanism, discharge body fluid from the body fluid discharger, and remove a specific body fluid component An adsorption step for adsorbing to the adsorption unit;
Close the flow path opening / closing mechanism and connect to the second cleaning liquid discharger instead of the body fluid discharger, open the flow path by the flow path opening / closing mechanism, discharge the second cleaning liquid from the second cleaning liquid discharger, and at least A second cleaning step for cleaning the flow path including the adsorption unit;
An eluent discharger connection step of closing the flow path opening and closing mechanism and connecting to the eluate discharger instead of the second cleaning liquid discharger;
A flow path switching step for switching the outlet of the flow path switching mechanism to the component recovery unit side;
A bodily fluid component recovery method including a bodily fluid component recovery step of discharging the eluate from the eluate discharger and recovering the bodily fluid component adsorbed by the adsorption unit.   14. The body fluid component recovery according to claim 13, further comprising a third washing step for discharging a predetermined amount of eluate from the eluate discharger after the eluate discharger connection step and before the flow path switching step. Method.

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