CN105924497A - Inspissator - Google Patents
Inspissator Download PDFInfo
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- CN105924497A CN105924497A CN201610108598.5A CN201610108598A CN105924497A CN 105924497 A CN105924497 A CN 105924497A CN 201610108598 A CN201610108598 A CN 201610108598A CN 105924497 A CN105924497 A CN 105924497A
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- aqueous solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
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Abstract
An inspissator is provided. The inspissator used for concentrating protein aqueous solution generated by filtrating coelomic fluid can realize the concentration with high magnification and can guarantee the high recovery of protein. The separating membrane (60) of the inspissator (22) has the porosity of more than 60% and less than 80%, and the raising value of the liquid level of the separating membrane measured with a capillary rise method is 60mm-150mm when convert the value into the hollow fiber membrane with inner diameter of 200 mum. The conditions (1) and (2) are met, when performing the concentration process of the concentrated solution of the protein aqueous solution obtained by flowing the protein aqueous solution stoste with the concentration of 3g/dL at the flow velocity of 50Ml/min. (1) the maximum pressure difference between membranes of concentration of 5L protein aqueous solution stoste is less than 500 mmHg, and (2) the pressure difference between membranes of concentration of 2L protein aqueous solution stoste is A, and the pressure difference between membranes of concentration of 5L protein aqueous solution stoste is B, B/A<=1.6.
Description
Technical field
The present invention relates to the concentrator of the coelomic fluids such as ascites, hydrothorax, pericardial fluid.
Background technology
Such as the therapy of difficultly curing ascites disease, concentrate intravenous method (Cell-free and again just like lower abdomen water filtration
Concentrated Ascites Reinfusion Therapy): gather ascites from patient, this ascites is filtered, remove cancer thin
The causative agent such as born of the same parents, antibacterial, generates the protein aqueous solution comprising albumin etc., is concentrated by this protein aqueous solution afterwards, will
This concentrated solution re-injects to internal.
The concentration of above-mentioned protein aqueous solution generally uses and has the concentrator being connected with ascites treatment loop (with reference to patent
Document 1,2).This concentrator has hollow-fibre membrane etc. in body interior and separates film, makes the moisture of protein aqueous solution by dividing
Separate from film thus protein aqueous solution is concentrated.
Prior art literature
Patent documentation
Patent documentation 1: Japanese Unexamined Patent Publication 5-220219 publication
Patent documentation 2: Japanese Unexamined Patent Publication 5-168699 publication
Summary of the invention
The problem that invention is to be solved
But, the filtrations such as ascites the viscosity adhesiveness high, protein of the protein aqueous solution generated is high, therefore,
Even if being a small amount of concentration of about 1L, protein is also adhered to separate film, and the situation that separation film starts to produce blocking is more.Open
When beginning to produce blocking, moisture is difficult to the emptying aperture by separating film, therefore, it is impossible to remove moisture removal fully from protein aqueous solution,
It is difficult to the powerful concentration of about 5 times.Herein, concentration rate refers to, the protein aqueous solution amount before concentration is divided by dense
Contracting liquid measure and the value that obtains.On the other hand, it is desirable to during suppression blocking, if improving the porosity separating film, then current protein
Also can spill by separating the emptying aperture of film together with moisture.Its result, the egg in the protein solution being concentrated (concentrated solution)
The response rate step-down of white matter.
The application makes in view of above-mentioned aspect, it is intended that the egg generated filtering the coelomic fluids such as ascites
White matter aqueous solution carries out in the concentrator concentrated, it is achieved powerful concentration and guarantee the high-recovery of protein.
For solving the scheme of problem
The present inventor etc. find: by the porosity separating film of concentrator and hydrophilicity are adjusted to the model of regulation
Enclose, such that it is able to realize powerful concentration and realize high protein recovery, so far complete the present invention.
That is, the solution of the present invention includes following.
A () a kind of concentrator, it concentrates by separating film for the protein aqueous solution generated filtering coelomic fluid
Concentrator,
Aforementioned separation membrane is constituted as follows: the porosity of more than 60% and less than 80% and utilize capillary rise method to survey
The liquid level rising value of fixed aforementioned separation membrane is 60mm～150mm when being scaled the hollow-fibre membrane of internal diameter 200 μm, makes in enforcement
The protein aqueous solution stock solution of concentration 3g/dL is led to liquid with the flow velocity speed of 50mL/ minute and is obtained the concentration of protein aqueous solution
In the case of the enrichment process of liquid, meet following condition (1), (2).
(1) the intermembranous pressure differential of maximum when 5L protein aqueous solution stock solution being concentrated is below 500mmHg,
(2) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, by dense for 5L protein aqueous solution stock solution
In the case of intermembranous pressure differential during contracting is set to B, B/A≤1.6.
B (), according to the concentrator described in (a), wherein, aforementioned separation membrane is constituted as follows: in the feelings implementing aforementioned enrichment process
Under condition, meet following condition (3), (4) further.
(3) protein recovery of the concentrated solution obtained when 2L protein aqueous solution stock solution being concentrated is more than 40%,
(4) protein recovery of the concentrated solution obtained when 5L protein aqueous solution stock solution being concentrated is more than 70%.
C 5L protein aqueous solution stock solution, according to the concentrator described in (b), wherein, in aforementioned condition (4), is concentrated by ()
Time the albuminous response rate of concentrated solution that obtains be more than 80%.
D (), according to the concentrator according to any one of (a)～(c), wherein, aforementioned separation membrane is constituted as follows: before enforcement
In the case of stating enrichment process, meet following (5) further.
(5) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, by 10L protein aqueous solution stock solution
In the case of intermembranous pressure differential during concentration is set to C, C/A≤1.5.
E (), according to the concentrator according to any one of (a)～(d), wherein, the base material that aforementioned separation membrane is used is polysulfones
System, ethylene-vinyl alcohol system, acetate fiber prime system, polyethylene-based, Polyester polymer alloy (PEPA), polymethyl methacrylate
System (PMMA) or polyacrylonitrile.
F (), according to the concentrator according to any one of (a)～(e), wherein, aforementioned separation membrane is hollow-fibre membrane.
G (), according to the concentrator described in (f), wherein, aforementioned separation membrane is the hollow-fibre membrane of polysulfones system.
The effect of invention
According to the present invention, the protein aqueous solution generated filtering coelomic fluid carries out in the concentrator concentrated, Ke Yishi
Show powerful concentration and guarantee the high-recovery of protein.
Accompanying drawing explanation
Fig. 1 is the explanatory diagram of the summary of the composition illustrating ascites processing system.
Fig. 2 is the explanatory diagram of the longitudinal section of concentrator.
Fig. 3 is the figure illustrating intermembranous pressure differential relative to the variation of stock solution concentration amount.
Fig. 4 is to be exaggerated to separate the schematic diagram that film obtains.
Fig. 5 is the explanatory diagram of the summary of the ascites processing system illustrating embodiment.
Description of reference numerals
1 ascites processing system
22 concentrators
60 separate film
Detailed description of the invention
Hereinafter, referring to the drawings, the preferred embodiment of the present invention is illustrated.It should be noted that accompanying drawing is upper and lower
The position relationships such as left and right are as long as no special provision, it is simply that based on position relationship shown in the drawings.The dimensional ratios of accompanying drawing does not limits
Ratio due to diagram.And then, following embodiment is the example for the present invention is described, is not the present invention to be only defined in
This embodiment.It addition, the present invention can be carried out various deformation without departing from its purport.
Fig. 1 is the ascites processing system 1 of the coelomic fluid processing system of the concentrator 22 being shown as possessing present embodiment
The explanatory diagram of summary of composition.
As shown in Figure 1, ascites processing system 1 possesses such as ascites treatment loop 10 as fluid loop.Ascites
Treatment loop 10 has: as the ascites bag 20 of coelomic fluid reservoir；Filter 21；Concentrator 22；As concentrated solution reservoir
Concentration ascites bag 23；Connect ascites bag 20 and the first flow path 24 of filter 21；Connect the of filter 21 and concentrator 22
Two streams 25；With, connect concentrator 22 and concentrate the 3rd stream 26 of ascites bag 23.
Ascites bag 20, for example, by the container of the resin formation of the soft property such as polrvinyl chloride, can be received and adopt as from patient
The ascites of the coelomic fluid of collection.
Filter 21 has filter membrane 30, and described filter membrane 30 removes the specific cause of disease thing such as cancerous cell, antibacterial from ascites
Matter, the protein aqueous solution (filtrate) of the protein such as the albumin making to comprise in addition the hollow-fibre membrane shape passed through
Become.In filter 21, such as ascites is supplied to from the entrance of the primary side (inner side of hollow-fibre membrane) of filter membrane 30, this ascites
Discharged to the secondary side (outside of hollow-fibre membrane) of filter membrane 30 by filter membrane 30, such that it is able to filter ascites.Filter
The primary side of the filter membrane 30 of 21 outlet and do not connected by the not shown discharge opeing portion of discharge opeing by the composition of filter membrane 30.
It addition, such as ascites is supplied to from the entrance of the secondary side (outside of hollow-fibre membrane) of filter membrane 30, this ascites is by filtering
Film 30 is discharged to the primary side (inner side of hollow-fibre membrane) of filter membrane 30, thus can also filter ascites.
The pipe of the soft property such as first flow path 24 for example, polrvinyl chloride, from the filtration of the outlet of ascites bag 20 Yu filter 21
The entrance of the primary side of film 30 connects.Such as it is provided with tube pump 40 in first flow path 24, the ascites of ascites bag 20 can be delivered to
Filter 21.It should be noted that tube pump 40 can also be not provided with and the ascites of ascites bag 20 is fallen by gravity and was supplied to
Filter 21.
Concentrator 22 has separation film 60, and described separation film 60 is by by the moisture removal in the filtrate by filter 21
And the hollow-fibre membrane carrying out concentrating is formed.Concentrator 22 has cylindrical container 50, in the inside of cylindrical container 50, long along it
Degree direction is configured with separation film 60.The inner side (space) of separation film 60 it is provided with in the upper and lower of cylindrical container 50
Mouth 51,52, the side surface part at cylindrical container 50 is provided with 2 mouths 53,54 in the outside (space) separating film 60.Concentrator
The mouth 51 on the top of 22 connects with filter 21 via second flow path 25.The mouth 52 of the bottom of concentrator 22 is via the 3rd stream 26
Connect with concentrating ascites bag 23.The mouth 53 of the side surface part of concentrator 22 and the moisture removed are by the not shown discharge opeing of discharge opeing
Portion connects.It addition, the mouth 54 of filter 22 is such as closed.In concentrator 22, such as protein aqueous solution is from separating film 60
The entrance of primary side (inner side of hollow-fibre membrane) is supplied to, moisture contained in this protein aqueous solution by separate film 60 to
The secondary side (outside of hollow-fibre membrane) separating film 60 departs from, such that it is able to condensing protein aqueous solution.For concentrator 22
The details of composition aftermentioned.
The soft property pipes such as second flow path 25 for example, polrvinyl chloride, from the outlet of the secondary side of the filter membrane 30 of filter 21
Connect with the mouth 51 of the primary side that concentrator 22 separates film 60.Such as be provided with tube pump 70 in second flow path 25, can by by
The filtrate that filter 21 filters delivers to concentrator 22.
The soft property pipes such as the 3rd stream 26 for example, polrvinyl chloride, from the mouth 52 of the primary side separating film 60 of concentrator 22
It is connected with concentrating ascites bag 23.
Concentration ascites bag 23, can be with collecting bag containing by dense for example, by the container of the resin formation of the soft property such as polrvinyl chloride
The concentrated solution of the protein that contracting device 22 concentrates.
Then, the composition for concentrator 22 illustrates.Fig. 2 is the longitudinal section of the summary of the composition illustrating concentrator 22
Explanatory diagram.
Concentrator 22 has cylindrical container 50 as described above, in the inside of cylindrical container 50, joins along its length direction
It is equipped with the separation film 60 as hollow-fibre membrane.Cylindrical container 50 is by cylindric container body portion 50a and closes container body
The top cover 50b of the both ends open of portion 50a is constituted.Mouth 51,52 is formed at top cover 50b, and mouth 53,54 is formed at container body portion 50a.
The Embedding Material 80 of curable resin is passed through by embedding in the both ends separating film 60 at the both ends of cylindrical container 50
Processing.Thus, cylindrical container 50 is fixed at the both ends separating film 60, is formed with separation film 60 at the both ends of cylindrical container 50
The open end 81 of interior side opening of each hollow-fibre membrane.The hollow-fibre membrane separating film 60 of the inside of cylindrical container 50
Outer space connects with the mouth 53,54 of the side surface part of cylindrical container 50.The inner space of the hollow-fibre membrane separating film 60 passes through
Open end 81 connects with mouth 51,52.By above-mentioned composition, as the protein aqueous solution of filtrate from mouth 51 to separating film 60
Inner space flow into, the moisture of this protein aqueous solution by separate film 60 to separate film 60 outer space flow out, permissible
Moisture removal is gone to concentrate from protein aqueous solution.The moisture flowed into the outer space separating film 60 can be from mouth 53 row
Go out.It addition, by separate the inner space of film 60 eliminate the protein aqueous solution of moisture from mouth 52 to concentrate ascites bag 23 with
The form of concentrated solution is discharged.
Separate film 60 to constitute as follows: the porosity of more than 60% and less than 80% and utilize capillary rise method to measure
The liquid level rising value of aforementioned separation membrane be 60mm～150mm when being scaled the hollow-fibre membrane of internal diameter 200 μm, implement to make dense
The protein aqueous solution stock solution of degree 3g/dL is led to liquid with the flow velocity speed of 50mL/ minute and is obtained the concentrated solution of protein aqueous solution
Enrichment process P in the case of, meet following condition (1), (2).
(1) the intermembranous pressure differential of maximum when 5L protein aqueous solution stock solution being concentrated is below 500mmHg.
(2) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, by dense for 5L protein aqueous solution stock solution
In the case of intermembranous pressure differential during contracting is set to B, B/A≤1.6.
I.e., as shown in Figure 3, for separating film 60, make the protein aqueous solution stock solution of concentration 3g/dL with flow velocity
In the case of the speed of 50mL/ minute is led to liquid in this separation film 60 and concentrated, during so that 5L protein aqueous solution stock solution is concentrated
The intermembranous pressure differential of maximum (separating the maximum of the difference of the pressure of pressure and the secondary side of the primary side of film 60) be 500mmHg with
Under and B (intermembranous pressure differential when 5L protein aqueous solution stock solution is concentrated)/A (when 2L protein aqueous solution stock solution is concentrated
Intermembranous pressure differential) be less than 1.6 mode adjust porosity and hydrophilicity.Curve S1, S2, S3 in Fig. 3 illustrate satisfied
Above-mentioned condition (1), the separation film of (2), curve S4, S5 illustrate the separation film of the condition of being unsatisfactory for (1), (2).
It should be noted that porosity is defined by following formula.
Porosity=(Y-X) × 100/Y
X: the weight of a certain amount of film
Y: weight (when not having space) during assuming that a certain amount of film of X is filled up by base material.
In the present invention, porosity is necessary for more than 60% and less than 80%.More preferably more than 65% and less than 80%, as
Fruit is more than 65% and less than 75% the most further preferred.During less than 60%, during concentration, easily produce blocking, thus the most preferred.Separately
Outward, during more than 80%, it is big that protein during concentration spills quantitative change, for the most preferred.Separating film is flat membranaceous rather than doughnut
Also above-mentioned formula is utilized to calculate porosity time membranaceous.
In the present invention, hydrophilicity is measured by capillary rise method.In the present invention, so-called capillary rise method refers to,
One end of the hollow opening oral area of hollow-fibre membrane the one side of flat film (situation of flat film be) be impregnated in aqueous solution, after certain time
The method measuring the height of the water surface of the liquid level that distance utilizes capillarity to rise.Specifically refer to, at following front place
Reason (P), (Q), film distilled water for injection will be separated it is carried out (P), makes separation film fully be dried after (Q), will be dried
After the one end separating film impregnated in aqueous solution, measure distance after a certain time and utilize the water of liquid level that capillarity rises
The method of the height in face.
In the case of the separation film of tubular structure, rising about capillary tube, commonly known have following relational expression.
H=2 γ cos θ/r ρ g
H: the lifting height of distance liquid side
The surface tension of γ: liquid
θ: contact angle (from the angle of the contact surface of solid and liquid to liquid Yu the contact surface of gas)
R: pipe radius
The density of ρ: liquid
G: acceleration of gravity
That is, by measuring r (pipe radius), ρ (fluid density), h (lifting height of distance liquid side), such that it is able to measure
The surface tension of liquid, according to this relational expression, tubular body structure inner surface is to the moistening easiness of liquid, i.e. hydrophilic, hydrophobic
Property degree can according in capillary tube liquid level rise degree and evaluate.
Therefore, doughnut inner surface can also be measured to water by above-mentioned capillary rise method in the case of separating film
The degree of the moistening easiness of solution, i.e. hydrophilic (hydrophobicity).Even if it addition, be the different separation film of internal diameter, by measuring
Liquid level rising value in each capillary tube and internal diameter, carry out the relation according to above formula and be scaled the internal diameter separating film as benchmark
Correction, such that it is able to by the degree of each hydrophilic (hydrophobicity) using the shape of liquid level rising value separating film of the internal diameter as benchmark
Formula definitely compares.In the present invention, as liquid level rising value, use the school that the internal diameter of hollow-fibre membrane is scaled 200 μm
On the occasion of.When measuring the capillary tube rising value separating film, separate the moisture rate of film, measured value is impacted by internal diameter, it is therefore necessary to
Measured in advance moisture rate and internal diameter.As the moisture rate separating film, it is necessary to be less than 5%, when moisture rate is more than 5%, separate film
Being difficult to embody the hydrophobic character of the inner surface substantially being had, its capillary tube rising value becomes to demonstrate big mensuration
Value, it is impossible to measure accurately.
When measuring the liquid level rising value of aqueous solution based on capillarity, its minute is also important.Separate film
When being hydrophilic further, the speed of the aqueous solution being gradually increasing accelerates, and in the mensuration in the short time, measured value can produce ripple
Dynamic.In addition, it is difficult to a large amount of sample of single-time measurement.Practical minute be preferably will separate film immersion after aqueous solution through
The moment of more than 5 seconds, more practicably it is preferably set to the appropriate time within 3 minutes.In the present invention, it is shown that the value after 1 minute.
In the case of separation film is flat film, hydrophilicity is investigated by contact angle (chemistry brief guide etc.), or it is same to be set to use
Liquid level rising value based on capillary rise method in the hollow-fibre membrane of internal diameter 200 μm of the one same composition of material.
In the present invention, the rising value of the aqueous solution measured by capillary rise method, the internal diameter of hollow-fibre membrane is changed
Calculation is that the corrected value of 200 μm is necessary for more than 60mm and below 150mm.More preferably more than 65mm and below 145mm, if
More than 70mm and below 140mm are the most further preferred.As described later, less than 60mm, in the case of i.e. hydrophilic is too low, or
Higher than 150mm, in the case of i.e. hydrophilic is too high, the constraint protein layer F1 of separation membrane surface also becomes blocked up, concentration rate
Reduce, thus the most preferred.
As shown in Figure 4, such as in separating film 60 during logical liquid protein aqueous solution, the cumulative volume i.e. hole of 60a part
During gap rate height, during separation, be not likely to produce blocking, powerful concentration can be carried out, be but then protein also with moisture one
Rising and pass through, the response rate of protein reduces.Think by porosity is adjusted to suitable scope, such that it is able to guarantee permeable
Measure and do not make protein pass through.
And then, it will usually thinking, can be formed on the surface separating film 60 irreversibly to pile up has the egg of protein aqueous solution
The constraint protein layer F1 of white matter and reversibly pile up and have the free protein layer F2 of protein.This constraint protein layer F1 and from
Piled up by protein layer F2 and thickness increase time, produce separate film 60 blocking, through separate film 60 permeable amount reduce, concentrate
Rate reduces.Herein, present inventor etc. thinks, the thickness of constraint albumin layer F1 is adjusted to relatively thin and suppresses blocking.
Find that the thickness of constraint protein layer F1 depends on the hydrophilicity separating film 60.That is, find: overall the dredging of film
In situation that aqueous is too strong and the too strong situation both of these case of the overall hydrophilic of contrary mulch film, protein be easily adhered in
Separating film 60, protein layer F1 is thickening in constraint.Thus, the present invention is by adjusting the porosity and hydrophilicity that separate film 60
For being suitably worth, thus the thickness of constraint protein layer F1 is adjusted to suitable scope, accordingly ensure that separate the permeable of film 60
Amount, it is achieved high enrichment factor, and suppression protein is from separating spilling of film 60, it is ensured that the high-recovery of protein.
The base material that separation film 60 is used is ethylene-vinyl alcohol system, acetate fiber prime system, the polyethylene such as polysulfones system, Eval
System, Polyester polymer alloy (PEPA), polymethyl methacrylate system (PMMA) or polyacrylonitrile, particularly preferably polysulfones
The base material of system.It addition, hydrophilicity is adjusted by the hydrophilicity-imparting treatment implementing to add hydrophilic agent in base material, make
For hydrophilic agent, such as, can enumerate: the ethylene such as polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, polypropylene glycol, Eval-
Ethenol copolymer, Poly(Hydroxyethyl Methacrylate) etc..Separate the adjustment of hydrophilicity of film 60 by the kind adjusting such as base material
Class, the amount of hydrophilic agent, the kind of hydrophilic agent are carried out.
Such as drawn by adjustment in the case of the separation film of opening utilizing hot-stretch it addition, separate the porosity of film 60
Stretch temperature, draw speed, draw roll diameter are carried out.It addition, in the case of using double-spinneret etc. to carry out wet spinning, pass through
The adjustment velocity of discharge of polymer dope, the composition of interior liquid, spinning temperature are carried out.
According to present embodiment, the value of maximum intermembranous pressure differential will not become greatly (even if entering in the enrichment process P of rated condition
Row 5L concentrate also can maintain below 500mmHg) and the climbing of intermembranous pressure differential little (in enrichment process P B/A≤1.6 with
Under), it is therefore contemplated that the porosity and hydrophilicity that separate film 60 to be set as the result of the scope being specifically worth is,
The thickness of constraint protein layer F1 can be adjusted to the scope of desired value.Thus, the protein generated filtering ascites is water-soluble
Liquid carries out in the concentrator concentrated, it can be ensured that separate the permeable amount of film 60, suppresses protein spilling from separation film 60, because of
This, it is possible to achieve powerful concentration and realize the high-recovery of protein.
In above-mentioned embodiment, separate film 60 and constitute as follows: the porosity of more than 60% and less than 80% and utilize hair
The liquid level rising value of aforementioned separation membrane that tubule rise method measures when being scaled the hollow-fibre membrane of internal diameter 200 μm be 60mm～
150mm, makes the protein aqueous solution stock solution of concentration 3g/dL lead to liquid with the flow velocity speed of 50mL/ minute in enforcement and obtains albumen
In the case of the enrichment process P of the concentrated solution of matter aqueous solution, following condition (3), (4) can be met further.
(3) protein recovery of the concentrated solution obtained when 2L protein aqueous solution stock solution being concentrated is more than 40%.
(4) protein recovery of the concentrated solution obtained when 5L protein aqueous solution stock solution being concentrated is more than 70%.
In the case of above-mentioned, for separating film 60, by porosity and hydrophilicity being set as the scope of desired value, from
And spilling of the protein in separation film 60 can be reduced, it is achieved the high-recovery of protein.
It addition, for separate film 60, can 5L protein aqueous solution stock solution is concentrated under above-mentioned condition (4) time obtain
The albuminous response rate of concentrated solution be further more than 80% mode set porosity and hydrophilicity.
It addition, in above-mentioned embodiment, separate film 60 and constitute as follows: the porosity of more than 60% and less than 80% and
The liquid level rising value utilizing the aforementioned separation membrane that capillary rise method measures when being scaled the hollow-fibre membrane of internal diameter 200 μm is
60mm～150mm, makes the protein aqueous solution stock solution of concentration 3g/dL lead to liquid with the flow velocity speed of 50mL/ minute in enforcement and obtains
In the case of the enrichment process P of the concentrated solution of protein aqueous solution, following condition (5) can be met further.
(5) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, by 10L protein aqueous solution stock solution
In the case of intermembranous pressure differential during concentration is set to C, C/A≤1.5.
That is, for separating film 60, (10L protein aqueous solution stock solution is concentrated implementing in the case of enrichment process P, C
Time intermembranous pressure differential)/A (intermembranous pressure differential when 2L protein aqueous solution stock solution is concentrated) be less than 1.5 mode adjust
Porosity and hydrophilicity.
It is believed that in the case of above-mentioned, the rising of intermembranous pressure differential when can concentrate carrying out 10L in enrichment process P
Rate suppression for less, concentrates more protein aqueous solution even if therefore long-time, and intermembranous pressure differential also will not rise, can be by
The thickness of compacted zone F1 is maintained suitably value.Thus, ascites will be filtered and that the protein aqueous solution that generates carries out concentrating is dense
In contracting device, it can be ensured that separate the permeable amount of film 60, suppression protein, from separating spilling of film 60, therefore can realize high magnification
Concentration, and realize the high-recovery of protein.
Above, the preferred embodiment of the present invention is illustrated on limit by limit referring to the drawings, but the present invention is not limited to above-mentioned
Example.It will be apparent to those skilled in the art that it is contemplated that each in the thought range described in claim
Plant modification or fixed case, it is thus understood that these also be would naturally fall within to the technical scope of the present invention.
The composition of the concentrator 22 in the most above-mentioned embodiment is not limited to this.It addition, have the ascites of concentrator 22
The composition of processing system 1 is also not limited to this.The separation film 60 of concentrator 22 can be hollow-fibre membrane, as long as egg can be separated
The moisture of white matter aqueous solution, it is also possible to for other kinds of film, the most flat film.
It addition, the present invention can also be applied to other coelomic fluids beyond by ascites, such as hydrothorax, pericardial fluid concentrate dense
Contracting device.
Embodiment
In below example, it is shown that the ascites concentration rate in the present invention and final protein recovery are carried out
The experimental result of checking.In the present embodiment, the liquid of the protein aqueous solution before simulation being concentrated is referred to as " stock solution ".
As shown in Figure 5, configuration stock solution reservoir 100, concentrator 101, concentrated solution reservoir 102, piezometer 103,
104,105 and pump 106,107, it is attached with loop.As piezometer, use Manometer (NIDEC COPAL
ELECTRONICS CORP. manufacture, PG-200-102GP-P).Pump uses the roller pump (RP-1000) of EYELA Co., Ltd.,
The mode that pump 106 is 50mL/ minute with flow velocity is set, and the mode that pump 107 is 40mL/ minute with flow velocity is set.
Manufacture method ＞ of ＜ stock solution
Make the simulation ascites comprising blood cell composition of the blood using cattle.First, the liver as anticoagulant will be added with
The bovine blood of element sodium injection (10,000 units/bovine blood 1L) is centrifuged separating, and obtains plasma layer, layer of red blood cells and erythrocyte sedimentation rate palm fibre
They are separately recovered, thus obtain blood plasma by each solution of yellow layer (buffy coat).Then, with filter (Asahi Kasei medical treatment
The ascites filter AHF-MO-W that Co., Ltd. manufactures) filtered plasma, then mix normal saline, thus be prepared as albumen
Matter concentration 3.0 (g/dL), stock solution 10L of albumin concentration 1.5 (g/dL).
The assay method of ＜ protein concentration and the calculation method ＞ of protein recovery
Protein concentration is measured by Biuret Method.Use automatic analysing apparatus (Tokyo trade medical system Co., Ltd.
Manufacture, Biolis24i), use Iatro TPII (LSI Medience Corporation manufacture) as mensuration reagent.
Albumen quality in stock solution is set to TP1, the albumen quality of concentrated solution is when being set to TP2, and protein recovery uses
Below formula calculates.
Protein recovery=TP2/TP1 × 100 (%)
The assay method of ＜ albumin concentration and the calculation method ＞ of the albumin response rate
Albumin concentration is measured by BCG method.Use automatic analysing apparatus (Tokyo trade medical system Co., Ltd. system
Make, Biolis24i), use Iatrofine ALBII (LSI Medience Corporation system as mensuration reagent
Make).
When the albumin amount that albumin amount in stock solution is set in ALB1, concentrated solution is set to ALB2, the albumin response rate
Below formula is used to calculate.
The albumin response rate=ALB2/ALB1 × 100 (%)
The assay method ＞ of the intermembranous pressure differential of ＜
When pressure shown in piezometer 103, piezometer 104, piezometer 105 is set to P1, P2, P3, intermembranous pressure
Official post calculates by following formula.
Intermembranous pressure differential=(P1+P2)/2-P3 (mmHg)
The calculation method ＞ of the ratio (B/A, C/A) of the intermembranous pressure differential of ＜
Intermembranous pressure differential when intermembranous pressure differential when stock solution 2L being processed is set to A (mmHg), stock solution 5L processes is set to B
(mmHg) intermembranous pressure differential when, stock solution 10L processes is set to C (mmHg).The ratio of intermembranous pressure differential be set to above-mentioned B and C divided by A,
By the 2nd value rounded up and obtain of arithmetic point.
＜ concentration rate ＞
Stock solution amount is set to 10L, using its divided by concentrate liquid measure X gained value as concentration rate, carry out as described below
Judge.
Concentration rate is 5 times
Concentration rate less than 5 times ×
In the present embodiment, the flow of pump 106 is 50mL/ minute, and the flow of pump 107 is 40mL/ minute, if therefore existed
Can not carry out total amount concentration in the case of blocking, then concentrating liquid measure is 2L, and concentration rate is 5 times.
＜ final protein recovery ＞
When albumen quality in concentrated solution albumen quality in stock solution is set to TP1, finally giving is set to TP3, finally
Protein recovery uses below formula to calculate.
Final protein recovery=TP3/TP1 × 100 (%)
It addition, judge final protein recovery as described below.
Final protein recovery is more than 50%
Final protein recovery less than 50% ×
(embodiment 1)
As concentrator, use internal diameter 200 μm, thickness 45 μm, length 330mm, porosity 78%, rise based on capillary tube
The liquid level rising value 110mm's of method is dense by polysulfones/polyvinylpyrrolidone doughnut 9000 hollow fiber membrane-type formed
Contracting device.Show the result in table 1.
(embodiment 2)
As concentrator, use internal diameter 185 μm, thickness 45 μm, length 330mm, porosity 73%, rise based on capillary tube
The liquid level rising value 120mm of method (with the value of internal diameter 200 μm conversion) by polysulfones/polyvinylpyrrolidone doughnut 10600
The hollow fiber membrane-type concentrator that root is formed, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
(embodiment 3)
As concentrator, use internal diameter 185 μm, thickness 45 μm, length 330mm, porosity 60%, rise based on capillary tube
The liquid level rising value 120mm of method (with the value of internal diameter 200 μm conversion) by polysulfones/polyvinylpyrrolidone doughnut 10600
The hollow fiber membrane-type concentrator that root is formed, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
(embodiment 4)
As concentrator, use internal diameter 185 μm, thickness 45 μm, length 330mm, porosity 72%, rise based on capillary tube
The liquid level rising value 150mm of method (with the value of internal diameter 200 μm conversion) by ethylene-vinyl alcohol copolymer (Eval) doughnut
10600 hollow fiber membrane-type concentrators formed, in addition, carry out experiment similarly to Example 1.Show the result in table
1。
(embodiment 5)
As concentrator, use internal diameter 200 μm, thickness 45 μm, length 330mm, porosity 80%, rise based on capillary tube
The liquid level rising value 110mm's of method is dense by polysulfones/polyvinylpyrrolidone doughnut 9000 hollow fiber membrane-type formed
Contracting device, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
(embodiment 6)
As concentrator, use internal diameter 200 μm, thickness 45 μm, length 330mm, porosity 63%, rise based on capillary tube
The liquid level rising value 70mm's of method is dense by polyether sulfone/polyvinylpyrrolidone doughnut 9000 hollow fiber membrane-type formed
Contracting device, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
(embodiment 7)
As concentrator, use internal diameter 200 μm, thickness 45 μm, length 330mm, porosity 70%, rise based on capillary tube
The hollow fiber membrane-type concentrator formed by Triafol T doughnut 9000 of the liquid level rising value 60mm of method, except this
Outside, carry out experiment similarly to Example 1.Show the result in table 1.
(comparative example 1)
As concentrator, use internal diameter 200 μm, thickness 45 μm, length 330mm, porosity 52%, rise based on capillary tube
The liquid level rising value 180mm of method by 9000 hollow-fibre membranes formed of ethylene-vinyl alcohol copolymer (Eval) doughnut
Type concentrator, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
(comparative example 2)
As concentrator, use internal diameter 185 μm, thickness 45 μm, length 330mm, porosity 55%, rise based on capillary tube
The liquid level rising value 110mm of method (with the value of internal diameter 200 μm conversion) by polysulfones/polyvinylpyrrolidone doughnut 10600
The hollow fiber membrane-type concentrator that root is formed, in addition, carries out experiment similarly to Example 1.Show the result in table 1.
[table 1]
Industrial applicability
The present invention carries out realizing high magnification in the concentrator concentrated at the protein aqueous solution generated filtering coelomic fluid
Concentration and be useful when guaranteeing the high-recovery of protein.
Claims (7)
1. a concentrator, it carries out the concentration concentrated for the protein aqueous solution generated filtering coelomic fluid by separation film
Device,
Described separation film is constituted as follows: the porosity of more than 60% and less than 80% and utilize capillary rise method to measure
The liquid level rising value of described separation film is 60mm～150mm when being scaled the hollow-fibre membrane of internal diameter 200 μm, makes concentration in enforcement
The protein aqueous solution stock solution of 3g/dL is led to liquid with the flow velocity speed of 50mL/ minute and is obtained the concentrated solution of protein aqueous solution
In the case of enrichment process, meet following condition (1), (2),
(1) the intermembranous pressure differential of maximum when 5L protein aqueous solution stock solution being concentrated is below 500mmHg,
(2) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, when 5L protein aqueous solution stock solution being concentrated
Intermembranous pressure differential be set to B in the case of, B/A≤1.6.
Concentrator the most according to claim 1, wherein, described separation film is constituted as follows: implementing described enrichment process
In the case of, meet following condition (3), (4) further,
(3) protein recovery of the concentrated solution obtained when 2L protein aqueous solution stock solution being concentrated is more than 40%,
(4) protein recovery of the concentrated solution obtained when 5L protein aqueous solution stock solution being concentrated is more than 70%.
Concentrator the most according to claim 2, wherein, in described condition (4), concentrates 5L protein aqueous solution stock solution
Time the albuminous response rate of concentrated solution that obtains be more than 80%.
4. according to the concentrator according to any one of claims 1 to 3, wherein, described separation film is constituted as follows: described in implementing
In the case of enrichment process, meet following (5) further,
(5) intermembranous pressure differential when 2L protein aqueous solution stock solution being concentrated is set to A, 10L protein aqueous solution stock solution is concentrated
Time intermembranous pressure differential be set to C in the case of, C/A≤1.5.
5. the base material that according to the concentrator according to any one of Claims 1 to 4, wherein, described separation film is used is polysulfones
System, ethylene-vinyl alcohol system, acetate fiber prime system, polyethylene-based, Polyester polymer alloy (PEPA), polymethyl methacrylate
System (PMMA) or polyacrylonitrile.
6. according to the concentrator according to any one of Claims 1 to 5, wherein, described separation film is hollow-fibre membrane.
Concentrator the most according to claim 6, wherein, described separation film is the hollow-fibre membrane of polysulfones system.
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|---|---|---|---|---|
| CN113049278A (en) * | 2019-12-27 | 2021-06-29 | 旭化成医疗株式会社 | Evaluation test method of coelomic fluid concentrator |
| TWI794706B (en) * | 2019-12-27 | 2023-03-01 | 日商旭化成醫療股份有限公司 | Test solution for evaluating protein recovery performance of body cavity fluid concentrator and manufacturing method thereof |
| TWI808366B (en) * | 2019-12-27 | 2023-07-11 | 日商旭化成醫療股份有限公司 | Evaluation test method for body cavity fluid concentrator |
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| JP7131038B2 (en) * | 2018-04-04 | 2022-09-06 | 東洋紡株式会社 | Hollow fiber membrane for ascites filtration |
| JP7395348B2 (en) * | 2019-12-27 | 2023-12-11 | 旭化成メディカル株式会社 | Evaluation test method for body cavity fluid concentrator |
| JP7402680B2 (en) * | 2019-12-27 | 2023-12-21 | 旭化成メディカル株式会社 | Test liquid for evaluating protein recovery performance of body cavity fluid concentrator and its manufacturing method |
| WO2022265104A1 (en) * | 2021-06-18 | 2022-12-22 | ニプロ株式会社 | Concentrator |
| WO2024181277A1 (en) * | 2023-02-28 | 2024-09-06 | ニプロ株式会社 | Ascites filter |
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| JP2016154809A (en) | 2016-09-01 |
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