CN1725998A

CN1725998A - Virus-removing bag and virus-removing method using the same

Info

Publication number: CN1725998A
Application number: CN 200380106024
Authority: CN
Inventors: 堀隆博; 佐藤一石; 高佐健治; 柳濑聪
Original assignee: Asahi Kasei Kogyo KK
Current assignee: Asahi Kasei Corp
Priority date: 2002-12-12
Filing date: 2003-12-12
Publication date: 2006-01-25

Abstract

The present invention provides a virus-removing bag for removing virus from a virus-containing suspension, including a bag-like casing (a) having at least one inlet and at least one outlet, and including a partition wall (b) at least portion of which is constructed from a virus-removing film, the partition wall (b) being reliably held inside the bag-like casing (1) and dividing the inside space of the bag-like casing (a) into a first compartment (c) communicating with the inlet and a second compartment (d) communicating with the outlet.

Description

Virus is removed bag and is used this virus to remove the method that bag removes virus removal

Background of invention

Invention field

The present invention relates to virus and remove bag, more specifically, the virus that the present invention relates to is removed bag and is comprised bag-like container (a), and it has the inlet of at least one suspension that is used to contain virus and at least one is used for removing the outlet of the suspension of virus removal; And barrier film (b), it is firmly held in the bag-like container (a) and with the inner space in the bag-like container (a) and is divided into first Room (c) that communicates with inlet and second Room (d) that communicates with outlet, at least a portion of its septation (b) is removed striping by virus and is made, described virus is removed striping and is used for removing virus removal by filtering from the suspension that contains virus, obtain filtrate, this filtrate is for removing the suspension of virus removal, and wherein first Room (c) is used to hold the suspension of introducing by inlet that contains virus, and second Room (d) is used to collect by virus and removes the filtrate that suspension that membrane filtration contains virus obtains.The invention still further relates to by using above-mentioned virus to remove the method that bag removes virus removal.Remove bag when virus of the present invention and be used for removing the filtrate of bag internal gathering as the suspension that removes virus removal in virus when the suspension that contains virus removes virus removal, therefore the container that does not need to provide independent is used to hold filtrate.Therefore, the advantage that virus of the present invention is removed bag is not only its simple structure, and can remove by being easy to operation realization virus.The invention still further relates to preparation and removed the method for the blood plasma of virus removal.The advantage of method of the present invention is, can not carry out the sterile working of any complexity and use large-scale instrument and easily remove all viruses, comprise the virus of the method for detecting virus not included that is adopted in the virus of window phase and the blood treatment field from blood plasma.Therefore, the method for the application of the invention can easily prepare the extremely low blood transfusion blood plasma of danger of viral infection with low cost.

Prior art

Human or animal's blood plasma not only can be used for blood transfusion, and can be used as the raw material of blood plasma product and blood plasma derived product and the material that conduct is used for multiple biotechnology applications.Yet blood plasma has the potential danger of viral pollution.Particularly when using blood plasma, receive this patient and face high risk from viral infection by the blood plasma of viral pollution from being transfused blood by the blood preparation of donating blood of viral pollution.

Donate blood blood by the method for viral infection as preventing, what at first mention is that screening is analyzed.This screening analysis comprises blood donor's application form and the infection analysis of the blood of donating blood.Particularly, carry out the antigen-antibody reaction analysis to causing the virus of severe infections.For several viruses that comprise hepatitis B virus, hepatitis C virus and HIV (human immunodeficiency virus) (Human Immunodeficiency Virus), except the blood of donating blood by the analysis of automatic hematology analyzer device, also carry out manual analysis, any blood that shows positive reaction all goes out of use.

Can't get rid of probability satisfactorily by the said method of current use from the viral infection of the blood of donating blood.In the process of preparation blood plasma derived product, have before virus removes the final processing of filter membrane of ability in use, plasma component is through several purification steps.Therefore, the blood plasma derived product that so obtains only has minimum risk from viral infection.On the other hand,, may not detect some virus that comprises in the blood, therefore, be difficult to fully get rid of the danger that blood transfusion is infected by infection analysis producing blood transfusion with in the process of blood plasma.When virus is used method for detecting virus those whens virus that can not cover and when virus is in so-called " window phase ", can not detect the virus that comprises in the blood by infection analysis.At window phase, virus is not subjected to specially the influence for its antigen-antibody reaction of carrying out.When the virus that comprises in the blood of donating blood was in window phase, this blood can be analyzed by screening.

As another method of getting rid of the viral infection probability from the blood of donating blood, developed and be used for making the virally inactivated technology that blood comprises of donating blood.Be used for making virally inactivated conventional method, two kinds of foremost methods for solvent/detergent treatment of wherein blood of collecting contact with the solution that comprises surfactant and wherein make collect the viral absorbing activity material (for example psoralen derivant) that comprises in the blood thus and make the virus that comprises active substance pass through the genomic photochemistry inactivation processing of photochemical reaction break virus through active light radiation.Yet said method is not all effective to all types of viruses.In addition, the problem that has the low and preparation blood transfusion of the safety that for example is used to make virally inactivated material to increase with the cost of blood or blood constitutent.

Can have the hole by use and for example can prevent that virus from passing the virus that removing by filter of filter comprises in the blood.Can remove by filter effectively, and no matter Virus Type that comprises in the blood (that is, no matter the method for detecting virus whether virus is used covers) and no matter the infective stage (being whether virus is in the window phase) of virus.For example, unexamined Japanese patent application Sho62-67456 and Sho 63-88130 disclose separately by using the filter of being made by hollow fibre to remove the system of virus removal from blood plasma.Particularly, unexamined Japanese patent application Sho 62-67456 has described and wherein blood has been incorporated in the filter element of being made by doughnut, and by using the filtering centrifugal force of promotion that blood is filtered by filter element.In addition, unexamined Japanese patent application Sho 63-88130 described the blood (whole blood) of wherein will donating blood be incorporated in the bags of blood and by centrifugal action from the separation of whole blood plasma component, make isolating plasma component remove the method for filter by virus then.

Yet, when comprising make the blood that is collected in the bags of blood through centrifugal action with blood separation to be virus that the conventional blood processing of hemocyte component and plasma component step is introduced above-mentioned use filter element when removing step, this method has following problem.For the above-mentioned filter element that is filled with doughnut, the outer housing of filter element is made by hard material, therefore problem has been proposed:, have bags of blood to be filtered the destructive danger of unitary outer housing when the bags of blood that comprises whole blood is connected to bags of blood under the condition of filter element when separation of whole blood is the centrifugal action of blood constitutent therein.In order to address this problem, the bags of blood (and not connecting filter element in the above) that need carry out wherein only will comprising whole blood is centrifugal, then with the aseptic operation that is connected to the bags of blood of centrifugal mistake of filter element.Yet, carry out the actual field of blood treatment therein, be difficult to usually be provided for the aseptic aseptic area that is connected to bags of blood of filter element.In addition, passed in and out moving of this aseptic area by for example people and when destroying, the behavior that filter element is connected to the bags of blood step under this non-sterile condition may become another cause of infection when the aseptic condition of aseptic area.

In addition, as meaning in order to obtain the blood of donating blood for bags of blood connects filter element in the above-mentioned method, every blood donor uses a filter element, therefore abandons each filter element after the single of only handling 200 to 400ml (it is the blood flow volume that derives from every blood donor) blood of donating blood uses.Preferred disposable filtering unit has simple as far as possible structure, to reduce its production cost.From this viewpoint, use the filter element of doughnut not to be always adapted to as the disposable filtering unit.As having the more filter element of simple structure, can mention that disclosed leukocyte is not removed filter element in examining Japanese patent application Hei 7-267871.This filter element has wherein will be used for adsorbing removes structure leukocytic, that filter medium that made by supatex fabric is contained in flexible shell.Yet, when will not examine the disclosed filter element of Japanese patent application Hei 7-267871 and be used for centrifugal force and filter, be necessary before filtration comprises the bags of blood of blood filter element and the blood collection bag that is used to collect filtering blood is producing by pipe and arranges continuously on the direction of centrifugal force and be linked in sequence.Cloth bag and filter element need very large space in this way, and the problem of the position relationship change between the bag and filter element in centrifugal process is arranged in addition, thereby make the stable centrifugally operated difficulty that becomes.Therefore, even the filter medium that uses in not examining the disclosed filter element of Japanese patent application Hei 7-267871 is suitable for substituting except that the filter medium of virus removal, leukocyte is removed unitary the problems referred to above and is not resolved yet, just, the required big space of centrifugal filtration and be not resolved yet owing to the position relationship change between bag and the filter element in the centrifugal process makes the become problem of difficulty of stable centrifugally operated.

In addition, when making when the blood plasma process of the blood of donating blood is filtered, particularly when using filter to be used for blocking virus, become serious problem by the blocking filters such as lipid that comprise in the blood plasma with very little aperture.This problem does not occur in the production of the blood plasma derived product after blood plasma wherein filters through several purification steps and to the refining blood plasma that comprises the material that causes obstruction hardly.The blood plasma that obtains immediately after hemocyte component separated plasma at the centrifugal blood of will donating blood is called " fresh plasma ", and there is individual variation in the composition of fresh plasma.Particularly, suffer from hyperlipemia or have the amount of the lipid composition that the people's of high hyperlipemia danger blood plasma may comprise, make when with the blood plasma cool to room temperature, be visually perceptible for the big lipid globule that in blood plasma, forms.When handling this blood plasma,, film cause the amount reduction of handling blood plasma often to become problem because blocking with film.For the method that addresses this is that, unexamined Japanese patent application Hei3-146067 discloses the method that a plurality of filter elements that wherein will have different apertures link together.Yet, produce in this way from donating blood blood preparation blood transfusion (promptly when making with the system of blood plasma, be used for from donate blood blood separation blood plasma and remove the system of virus removal from isolating blood plasma) time, need to adopt a plurality of filter elements of hollow fibre to link together separately.The result is that the major part that virus is removed system length is made of filter element, thereby makes the centrifugally operated difficulty.In addition, the practical problem that has the cost of filter element to uprise.

From above-mentioned apparent, do not have simple virus to remove system or method at present and be suitable for conventional blood processing system and can wherein make the fresh plasma that obtains immediately after donating blood through removing the processing of whole viruses, described virus comprises the virus that is in window phase and can not be by the viral detected virus that is adopted in the blood treatment field.

Summary of the invention

In this case, the inventor has carried out extensive research, to address the above problem.The result, unexpectedly find, remove bag when the suspension that contains virus removes virus removal when using virus, described virus is removed bag and is comprised the bag-like container (a) with entrance and exit and be firmly held in the bag-like container (a) and the inner space of bag-like container (a) is separated into barrier film (b) when entering the mouth first Room (c) that communicates and second Room (d) that communicates with outlet, at least a portion of its septation (b) is removed striping by virus and is made, in first Room (c), collect the suspension that contains virus, the virus of at least a portion by constituting barrier film (b) is removed membrane filtration then, and collection removes the suspension of virus removal, i.e. filtrate in second Room (d).The virus that has a said structure when use is removed bag when the suspension that contains virus removes virus removal, collects filtrate in virus is removed bag, and this filtrate is the suspension except that virus removal.Rely on this performance, the advantage that virus is removed bag is that not only it has simple structure, and is and can removes by being easy to operation realization virus.In addition, the inventor finds, above-mentioned virus is removed bag be attached to the virus that obtains in the conventional plasma treatment system and remove system by using, the blood transfusion blood plasma that can easily have low-down risk from viral infection with the low cost preparation, and need not complicated sterile working or large-scale instrument, the blood transfusion of preparation does not contain any virus with blood plasma, and described virus comprises the virus that virus that is in window phase and the method for detecting virus that is not adopted in the blood treatment field cover.Finished the present invention based on these new discoveries.

Therefore, the purpose of this invention is to provide the virus that not use independent container to hold filtrate by being easy to viral the removing of operation realization and remove bag.

Another object of the present invention provides by using above-mentioned virus to remove bag removes virus removal from the suspension that contains virus method.

Another object of the present invention provides by using above-mentioned virus to remove the be removed method of blood plasma of virus of bag.

By accompanying drawing and additional claim and following detailed description are interrelated, to those skilled in the art, above and other objects of the present invention, feature and advantage are conspicuous.

Description of drawings

In the accompanying drawings:

Fig. 1 represents to have plate diaphragm, and the virus of the present invention of (b) is removed the schematic plan view of the example of bag;

Fig. 2 represents to illustrate that the virus of the present invention of the barrier film (b) of all forms of membranaceous surrounding wall with filter bag removes the sketch map of example of bag, and wherein Fig. 2 (a) removes the plane graph of bag for virus, and Fig. 2 (b) is the cutaway view along the line II-II of Fig. 2 (a);

Fig. 3 represents as the schematic cross sectional views of virus except that the example of the complex filter of striping;

Fig. 4 represents as the schematic cross sectional views of virus except that the example of the complex filter of striping;

Fig. 5 represents to remove as virus the schematic plan view of example of the complex filter of striping, has wherein represented for the integrated and adhesion area that provides of lamination filtering material and supatex fabric is provided;

Fig. 6 represents the sketch map as the example of the filter bag of barrier film (b), wherein each represents that wherein whole surrounding wall integral body of its filter bag are made except that striping by virus to Fig. 6 (a) in Fig. 6 (c), Fig. 6 (d) represents that wherein all parts of surrounding wall of filter bag are made except that striping by virus, and all remainders of the surrounding wall of filter bag are not made by the sheet that does not see through the suspension that contains virus;

Fig. 7 represents to illustrate that virus of the present invention removes the volumetrical sketch map that the bag part is used to determine second Room (d), wherein Fig. 7 (a) removes the plane graph of bag for the virus that comprises plate diaphragm (b), Fig. 7 (b) removes the plane graph of bag for the virus of barrier film (b) of all forms of membranaceous surrounding wall with filter bag, and Fig. 7 (c) is the cutaway view along the VII-VII line of Fig. 7 (b);

Fig. 8 represent the explanation remove the sketch map at the junction surface between plate diaphragm in the bag (b) and the bag-like container (a) in virus of the present invention, the junction surface that forms between the inwall of Fig. 8 (a) expression plate diaphragm (b) and bag-like container (a) wherein, Fig. 8 (b) represents that peripheral part that the peripheral part by plate diaphragm (b) will form at least two sheets of bag-like container (a) adheres to each other the junction surface of formation;

Fig. 9 has represented to be illustrated as and has obtained that virus of the present invention is removed bag and method that filter bag is connected with bag-like container (a), wherein only by as the conduit 13 of inlet filter bag and bag-like container (a) virus connected to one another being removed bag, Fig. 9 (b) wherein removes bag along the whole top periphery part of bag-like container (a) with filter bag and bag-like container (a) virus connected to one another to Fig. 9 (a) for wherein;

Figure 10 (a) is illustrated in the plane graph of the example of the filter bag that the internal diameter of observing filter bag on the flow direction of suspension that contains virus reduces gradually towards the filter bag leading section separately to 10 (f);

Figure 11 represents to illustrate that the virus that comprises spongy adsorbing material in first Room removes the sketch map of the example of bag, and wherein Figure 11 (a) removes the plane graph of bag for virus, and Figure 11 (b) is the cutaway view along the XI-XI line of Figure 11 (a);

Figure 12 represents to illustrate the sketch map of the example of the locating rack (spacer) that uses among the present invention, and wherein Figure 12 (a) is for wherein comprising the plane graph of the locating rack of filter bag, and Figure 12 (b) is the cutaway view along the XII-XII line of Figure 12 (a);

Figure 13 to 22 represents that separately explanation can remove the sketch map of the example of system in the present invention's be used for being removed closed virus that the method for blood plasma of virus uses;

Figure 23 represents to illustrate that the virus that places the centrifuge cup removes the sketch map of example of bag;

Figure 24 represents to illustrate and is used for virus is removed bag sketch map of the example of the fixation hook that is fixed to the centrifuge cup that wherein Figure 24 (a) is the schematic plan view of fixation hook, and Figure 24 (b) is the schematic side elevational view of fixation hook;

Figure 25 represents to illustrate by virus being removed the sketch map that bag applies the example of the filtering method of centrifugal forces enhance, wherein Figure 25 (a) is for connecting the sketch map that virus is removed two rotary bodies of bag between it, Figure 25 (b) is for connecting the sketch map that virus is removed a rotary body of bag at its outer surface, Figure 25 (c) removes the sketch map of a rotary body of bag for the virus of side surface connection within it, Figure 25 (d) is for connecting the sketch map that virus is removed a rotary body of bag at its outer surface, and wherein virus is removed the length of bag the circumference with rotary body is identical basically.

Figure 26 represents to illustrate that the virus that places the centrifuge cup removes the sketch map of example of bag;

Figure 27 represents to illustrate by using the roll-type compressor that virus is removed bag and exerts pressure with the sketch map of the example that promotes filtering method;

Figure 28 represents to illustrate by using board-like compressor that virus is removed bag and exerts pressure with the sketch map of the example that promotes filtering method;

Figure 29 represents to illustrate that comprising pressurization by use removes bag sketch map of the example of the method for exerting pressure with the bag of gas to virus;

Figure 30 represents to illustrate among the embodiment 7 that the virus of producing removes the sketch map of bag constructions;

Figure 31 represents to be used for the sketch map of structure of the tubular hard polysulfones container of reference example 2, and wherein container is as the model of conventional doughnut filtering module; With

Figure 32 represents to illustrate the sketch map of the filter bag shape of producing among the embodiment 8.

The reference number explanation

1 bag-like container (a)

2 plate diaphragms (b)

Room (c) 3 first

Room (d) 4 second

5 inlets

6 outlets

7 filter bags

7a virus is removed striping

7b does not see through the sheet that contains viral suspension

8 viruses are removed filter

9 prefilters

10 supatex fabric

11 complex filters

12 adhesion areas

13 conduits as inlet

The hermetic unit of 14 bag-like containers (a)

Junction surface between 15 barrier films (b) and the bag-like container (a)

16 spongy adsorbing materials

17 locating racks

18 blood taking needles

19 are used for tube for transfusion part melting sealed and that cut off

20 are used for the bags of blood of whole blood

21 the bags of blood of blood plasma after being used to filter

22 leukocyte are removed the unit

23 are used to remove the bags of blood of leukocytic blood

24 are used for the bags of blood of buffy coat

25 comprise the bag of additive etc.

26 are used for removing the bag that bag is removed air from virus

27 comprise the bag of pressurization with gas

28 centrifuge cups

29 fixation hooks

30 hold-down bars

31 centrifugal force directions

32 hooks

33 holding plates

34 standing screws

35 viruses are removed the top of bag

36,37 rotary bodies

38 auxiliary tanks

The roller of 39 roll-type pressue devices

40 alligator clamps

The plate of 41 board-like pressue devices

42 retaining collars

43 hard polysulfones cylindrical containers

Detailed Description Of The Invention

In one aspect of the invention, provide the suspension that is used for from containing virus to remove bag except the virus of virus removal, it comprises:

Bag-like container (a), it has the entrance of at least one suspension that is used for containing virus and at least An outlet that is used for except the suspension of virus removal; With

Barrier film (b), it is firmly held in the bag-like container (a), and the inner space of bag-like container (a) is separated into first Room (c) that communicates with entrance and second Room (d) that communicates with outlet,

At least a portion of its septation (b) is made except striping by virus, be used for obtaining filtrate by filtering from the suspension that contains virus except virus removal, this filtrate for except the suspension of virus removal and

Wherein first Room (c) is used for holding the suspension that contains virus of introducing by entrance, second Room (d) remove membrane filtration for collection by virus and contain the filtrate that viral suspension obtains.

In order to understand the present invention easily, basic feature of the present invention and multiple embodiment preferred have below been enumerated.

1. be used for removing bag from the suspension that contains virus except that the virus of virus removal, it comprises:

Bag-like container (a) has the outlet that the inlet of at least one suspension that is used to contain virus and at least one are used for removing the suspension of virus removal; With

Barrier film (b), it is firmly held in the described bag-like container (a) and the inner space of described bag-like container (a) is separated into first Room (c) that communicates with described inlet and second Room (d) that communicates with described outlet,

At least a portion of wherein said barrier film (b) is removed striping by virus and is made, and this virus is removed striping and is used for removing virus removal from the suspension that contains virus and obtaining filtrate by filtering, this filtrate for the suspension that removes virus removal and

Wherein said first Room (c) is used to hold the suspension of introducing by described inlet that contains virus, and described second Room (d) is used to collect by described virus removes the filtrate that suspension that membrane filtration contains virus obtains.

2. the virus of above-mentioned project 1 is removed bag, and wherein said barrier film (b) is all forms of membranaceous surrounding wall of filter bag,

Wherein said filter bag is firmly held in the described bag-like container (a), make the membranaceous surrounding wall of described filter bag all the inner space of described bag-like container (a) is separated into first Room (c) that communicates with described inlet and second Room (d) that communicates with described outlet, first Room (c) is the inner space of described filter bag, second Room (d) for described bag-like container (a) remove filter bag part the inner space and

At least a portion of the surrounding wall of wherein said filter bag is made except that striping by being used for removing the virus of virus removal by filtration from the suspension that contains virus.

3. the virus of above-mentioned project 2 is removed bag, wherein remove on the flow direction that contains viral suspension in the bag and observe in described virus, the internal diameter of filter bag reduces gradually towards the leading section of filter bag, and wherein internal diameter reduces gradually that rearward end at described filter bag begins or begins between the leading section in the rearward end of described filter bag.

4. each virus is removed bag in the above-mentioned project 1 to 3, it is complex filter that wherein said virus is removed striping, wherein at least one prefilter and at least one virus are removed filter with observed this order lamination on the flow direction of the suspension that contains virus, thereby the formation complex filter wherein provides supatex fabric at least one side of complex filter.

5. each virus is removed bag in the above-mentioned project 1 to 4, and it is that average pore size is 1 to 100nm perforated membrane that wherein said virus is removed striping.

6. each virus is removed bag in the above-mentioned project 1 to 5, and it is the Hydrophilized porous membrane that obtains by additional hydrophilic compounds on the surface of perforated membrane that wherein said virus is removed striping.

7. the virus of above-mentioned project 6 is removed bag, and adding of wherein said hydrophilic compounds is the graft polymerization reaction of hydrophilic monomer.

8. each virus is removed bag in the above-mentioned project 1 to 7, and it is flexible.

9. each virus is removed bag in the above-mentioned project 1 to 8, and the volume of wherein said second Room (d) is enough collected by described virus and removed all filtrates of obtaining of suspension that membrane filtration contains virus.

10. each virus is removed bag in the above-mentioned project 1 to 9, and wherein said first Room (c) comprises spongy adsorbing material.

11. each virus is removed bag in the above-mentioned project 1 to 10, the volume of wherein said second Room (d) is 100 to 800cm ³

12. each virus is removed bag in the above-mentioned project 1 to 11, its sterilely and liquid thickly be connected at least one and have and be different from virus and remove on the function bag of function of function, thereby provide many bags of airtight viruses to remove system.

13. be used for removing from the suspension that contains virus the method for virus removal, it comprises:

(1) provide in the above-mentioned project 1 to 12 each at least one virus to remove bag;

(2) suspension that will contain virus by described inlet is incorporated into described virus and removes in the bag, holds the described suspension that contains virus in described first Room (c);

(3) remove the described suspension that contains virus of membrane filtration by described virus, thereby remove virus removal from described suspension;

(4) collect filtrate in second Room (d), this filtrate is for removing the suspension of virus removal; With

(5) discharge the described suspension that removes virus removal by described outlet.

14. the method for above-mentioned project 13, wherein, in step (3), the described suspension that contains virus removes striping by described virus filtration obtains promoting by the suspension that contains virus in described first Room (c) being applied centrifugal force.

15. the method for above-mentioned project 13, wherein, in step (3), the described suspension that contains virus removes striping by described virus filtration obtains promoting by the suspension that contains virus in described first Room (c) is exerted pressure.

16. each method in the above-mentioned project 13 to 15, the wherein said suspension that contains virus is a whole blood.

17. each method in the above-mentioned project 13 to 15, the wherein said suspension that contains virus is a blood plasma.

18. the method for above-mentioned project 17, wherein said blood plasma never passes through freezing processing.

19. the method for above-mentioned

project

17 or 18, wherein said blood plasma is for removing leukocytic blood plasma.

20. each method in the above-mentioned project 13 to 19 wherein, in step (4), is removed all filtrates of obtaining of suspension that membrane filtration contains virus by described virus and is collected in before in described second Room (d) carrying out step (5).

21. preparation removes the method for the blood plasma of virus removal, it comprises:

(1) provide airtight virus to remove system, it comprises:

Be used to collect the whole blood that comprises blood plasma and hemocyte and from the separation of whole blood and the sampled plasma mechanism (i) of collecting blood plasma, the wherein said whole blood virus that contains under a cloud,

In the above-mentioned project 1 to 11 each at least one virus remove the bag (ii) and

Be used to reclaim except that the blood plasma recovering mechanism of the blood plasma of virus removal (iii),

Described sampled plasma mechanism (i) sterilely and liquid thickly be connected to described virus remove the bag (ii), and described virus remove the bag (ii) sterilely and liquid thickly be connected to described blood plasma recovering mechanism (iii);

(2) gather whole blood to described sampled plasma mechanism (i) from the blood donor;

(3) be blood plasma and hemocyte by centrifugal separation of whole blood with collection;

(4) with isolating blood plasma from described sampled plasma mechanism (i) be incorporated into described at least one virus remove bag (ii), remove in (ii) described first Room (c) of bag in described virus and to hold described isolating blood plasma;

(5) remove bag described virus (ii) by described virus and remove the described isolating blood plasma of membrane filtration, thereby remove virus removal from described isolating blood plasma;

(6) remove collection filtrate in bag described second Room (d) (ii) in described virus, this filtrate is for removing the blood plasma of virus removal; With

(7) from described virus remove blood plasma that bag (ii) discharge to remove virus removal to described blood plasma recovering mechanism (iii).

22. the method for above-mentioned project 21 wherein, in step (6), is collected in described virus before and removes in bag described second Room (d) (ii) carrying out step (7) by filtering all filtrates that described isolating blood plasma obtains.

23. human or animal's blood plasma that the method by above-mentioned

project

21 or 22 obtains.

The present invention is below described in more detail.

The invention provides from the suspension that contains virus and remove bag except that the virus of virus removal, it comprises:

Bag-like container (a), it has the outlet that the inlet of at least one suspension that is used to contain virus and at least one are used for removing the suspension of virus removal; With

Barrier film (b), it is firmly held in the bag-like container (a), and the inner space of bag-like container (a) is separated into and first Room (c) that communicates and second Room (d) that communicates with outlet of entering the mouth,

At least a portion of its septation (b) is removed striping by virus and is made, be used for removing virus removal from the suspension that contains virus and obtaining filtrate by filtering, this filtrate for the suspension that removes virus removal and

Wherein first Room (c) is used to hold the suspension of introducing by inlet that contains virus, and second Room (d) is used to collect by virus and removes the filtrate that suspension that membrane filtration contains virus obtains.

Virus of the present invention is removed bag and is comprised bag-like container (a), and it has the outlet that the inlet of at least one suspension that is used to contain virus and at least one are used for removing the suspension of virus removal; Be firmly held in bag-like container (a) in and the inner space of bag-like container (a) is separated into barrier film (b) with second Room (d) that enters the mouth first Room of the reduction of fractions to a common denominator mutually (c) and communicate with outlet.Remove the bag-like container (a) that uses in the bag for virus of the present invention and be not specifically limited, as long as this container has at least one inlet and at least one outlet and has the structure that can keep solution therein.In addition, be not specifically limited for the material that is used to produce bag-like container (a), as long as this material can not see through suspension, as the suspension (or removing the suspension of virus removal) that contains virus gets final product, and preferably bag-like container (a) is made by following flexible material.Size for bag-like container (a) is not specifically limited, as long as this bag-like container (a) keeps barrier film (b) in the portion space within it securely, and the size of bag-like container (a) can be according to the size of barrier film (b) and the pending capacity decision that contains viral suspension.

The barrier film (b) that virus of the present invention is removed bag can be lamellar (promptly flat membranaceous) form, perhaps is all forms of membranaceous surrounding wall of filter bag.(hereinafter, usually abbreviating the barrier film (b) of all forms of membranaceous surrounding wall of filter bag as bag a shape barrier film (b) or a filter bag).Comprise bag virus of shape barrier film (b) and remove bag and remove bag for the virus of barrier film (b) of all forms of membranaceous surrounding wall that comprise filter bag,

Wherein filter bag is firmly held in the bag-like container (a), make the membranaceous surrounding wall of filter bag all the inner space of bag-like container (a) is separated into and first Room (c) that communicates and second Room (d) that communicates with outlet of entering the mouth, first Room (c) is the filter bag inner space, second Room (d) for bag-like container (a) remove filter bag part the inner space and

Wherein at least a portion of the surrounding wall of filter bag is by making except that striping except that the virus of virus removal by filtering from the suspension that contains virus.In the present invention, " the membranaceous surrounding wall of filter bag is all " film for constituting filter bag and the inner space and the outside of filter bag being separated.

Virus of the present invention is removed bag as shown in figs. 1 and 2.Fig. 1 represents to have plate diaphragm, and the virus of (b) is removed the example of bag, and this virus removes that bag comprises bag-like container 1, barrier film 2, first Room 3, second Room 4 and the inlet 5 that is made of conduit and export 6.Fig. 2 represents to have the example that bag virus of shape barrier film (b) (filter bag) is removed bag, and wherein Fig. 2 (a) is the viral plane graph of removing bag, and Fig. 2 (b) is the cutaway view along the II-II line of Fig. 2 (a).Virus shown in Fig. 2 removes that bag comprises bag-like container 1, filter bag 7, first Room 3, second Room 4 and the inlet 5 that is made of conduit and export 6.

Virus of the present invention is removed at least a portion of the barrier film (b) of bag and is made except that striping by removing the virus of virus removal by filtration from the suspension that contains virus.Term " at least a portion of barrier film (b) is removed striping by virus and made " is meant at least 10% of (barrier film (b)) area of contacting with the suspension that contains virus, preferably at least 20% is made except that striping by virus.Therefore, virus is removed striping can constitute whole barrier film (b), but alternately, barrier film (b) can have that a part of wherein having only barrier film (b) removes by virus that striping is made and the remainder of barrier film (b) by not seeing through the structure that the sheet that contains viral suspension is made.Not seeing through the sheet contain viral suspension illustrates in the following content that relates to filter bag.

The virus that constitutes at least a portion of barrier film (b) is removed striping for preventing to contain the virus infiltration that comprises in the suspension of the virus film by film, is known in the art many viruses with this ability and removes striping.Remove striping for the virus of using among the present invention and be not specifically limited, can use the virus of any routine to remove filter.Virus is removed filter itself and be can be used as virus except that striping, but it is complex filter that preferred virus removes striping, wherein at least one prefilter and at least one virus are removed filter with observed this order lamination on the flow direction of the suspension that contains virus, thereby the formation complex filter wherein provides supatex fabric at least one side of complex filter.By using this complex filter, might obtain having gratifying mechanical strength and can be used for stably carrying out long-time filtering virus and remove bag.

In the present invention, the average pore size that preferred virus removes striping is 1 to 100nm, more preferably 10 arrives 80nm, most preferably is 30 to 70nm.When the average pore size of film is 1 to 100nm, can remove virus removal from the suspension that contains virus.Virus may be present in the blood plasma as HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) (HIV, mean diameter: 100 to 120nm) and cause the serious symptoms of human body.In the present invention, the average pore size of film is the aperture of measuring according to the method for ASTM F316-86 and E128-61 regulation.Remove the ability that striping is removed virus in order to estimate virus exactly, can use logarithm minimizing value.The logarithm minimizing value (LRV) of removing the performance of striping as virus is expressed from the next-log ₁₀(as the virus concentration of the suspension that removes virus removal of filtrate)/(virus concentration that contains viral suspension before filtering).In the present invention, preferred LRV is 3 to 10, more preferably 4 to 9.The logarithm minimizing of removing film properties as virus is worth following mensuration.Infect the MDBK cell of in comprising the Dulbecco ' s MEM of 5% horse serum, cultivating with bovine viral diarrhea virus, thereby form, thereby collect the suspension that culture supernatants obtains containing virus by the culture supernatants of the cell of viral infection.The part that will contain the outstanding supernatant liquid of virus is that 0.1MPa and temperature are to remove membrane filtration by virus under 25 ℃ the condition at pressure, and collects 10 parts for each self-contained 2ml filtrate of the filtrate that obtains.From 10 parts every part is got the 1ml sample and is mixed, thus the suspension of the virus that is removed.Use the MDBK cell of cultivating to pass through TCID ₅₀Method is measured the suspension (before the filtration) contain virus and suspension (filtrate) virus concentration separately that removes virus removal, and calculates logarithm minimizing value according to the virus concentration of suspension of measuring that contains virus and the suspension that removes virus removal.

The complex filter that is used for the present invention has at least one prefilter and removes filter with at least one virus, and it is with observed this order lamination on the flow direction of the suspension that contains virus.The average pore size that the average pore size of the prefilter that uses among preferred the present invention is removed striping than virus is big.Particularly, the average pore size of preferred prefilter is removed 1.2 to 10.0 times of average pore size of filter for virus.In addition, the thickness that virus is removed filter and prefilter all is preferably 5 to 500 μ m, more preferably 10 to 200 μ m.Remove filter and prefilter for virus, when average pore size and thickness are respectively in above-mentioned scope, virus removes filter and prefilter all shows the abundant intensity of practical application, and the application of removing filter and this prefilter of this virus has prevented to take place the flow velocity reduction in time of liquid filtering in filter process.

The complex filter that is used for the present invention has supatex fabric on its at least one side.Provide supatex fabric to be used for protecting virus to remove filter and prefilter and be used to catch and be present in the macroparticle (for example, when the suspension that contains virus was blood plasma, macroparticle was a lipid etc.) that contains viral suspension.The supatex fabric that is preferred in the complex filter is the resin that is selected from polrvinyl chloride, polypropylene, polyethylene, polyethylene terephthalate, nylon, polyurethane, styrene-isobutylene-styrene copolymer, cellulose, cellulose acetate and composition thereof.In order to obtain full intensity with the protection filter with for trapped particle and lipid effectively, the per unit area weight of preferred supatex fabric is 1 to 100g/m ², the fibre diameter of preferred supatex fabric is 0.3 to 100 μ m.

The cutaway view that can be used for the complex filter among the present invention is as shown in Fig. 3 and 4.Filter 8 and supatex fabric 10 obtain complex filter shown in Fig. 3 for laminate nonwoven fabric 10, prefilter 9, virus are in the following order removed.In this complex filter, all provide supatex fabric 10 in the top and the bottom of laminated filter, but must on the top of laminated filter and bottom, all not provide supatex fabric.In addition, be not specifically limited for the number of laminated filter and supatex fabric, can the laminated multilayer prefilter and virus remove filter.For example, in the complex filter shown in Fig. 4, lamination three layers of virus remove filter.Particularly when needing complex filter to have high virus to remove performance, can remove efficient by a plurality of viruses being removed the high virus of filter and prefilter and supatex fabric realization laminated together.

After laminated filter and supatex fabric in the above described manner, preferably that the peripheral part of the filter of the laminated product that obtains and supatex fabric is bonded to each other, has the peripheral adhesion area of preset width with formation, because the complex filter that obtains operation easily in the following process process of complex filter with peripheral adhesion area.The example of this complex filter as shown in Figure 5.Fig. 5 represents to have the plane graph of the complex filter of adhesion area 12.Width " a " for adhesion area is not specifically limited.Yet when using complex filter to produce filter bag, though the width of adhesion area depends on the size of filter bag and difference, the width of preferred adhesion area is 1 to 20mm, more preferably 2 arrives 10mm.Preferred example as the method that forms adhesion area, can mention that heat bonding, ultrasound wave are bonding, high frequency binding and bonding by binding agent, binding agent such as epoxy resin, formaldehyde resin, unsaturated polyester resin, polyurethane resin, contain silicones, polyvinyl acetate resins and polyvinyl alcohol resin.

Also might comprise that virus removes the unified structure of filter and prefilter by coextrusion method preparation.The technology that coextrusion is extruded by the single punch die of extruder simultaneously for the different material that wherein will be used to prepare film.When using the coextrusion method to produce filter, in the situation that hot melt is handled, can pass through the average pore size of the mixing ratio controlled filter device of change plasticizer and filter stock, and in the situation of wet method processing, can pass through the average pore size of the mixing ratio controlled filter device of change solvent and filter stock.

In addition, can be by in addition on the top of complex filter and bottom, providing net or porous material to improve the intensity of the complex filter that uses among the present invention.

In the present invention, the material that removes striping (virus that is contained in the complex filter is removed filter or prefilter) for the virus of at least a portion that constitutes barrier film (b) is not specifically limited.Yet when the suspension that contains virus to be filtered was blood plasma, preferably the inner surface in the hole that contacts with blood plasma was a hydrophilic, and the inner surface in hole has the proteinic surface composition that comprises in the adsorbed plasma not.Can be used for preparing the virus with above-mentioned performance remove the examples of material of striping comprise hydrophilic polyvinylidene fluoride, hydrophilic polysulfones, polyacrylonitrile, cellulose, regenerated cellulose, cellulose acetate, cross-linking polyvinyl alcohol, ethylene-vinyl alcohol copolymer, and composition thereof.These materials can be used for by dry method or wet production perforated membrane.

In the present invention, preferred virus removes the Hydrophilized porous membrane of striping (virus that comprises in the complex filter is removed filter or prefilter) for obtaining by additional hydrophilic compounds on the surface of perforated membrane, and adding of preferred hydrophilic chemical compound is the graft polymerization reaction of hydrophilic monomer.Obtain this Hydrophilized porous membrane by producing perforated membrane and going up additional hydrophilic compounds on the surface of the perforated membrane of being produced (inner surface that comprises the hole).For the raw material that adds hydrophilic compounds perforated membrane before in its surface, can mention polyolefin, as polyethylene, polypropylene and polybutene; The copolymer of alkene and alkenyl halide; Polyvinylidene fluoride; Polyvinylidene chloride; Cellulose acetate; And composition thereof.Preferably the average pore size of the perforated membrane before additional hydrophilic compounds is 1 to 100nm, more preferably 10 arrives 80nm, most preferably is 20 to 70nm.The thickness of preferred perforated membrane is 5 to 500 μ m, more preferably 10 to 200 μ m.The porosity of preferred perforated membrane is 5 to 80%, more preferably 10 to 40%.

The example that is used to append to the lip-deep hydrophilic compounds of above-mentioned perforated membrane comprises hydrophilic monomer, as the ester of acrylic acid, methacrylic acid, acrylic or methacrylic acid and polyhydric alcohol, and composition thereof.Acrylic or methacrylic acid comprises glycidyl methacrylate, Hydroxypropyl acrylate, 2-(Acryloyloxy)ethanol, hydroxyethyl methylacrylate, acrylic acid methoxyl group ethyl ester, methyl methacrylate, ethyl acrylate, EHA and phenoxyethyl acrylate with the object lesson of the ester of polyhydric alcohol.In addition, can use on its main chain or side chain, have crosslinkable groups (as vinyl and pi-allyl) polymer as hydrophilic compounds.The object lesson of this polymer comprises having vinyl or allylic poly(ethylene oxide), polygricydol and polyvinylpyrrolidone.Also can use the copolymer that comprises the monomeric unit that is selected from the monomeric unit that constitutes above-mentioned polymer as hydrophilic compounds.For the lip-deep method that hydrophilic compounds is appended to perforated membrane, thereby thereby optimal be wherein make perforated membrane through electron beam or gamma-ray ionizing radiation produce free radical, and the perforated membrane that has free radical that will obtain contact the method for carrying out addition reaction (that is graft polymerization reaction) with the hydrophilic compounds of liquid or gas form.As the lip-deep optionally method that hydrophilic compounds is appended to perforated membrane, can mention being used in wherein that the above-mentioned polymer that has crosslinkable groups (as vinyl or pi-allyl) in its main chain or the side chain covers the surface of perforated membrane and making the crosslinked method of polymer coating that obtains by heating, radiation or cross-linking agent; Wherein use hydrophilic polymer such as polyvinyl alcohol or vinyl-vinyl alcohol copolymer to cover the method on the surface of perforated membrane.These methods are from the recommendable method of the angle of easy operating.In addition, use therein by addition reaction under the situation of the method for additional hydrophilic compounds on the perforated membrane, might carry out wherein with the addition reaction of perforated membrane before, make the blended operation of diacrylate ester compounds such as polyethyleneglycol diacrylate and hydrophilic compounds, after addition reaction, the perforated membrane that makes the additional modification that obtains is through cross-linking reaction.

Remove the hydrophilic of the material of filter or prefilter for virus, the contact angle of preferably measuring flat film is 0 to 140 °, more preferably 0 to 120 °, and more preferably 0 to 90 °.When contact angle is 140 ° to the maximum, might obtain high liquid permeability.In the present invention, contact angle is measured the value that the flat film of porous obtains for using automatic contact angle meter (DCA-VM type, by the Kyowa InterfaceScience Co. of Japan, Ltd. produces and sells).

Below, remove the filter bag that uses in the bag and describe for having bag virus of shape barrier film (b).As mentioned above, at least a portion of the surrounding wall of filter bag is by making except that striping except that the virus of virus removal by filtering from the suspension that contains virus.Make filter bag that bag obtains using among the present invention or will remove filter and be connected in the composite that the sheet made by another kind of material prepares and make the filter bag that bag obtains using among the present invention by virus being removed striping (for example virus is removed filter or above-mentioned complex filter) by virus.Fig. 6 (a) makes bag sketch map of the filter bag of preparation to 6 (c) expression by virus being removed striping.Fig. 6 (a) expression overlaps each other to form and has four limit laminated construction by two viruses being removed striping, seals three limits in four limits of laminated construction then, makes the filter bag that bag obtains thereby two viruses are removed striping.Fig. 6 (b) and 6 (c) expression by a virus is removed striping be folded into two-layer (particularly, folded the left side edge of the filter bag shown in Fig. 6 (b) and the bottom margin shown in Fig. 6 (c)) form and to have four limits the laminated construction of (comprising not folded edge of a folded edge and three), with two in four limits of laminated construction not folded edge sealings,, virus makes bag and the filter bag of acquisition then thereby being removed striping.The width of hermetic unit can be depending on the size of filter bag and changes, but usually, is preferably 1 to 20mm, more preferably 2 arrives 10mm.Can process the opening of filter bag, the structure that formation wherein makes the opening of filter bag communicate with the viral inlet seal of removing bag.For example, the opening that can process filter bag forms its split shed for closely airtight so that the structure of insertion tube wherein, wherein the opening of the opening of filter bag and bag-like container (a) can be along the whole length of the opening of bag-like container (a) the whole top periphery part of bag-like container (a) (that is, along) overlapping and closely be sealed (referring to Fig. 9).

As described above, all at least a portion of the membranaceous surrounding wall of the filter bag that uses among the present invention are made except that striping by virus.Particularly, with at least 10% of the membranaceous surrounding wall area of the filter bag that contact of suspension that contains virus, preferably at least 20% make except that striping by virus.Therefore, if any, all parts (not removing striping by virus makes) of the membranaceous surrounding wall of filter bag can be made by the sheet that does not see through the suspension that contains virus.Be used to produce this employed examples of material of sheet that does not see through the suspension that contains virus and comprise resin, as polrvinyl chloride, polypropylene, polyethylene, polyethylene terephthalate, nylon, polyurethane and styrene-isobutylene copolymers.Preferred this resin is the soft material that comprises plasticizer etc.Fig. 6 (d) represents filter bag, and wherein all parts of the surrounding wall of filter bag are made except that striping 7a by virus, and all remainders of surrounding wall are not made by the sheet 7b that does not see through the suspension that contains virus.In this filter bag, virus is removed striping 7a and is in the same place with not being attached to each other through the sheet 7b that contains viral suspension.

Preferred virus of the present invention is removed bag for flexible.In the present invention, term " virus remove bag for flexible " is meant that constituting virus removes the great majority of the parts of bag (be bag-like container (a), barrier film (b), filter bag and as the conduit of inlet or outlet) and made by flexible material.Particularly, in order to keep virus to remove all intensity of bag, virus is removed the junction surface of the part (as being used to hold the part that filter bag is connected to the conduit of another function bag) of bag and formation between filter bag and bag-like container (a) and can be made by inflexibility material (as rigid plastics).Yet, in the present invention, recommend bag-like container (a) and filter bag to make by flexible material.When the virus that is connected in other function bag etc. being removed bag apply centrifugal force, flexible virus is removed bag can prevent that other function bag is destroyed.Remove the used flexible material of bag as being used to produce virus, can mention that particularly preferred material is to comprise soft PVC, polyurethane or the ethylene-vinyl acetate copolymer thermoplastic elastomer (TPE) as its key component by add the soft material that plasticizer etc. obtains in polymeric material such as polrvinyl chloride, polyurethane, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, polyethylene terephthalate and nylon.In this article, flexible material can enough hands bend flexible materials for having.

Remove in the bag in virus of the present invention, the volume of preferred second Room (d) is enough collected by virus and is removed all filtrates of obtaining of suspension that membrane filtration contains virus.The advantage that the virus that use has this second Room (d) is removed bag is following reason.In the situation of using this second Room (d), when will contain virus suspension be incorporated into virus remove the bag first Room (c) in and by virus remove membrane filtration (for example using centrifugal force) contain virus suspension the time, collect all filtrates that obtain in second Room (d), this filtrate is for removing the suspension of virus removal.Therefore, needn't provide additional sack to be used to collect filtrate, wherein additional sack is connected in virus separately by liquid transfer tube etc. and removes bag.In the present invention, term " volume of second Room (d) is enough collected by virus and removed all filtrates of obtaining of suspension that membrane filtration the contains virus " volume that is meant second Room (d) is identical or bigger with the volume that contains the supernatant liquid that virus hangs to be filtered.The virus that Fig. 7 (a) expression comprises plate diaphragm (b) is removed the sketch map of bag, and the volumetrical virus that is used for determining second Room (d) is removed the bag part and represented by hacures.In addition, the virus of barrier film (b) that Fig. 7 (b) and 7 (c) expression has all forms of membranaceous surrounding wall of filter bag is removed the sketch map of bag, and the volumetrical virus that is used for determining second Room (d) is removed the bag part and represented by hacures.The above-mentioned two types virus of following mensuration is removed the volume of second Room (d) of bag.Using alligator clamp to clamp virus removes the contact point between the bag outlet and second Room and add pure water in second Room.Make the virus that comprises pure water that obtains remove bag and place, perhaps, make the virus that obtains remove bag, measure the volume of the pure water that second Room (d) partly comprises in (it is equivalent to the dashed area shown in Fig. 7) then with the erectility suspention with erectility.Measured value is as the volume of second Room (d).

Remove bag when being used for processing blood or blood plasma when virus of the present invention, consider every blood donor's the standard amount of donating blood, the volume that preferred virus is removed first Room (c) of bag is 100 to 600cm ³, more preferably 150 arrive 250cm ³It is preferred that enough to be used to collect the volume of removing second Room (d) of all filtrates that suspension that membrane filtration contains virus obtains by virus be 100 to 800cm ³, more preferably 150 arrive 400cm ³

Remove in the bag in the virus with plate diaphragm (b), barrier film (b) is firmly held in the bag-like container (a) and the inner space of bag-like container (a) is separated into and first Room (c) that communicates and second Room (d) that communicates with outlet of entering the mouth.Be not specifically limited for the method that barrier film (b) is firmly held in the bag-like container (a), can mention that for example heat bonding, ultrasound wave are bonding, high frequency binding and bonding by binding agent, binding agent such as epoxy resin, formaldehyde resin, unsaturated polyester resin, polyurethane resin, contain silicones, polyvinyl acetate resins or polyvinyl alcohol resin.Fig. 8 represents to illustrate that virus of the present invention removes the sketch map at the junction surface between plate diaphragm in the bag (b) and the bag-like container (a).Fig. 8 (a) is illustrated in the junction surface that forms between the inwall of plate diaphragm (b) and bag-like container (a).Can remove bag by bag-like container (a) and plate diaphragm (b) being provided respectively and barrier film (b) being fixed to the last virus with this structure of producing of bag-like container (a) by binding agent.Fig. 8 (b) expression makes the junction surface of the peripheral part formation bonded to each other of at least two sheets (forming bag-like container (a)) by the peripheral part of plate diaphragm (b).Can be by at least two sheets that are used to produce bag-like container (a) and the peripheral part of at least two sheets is bonded to each other by the peripheral part of plate diaphragm (b) be provided.For example, can remove bag according to the method production virus of using among the embodiment 7 of this description.Particularly, two outer housing equal portions (the first and second outer housing equal portions) that each comfortable its periphery has retaining collar are provided, and (wherein the first outer housing equal portions have inlet, the second outer housing equal portions have outlet), and the retaining collar of the first and second outer housing equal portions is bonded to each other by the peripheral part of barrier film (b), removes bag thereby obtain virus.For the junction surface that forms between plate diaphragm (b) and bag-like container (a), the junction surface shown in preferred Fig. 8 (b) is because this associative list reveals high bonding strength.

Remove in the bag having bag virus of shape barrier film (b) (filter bag), filter bag is firmly held in the bag-like container (a), make the membranaceous surrounding wall of filter bag all the inner space of bag-like container (a) is divided into first Room (c) that communicates with inlet and second Room (d) that communicates with outlet, first Room (c) is the inner space of filter bag, and second Room (d) removes the inner space of filter bag part for bag-like container (a).Be not specifically limited for the method that filter bag is firmly held in the bag-like container (a), in the situation of plate diaphragm (b), can use heat bonding, bonding, the high frequency binding and bonding of ultrasound wave by binding agent.Filter bag and bag-like container (a) can be connected to each other by for example method shown in Fig. 9.In Fig. 9 (a), filter bag 7 is connected in bag-like container 1 by conduit 13 as inlet 5.Remove in the bag in this virus, unique junction point is present in and is used to introduce conduit 13 places that contain viral suspension between filter bag 7 and the bag-like container 1.Fig. 9 (b) represents that wherein filter bag 7 and bag-like container 1 are removed bag along the whole upper periphery part virus connected to one another of bag-like container 1.Therefore remove in the bag in this virus with the big junction surface that forms between bag-like container and filter bag, this combination is very strong, and this virus is removed bag and is advantageously used in by virus being removed the centrifugal filtration that bag produces big stress.The hermetic unit 14 of in Fig. 9 (a) and 9 (b), all having represented bag-like container 1.When being clipped in conduit 13 (as inlet 5) between two walls of bag-like container and make the sandwich that obtains through heat-sealing, importantly to control temperature, pressure and time that heat-sealing is used, flatten fully to prevent conduit.

In the present invention, the internal diameter of preferred filter bag is removed the leading section of observing towards filter bag on the flow direction of the suspension that contains virus in the bag in virus and is reduced gradually, and wherein internal diameter reduces gradually that rearward end at filter bag begins or begins between the leading section in the rearward end of filter bag.In other words, the filter bag that uses among preferred the present invention has the shape that internal diameter reduces gradually, as the sack that tightens up in its bottom.The leading section towards filter bag be the filter bag that reduces gradually of internal diameter example as shown in Figure 10.For the filter bag that uses among the present invention, the filter bag as shown in Figure 10 (b) and 10 (c), internal diameter reduces gradually and can begin in the rearward end of filter bag.Perhaps, as Figure 10 (a), 10 (d), 10e) and 10 (f) as shown in filter bag, internal diameter reduces gradually and can begin between the leading section in the rearward end of filter bag.The filter bag as shown in Figure 10 (d) and 10 (e) for example, the internal diameter of filter bag reduces to make filter bag to have curved profile gradually.In order to produce the filter bag that internal diameter reduces gradually, the method of recommend using is removed film cutting that striping makes by virus and is obtained two same diaphragms as shape shown in Figure 10 (a) is one of in 10 (f) for for example wherein virus being removed striping or its at least a portion, then that the diaphragm-operated peripheral part in correspondence with each other of gained is bonded to each other by heat-sealing or binding agent, thus the filter bag that internal diameter reduces gradually obtained.

In the present invention, preferred virus remove the bag first Room (c) comprise spongy adsorbing material.The example that virus with the filter bag (i.e. first Room (c)) that comprises spongy adsorbing material is removed bag as shown in Figure 11.When virus was removed sack and comprised spongy adsorbing material, lipid and other impurity of being contained in the suspension that contains virus were adsorbed by spongy adsorbing material, and this makes filter efficiency improve.The example of preferred spongy adsorbing material comprises polyurethane foam and melamine foamed plastic, and its every kind not only can easily be compressed by it is exerted pressure, and can be through the pressurized heat sterilization.Size for spongy adsorbing material is not specifically limited, but the volume of preferred spongy adsorbing material is volumetrical 30 to 90% of first Room (c).

Using the virus that comprises filter bag to remove bag filtration therein contains in the situation of viral suspension, when the suspension that contains virus promotes by the suspension that contains virus in first Room (c) is exerted pressure by the viral filtration that removes striping, in order to guarantee as the passing through of the filtrate of the suspension that removes virus removal, in the locating rack of preferably filter bag being packed into.The resin web of the locating rack that uses among the present invention for making by polypropylene, polyethylene, polyethylene terephthalate etc., and preferably its size of mesh is 0.5 to 20mm.Locating rack is to be large enough to the sack of filter bag of packing into therein, and the locating rack that preferably will comprise filter bag is firmly held in the bag-like container (a).The example of the filter bag in the locating rack of packing into as shown in Figure 12.In Figure 12, locating rack 17 covers filter bag 7, and preferably is positioned at the locating rack outside by the feasible end that is connected in the conduit 13 (as inlet 5) of filter bag of locating rack covering filter bag.

Preferably virus of the present invention is removed bag sterilely and liquid thickly be connected in to have and be different from least one function bag that virus is removed the function of function, thereby provide many bags of airtight viruses to remove system.In the present invention, " many bags of airtight viruses are removed system " is for having the wherein conventional function bag that is used for the blood treatment field (particularly, for being used to collect the bags of blood of blood constitutent etc.) sterilely and liquid thickly be connected in the closed system that above-mentioned virus is removed the structure of bag, wherein this system can be used for removing virus removal from the suspension that contains virus.Remove the object lesson of system as many bags of airtight viruses, can mention that the virus that is used to prepare except that shown in Figure 13 to 22 of the blood plasma of virus removal removes system.

Be used to prepare many bags of virus systems of removing except that the blood plasma of virus removal and comprise bags of blood as function bag." bags of blood " is for being used to collect the function bag of blood constitutent.In the present invention, term " blood constitutent " comprises whole blood, blood plasma, erythrocyte, leukocyte, platelet and composition thereof the buffy coat of leukocyte and platelet mixture (for example as).Usually, gathering blood (whole blood) afterwards, before storing, the blood separation of gathering is being become blood constitutent by centrifugal grade.Therefore, be used for many bag systems of processing blood, with bag (for example be used for whole blood bags of blood, be used for the bags of blood of blood plasma and be used for the bags of blood of hemocyte) and functional element (for example following remove leukocytic filter element) pre-assembled, comprise a plurality of bags and unitary system thereby form.In addition, can provide the bag of many bag systems to be used to comprise physiological solution (for example normal saline) or additive (for example anticoagulant).Perhaps, the bag that might provide the independent bag that comprises additive also will comprise additive is connected to many bag systems.When virus is removed the filter bag of bag when comprising above-mentioned spongy adsorbing material, before being incorporated into blood plasma in the filter bag, must remove the air that comprises in the spongy adsorbing material, therefore, need independent bag to be used for collecting the air that spongy adsorbing material comprises.Can be connected to many bag systems with being used for removing a bag this bag of removing air from virus.In addition, thereby finish when filtering by the filtration of air being delivered to virus and being removed in the bag and promote to remain in liquid wherein when intention, can will comprise bag the be connected to many bag systems of pressurization with gas to the bag pressurization.Preferably above-mentioned bag is connected to each other, the described tube for transfusion flexible pipe that the flexible material identical with the flexible material that is used to produce bag made of serving as reasons by tube for transfusion.

The virus of using in the method for the invention of the present invention that comprises is removed in " many bags of airtight viruses are removed system " and following " airtight virus is removed system " of bag, and virus is removed bag sterilely and liquid thickly is connected in other function bag and filter element.In the present invention, term " sterilely and liquid thickly connect " is meant wherein inserting the liquid into virus and makes virus remove bag before removing in the bag to be connected to function bag etc. by tube for transfusion (as conduit), thereby formation assembly, and the assembly that obtains is sealing, thereby obtains the wherein inner situation that keeps the closed system of aseptic condition.Under this condition, the inside of function bag keeps not contacting outside air, thereby might prevent that antibacterial and viral pollution from using the liquid of this system handles.Yet in order can be as required to discharge from system or to wherein adding liquid, the part of system does not provide the mechanism that blood taking needle with tap maybe can be opened.In addition, can be by function bag and virus be removed the packed many bag systems of formation of joining, and the many bag systems that make assembling are through using heating, steam or radiation killing the antibacterial that is present in many bag systems inside and the sterilization treatment of virus, and have wherein been suppressed many bag systems of antibacterial and virus multiplication.Remove in the system in many bags of viruses, in most of the cases, virus is removed bag and is connected in the several function bag, therefore, preferably system is connected to each other through the institute's marsupial that many bags of viruses is removed before the sterilization treatment to comprise in the system.For example, when using heating to sterilize, preferred sterilising temp is 90 ℃ to 150 ℃, and more preferably 100 ℃ to 130 ℃, sterilization time is 5 to 120 minutes, more preferably 20 to 60 minutes.In many bag systems, the number that the virus that is connected in function bag is removed bag is not limited to one, can connect several viruses according to the amount of the suspension that contains virus that will use many bag systems to handle and remove bag.

Figure 13 to 22 represent separately explanation be used to be removed virus blood plasma, comprise that virus of the present invention removes the sketch map that the airtight virus of bag is removed the example of system.Each system shown in Figure 13 to 22 comprises the blood sampling mechanism that has blood taking needle 18 and be used for the bags of blood 20 of whole blood; Virus with bag-like container 1 is removed bag; Blood plasma recovering mechanism with the bags of blood 21 that comprises the blood plasma after being used to filter.In the drawings, the line of connection blood taking needle, bag etc. is a tube for transfusion.Figure 13 represent by blood taking needle 18, the bags of blood 20 that is used for whole blood, virus with bag-like container 1 remove bag and be used to filter after the simple system that forms of the bags of blood 21 of blood plasma.Figure 14 represents by adding that for the system shown in Figure 13 leukocyte removes unit 22 and be used to remove the system that the bags of blood 23 of leukocytic blood obtains.Figure 15 represents the system by adding that for the system shown in Figure 13 the bags of blood 24 that is used for buffy coat obtains.Figure 16 represents the system by adding that for the system shown in Figure 13 the bags of blood 25 that comprises (for example anticoagulants) such as additives obtains.Figure 17 represents the system by adding that for the system shown in Figure 13 bags of blood 25 that comprises (for example anticoagulants) such as additives and the bags of blood 24 that is used for buffy coat obtain.Figure 18 represents the system by adding that for the system shown in Figure 14 bags of blood 25 that comprises (for example anticoagulants) such as additives and the bags of blood 24 that is used for buffy coat obtain.Figure 19 represents to be used for removing bag 26 systems that obtain that bag is removed air from virus by adding for the system shown in Figure 18.Figure 20 represents to comprise bag 27 systems that obtain of pressurization with gas by adding for the system shown in Figure 18.Figure 21 represents by removing the system that unit 22 obtains for the system shown in Figure 13 adds leukocyte, and wherein leukocyte is removed unit 22 and just is positioned at the virus with bag-like container 1 and removes a bag front.Figure 22 represents to be used for removing bag 26 systems that obtain that bag is removed air from virus by adding for the system shown in Figure 13.In addition, represented to be melted the part 19 of the tube for transfusion that seals and cut in Figure 13 and 22, part 19 is illustrated in blood plasma is incorporated into the part that virus is removed in the bag system that preferably is cut off (for example by melting sealed/cutting) afterwards.

In another embodiment of the invention, the invention provides the method for removing virus removal from the suspension that contains virus, it comprises:

(1) provide at least one virus to remove bag;

(2) suspension that will contain virus by inlet is incorporated into virus and removes in the bag, holds the suspension that contains virus in first Room (c);

(3) remove the suspension that membrane filtration contains virus by virus, thereby remove virus removal from suspension;

(5) discharge the viral suspension of removing by outlet.

Used above-mentioned disclosed virus of the present invention to remove bag at the suspension that is used for from containing virus except that in the method for the present invention (usually being called hereinafter, " virus of the present invention is removed method ") of virus removal.The virus of using is removed bag can comprise a kind of in plate diaphragm (b) and bag shape barrier film (b) (being filter bag).

Remove in the step (2) of method in virus of the present invention, the suspension that will contain virus by entering the mouth is incorporated into virus and removes in the bag, thereby holds the suspension that contains virus in first Room (c).In step (3) subsequently, remove the suspension that membrane filtration contains virus by virus, thereby remove virus removal from suspension, in step (4), in second Room (d), collect filtrate as the suspension that removes virus removal.The method that contains the suspension of virus for filtration is not specifically limited.Yet, preferably contain viral suspension removes striping by virus filtration by the suspension that contains virus in first Room (c) being applied centrifugal force or pressure obtains promotion.

When the suspension that contains virus in first Room (c) was applied centrifugal force, the centrifugal force that applies made the suspension that contains virus in the chamber of winning (c) move through virus and enters into second Room (d) except that striping, thereby forms filtrate.In other words, make virus remove bag rotation, make to produce centrifugal force containing on the flow direction of viral suspension.Can remove the intensity selection of bag in the size of the centrifugal force of first Room (c) according to the size and the virus of the centrifuge that uses.Yet the size of preferred centrifugal force is 5G to 70,000G.When function bag etc. and virus are removed bag and are connected, if wish to consider to prevent the viewpoint of outside germ contamination, can make virus remove bag under the situation of bag break function bag etc. to carry out centrifugal (that is, be connected in virus remove the function bag etc. of bag can remove bag with virus and carry out centrifugal) not removing from virus.On the other hand, when being difficult to appropriate location in centrifuge when holding virus and removing bag and other function bag etc., can remove the pipe that bag is connected with virus by melting sealed/cutting cut-out and sealing function bag etc., be connected in the unnecessary assembly that virus is removed bag thereby remove.Then, can will only be necessary that assembly (for example function bag) is connected gained with it virus removes bag and carry out centrifugal.Preferably under 0 ℃ to 40 ℃ temperature, carry out centrifugal, more preferably 5 ℃ to 35 ℃.When in the said temperature scope, carrying out when centrifugal,, and do not cause the serious degeneration of the suspension that contains virus even when containing viral suspension and be blood plasma, can filter at a high speed yet.

Figure 23 represents to illustrate that the virus of the example that places the centrifuge cup removes the sketch map of bag, and the virus shown in Figure 23 is removed bag and had with the virus shown in Fig. 2 and remove the same structure of bag.In Figure 23, the top that the virus that will have a bag-like container 1 is removed bag is securely fixed on the fixation hook 29, has connected virus and has removed the fixation hook 29 of bag and be fixed on the hold-down bars of installing in the Centrifuge Cup of centrifuge 30.Be fixed in centrifuge by by this way virus being removed bag, might suppress viral distortion of removing bag in the centrifugal process, and filter satisfactorily.Hollow arrow shown in Figure 23 is represented the direction 31 of centrifugal force, filters on this direction.Figure 24 represents to illustrate and is used to make virus to remove the sketch map of example that bag is fixed in the fixation hook of centrifuge cup.When the fixation hook that uses shown in Figure 24, the top 35 that virus is removed bag is sandwiched between the holding plate 33 with hook 32, and virus is removed bag is fixed on the fixation hook with standing screw 33.

Figure 25 represents to illustrate that by virus being removed the sketch map that bag applies the example of the filtering method of centrifugal forces enhance, wherein Figure 25 (a) is for illustrating by the virus with plate diaphragm (b) being removed the sketch map that bag applies the filtering method of centrifugal forces enhance.When filtering, as shown in FIG., virus is removed bag be firmly fixed at rotary body 36 and/or rotary body 37 (wherein rotary body is equivalent to the rotor of centrifuge) by the method shown in Figure 25 (a).When rotary body rotates with direction shown in the black arrow among Figure 25 (a), produce centrifugal force on the direction shown in the hollow arrow 31 in the drawings, thereby promote to filter.Virus is removed bag and can be firmly fixed in rotary body 36 and 37 one or two.When virus is removed bag when just being firmly fixed at a rotary body, another rotary body (do not connect virus and remove bag) is used for preventing that removing bag in the rotary course virus of rotary body breaks away from from rotary body.On the other hand, remove bag when virus in the rotary course at rotary body and break away from when having only very little probability, can only use a rotary body from rotary body.Figure 25 (b) and 25 (c) represent separately the explanation only use a rotary body to promote the sketch map of filtering method.In the method shown in Figure 25 (b), virus is removed the outer surface that bag is firmly fixed at rotary body, in the method shown in Figure 25 (c), virus is removed the inner surface that bag is firmly fixed at rotary body.Can carry out virus by any conventional method and remove fixing of bag and rotary body.For example, can mention and wherein virus is removed bag with the screw nail method on rotary body; Wherein so that removing bag, virus is fixed in method on the rotary body around rotary body by the roll of tape of removing bag with Corticovirus; Wherein on rotary body, be provided at and wherein hold the method that virus is removed the groove of bag.In addition, virus can be removed a bag coiling rotary body.For virus remove the bag length be not specifically limited, virus remove the bag length can be substantially the same with the girth of rotary body.Figure 25 (d) expression explanation makes virus remove the sketch map that bag carries out centrifugation method, and wherein virus is removed bag and had the length substantially the same with the girth of rotary body.The length of removing bag when virus can be removed virus bag and be fixed in rotary body during than the Zhou Changda of rotary body, and the end that makes virus remove bag overlaps each other.Can simultaneously a plurality of viruses be removed bag and be connected in rotary body, preferred this method is used for the suspension that single treatment contains virus in a large number.

Shown in Figure 26 for applying filtering another method of centrifugal forces enhance by the virus with plate diaphragm (b) being removed bag.Figure 26 represents to illustrate that the virus that places the centrifuge cup removes the sketch map of example of bag, and wherein virus is removed bag and had with the virus shown in Fig. 1 and remove the same structure of bag.In Figure 26, centrifuge cup 28 has auxiliary tank 38, be used for holding virus therein and remove bag, and on for the retaining collar that barrier film (b) is fixed on the bag that provides in the bag-like container (a) (referring to Fig. 8 (b)), virus removed bag and be firmly held in the auxiliary tank 38.When by this way virus being removed bag when being connected in the centrifuge cup, might suppress whole virus and remove bag moving at centrifugal direction.Being connected with virus in the above described manner removes the rotation of rotary body of the centrifuge of bag and makes produce centrifugal force that on the direction 31 that Figure 26 hollow core arrow is represented it promotes filtration.

The suspension that contains virus in first Room (c) is exerted pressure, make the suspension that contains virus in the chamber of winning (c) move through virus and remove striping and enter into second Room (d), thereby form filtrate.Promote the use of filtering pressure to be particularly suitable for when using the virus that comprises filter bag to remove bag.Can be according to the resistance to pressure selection of barrier film (b) or filter bag in the pressure size of first Room (c).Remove bag when being used to filter when virus of the present invention, the pressure that preferably acts on the film surface is 0.05 to 100kg/cm ²As example, thereby can mention that wherein using roll-type pressue device or board-like pressue device directly virus to be removed the bag pressurization collects the method except that the suspension of virus removal as filtrate in second Room (d) to the suspension method of exerting pressure that contains virus; The suspension that wherein will contain virus is incorporated into to be connected with and comprises in the filter bag of pressurization with the bag of gas, and by exerting pressure and compress filter bag inside with the bag of gas comprising pressurization, thereby filter the method that contains viral suspension.

Figure 27 represents to illustrate by use and is used for virus is removed the sketch map that bag roll-type pressue device of exerting pressure carries out the example of filtering method.In the device shown in Figure 27, the roller 39 of roll-type pressue device rotates the virus that compression has a bag-like container 1 at leisure and removes filter bag contained in the bag 7, exerts pressure thereby virus is removed bag.The result is, collects gradually by filtration to contain the filtrate that the suspension of virus obtains in second Room (d).The alligator clamp 40 that provides in the outer end of conduit portion as inlet 5 prevents to contain the backflow (that is suspension the flowing on the direction opposite with filtering direction that, contains virus) of viral suspension.Replace employed alligator clamp, can pass through melting sealed end seal conduit.

Figure 28 represents to illustrate by use and is used for virus is removed the sketch map that bag board-like pressue device of exerting pressure carries out the example of filtering method.In the device shown in Figure 28, filter bag 7 is between two plates 41 of board-like pressue device, and two plates reduce distance therebetween gradually, exerts pressure thereby virus is removed bag 7.The result is, collects gradually by filtration to contain the filtrate that the suspension of virus obtains in second Room (d).

Figure 29 represents that comprising pressurization by use removes bag sketch map of the example of the method for pressurization with the sack of gas to virus.In the device shown in Figure 29, enclosing hypoergia gas such as air, nitrogen or argon as comprising in the sack 27 of pressurization with the bag of gas.Use the plate 41 compression sacks 27 of board-like pressue device to be incorporated in the filter bag 7, thereby virus is removed the bag pressurization with the gas that will be contained in the sack 27.The result is, collects gradually by filtration to contain the filtrate that the suspension of virus obtains in second Room (d).

In any above-mentioned method, preferred virus is removed adding under the temperature that is pressed in 0 ℃ to 40 ℃ of bag and is carried out more preferably 5 ℃ to 35 ℃.When in the said temperature scope, pressurizeing, even when the suspension that contains virus is blood plasma, can carry out removing the filtration of striping at a high speed, and not cause the serious degeneration of the suspension that contains virus by virus.

Because filtrate (it is for removing the suspension of virus removal) is collected in second Room (d), in step (5), discharges the suspension that removes virus removal by outlet from second Room (d).Can discharge the suspension that removes virus removal by opening outlet.

Remove the viral suspension that contains that uses in the method for virus of the present invention and be not specifically limited, can mention the culture fluid that comprises virus and suspect body fluid such as blood and the blood plasma that comprises virus.The suspension that contains virus that is preferred among the present invention is human or animal's blood or blood plasma.In the present invention, term " blood plasma " is meant by remove the blood constitutent that hemocyte component such as erythrocyte, leukocyte and platelet obtain from whole blood.For example, the blood plasma that uses among the present invention is for adopting the plasma component that (apheresis) transfusion set obtains by the centrifugal supernatant that obtains of whole blood that will gather or as the use machine.Yet, in the present invention, can have the hemocyte content of 10 weight % at the most as the blood plasma that contains viral suspension.

The blood plasma that uses among preferred the present invention never passes through freezing processing.Usually, freezing in several hours behind blood collection as the blood plasma of blood products preparation, but when frozen plasma was thawed and pass through filtration, the strainability of blood plasma changed, and this blood plasma may cause the obstruction of filter.In this article, term " freezing " thus be meant wherein blood plasma kept making blood plasma become solid-state processing from liquid state at low temperatures, or make at least once processing of this temperature history of blood plasma experience.When will be never the blood plasma of freezing mistake when being used for virus of the present invention and removing method, might obtain the blood plasma that removes virus removal that practicality has consumption at short notice.

In addition, the blood plasma that uses among preferred the present invention is for removing leukocytic blood plasma.Remove leukocytic blood plasma for through removing that leucocyte-removing is handled and wherein leukocyte concentration be reduced to be no more than through leukocyte remove the blood plasma before handling leukocyte concentration 1/10, preferably be no more than 1/100.Removed filtration obstruction material owing to remove processing,, removed the stable filtration of realization easily of leukocytic blood plasma by use as leukocyte and the impurity that remains in the blood plasma by leukocyte.The leukocyte method of removing of removing leukocytic blood plasma for preparation is not specifically limited.The component that can make whole blood, blood plasma or contain blood plasma is removed filter by leukocyte and is filtered, thereby is removed leukocytic blood plasma.Remove the example of the method for processing as whole blood that blood collection is obtained through leukocyte, can mention wherein that the whole blood of gathering is centrifugally, with from the separation of whole blood plasma component, and make isolating blood plasma remove the method for processing through leukocyte; Perhaps wherein make by the use machine and adopt plasma component that transfusion set obtains is removed processing through leukocyte method.The filtration that realizes when the method for removing by above-mentioned leukocyte hinders removing of material when thereby subsequently virus is removed operating difficulties can not be satisfactory the time, can use the adsorption treatment of adsorbent or the membrane filter technique by micro-filter before removing method carrying out virus of the present invention, hinder material thereby remove remaining filtration.

In the present invention, the virus that is preferred for the removing virus removal volume of removing second Room (d) of bag enough is collected and is removed membrane filtration by virus and contain all filtrates that viral suspension obtains.Therefore, remove in the method, preferably in step (4), will remove all filtrate collections that suspension that membrane filtration contains virus obtains before by virus in second Room (d) carrying out step (5) in virus of the present invention.When all filtrate collections that obtain of suspension that filtration contained virus are in second Room (d), there is not filtrate to be back to the incomplete filtering danger that causes in first Room (c).In addition, in the method for the invention, need be before finishing filter operation not remove bag from virus and reclaim a filtrate (promptly removing the suspension of virus removal) or be provided for collecting the additional sack of filtrate, wherein additional sack is connected in virus independently by tube for transfusion etc. and removes bag.Therefore, can be by being easy to operate the viral suspension that is removed.

In another embodiment of the invention, provide preparation to remove the method for the blood plasma of virus removal, it comprises:

(1) provide airtight virus to remove system, it comprises:

Sampled plasma mechanism (i) is used to gather the whole blood that comprises blood plasma and hemocyte and from separation of whole blood and collect blood plasma, the whole blood virus that contains under a cloud wherein,

At least one virus is removed bag (ii); With

The blood plasma recovering mechanism (iii) is used to reclaim the blood plasma except that virus removal,

Sampled plasma mechanism (i) sterilely and liquid thickly be connected in virus remove the bag (ii), and virus remove the bag (ii) sterilely and liquid thickly be connected in the blood plasma recovering mechanism (iii);

(2) gather whole blood to sampled plasma mechanism (i) from the blood donor;

(3) by centrifugal the separation of whole blood of gathering is become blood plasma and hemocyte;

(4) with isolating blood plasma from sampled plasma mechanism (i) be incorporated at least one virus remove bag (ii), remove in (ii) first Room (c) of bag in virus and to hold isolating blood plasma;

(5) remove bag virus (ii) by virus and remove the isolating blood plasma of membrane filtration;

(6) remove the filtrate of collecting in bag second Room (d) (ii) in virus as the blood plasma that removes virus removal; With

(7) will except that the blood plasma of virus removal from virus remove bag be discharged to (ii) the blood plasma recovering mechanism (iii) in.

Be used for preparation method in the present invention except that the blood plasma of virus removal, as first step, provide airtight virus to remove system, it comprises and is used to collect the whole blood that comprises blood plasma and hemocyte and from the separation of whole blood and the sampled plasma mechanism (i) of collecting blood plasma, wherein the whole blood virus that contains under a cloud; At least one virus is removed bag (ii); Be used to reclaim except that the blood plasma recovering mechanism of the blood plasma of virus removal (iii), wherein sampled plasma mechanism (i) sterilely and liquid thickly be connected in virus remove the bag (ii), virus remove the bag (ii) sterilely and liquid thickly be connected in the blood plasma recovering mechanism (iii).The virus of using among the present invention is removed system for appending to the system that conventional many bag systems of being used for gathering blood constitutent obtain by virus of the present invention being removed bag, and wherein conventional many bag systems have been used to gather blood plasma.Remove system as this virus, can use the be removed many bags of viruses of blood plasma of virus of above-mentioned being used to remove system.The object lesson that virus is removed system comprises the system that schematically shows among Figure 13 to 22.In these figure, be positioned at function bag that virus removes bag upstream etc. and constituted sampled plasma mechanism (i), be positioned at function bag that virus removes bag downstream etc. and constituted the blood plasma recovering mechanism (iii).Even because when using separately, virus of the present invention is removed bag also can remove virus removal from blood plasma, the advantage of method of the present invention be its can do not change on a large scale be used for producing from the blood of donating blood blood products and blood transfusion with the situation of the conventional method of blood plasma under preparation remove the blood plasma of virus removal.

In the step (2) of method of the present invention, will remove in the sampled plasma mechanism (i) of system to virus from blood donor's whole blood collection, in step (3), be blood plasma and hemocyte by centrifugal separation of whole blood with collection.Can carry out the collection of whole blood and separating of blood plasma by any conventional method.

Then, in (6), (ii) remove virus removal in step (4) from isolating blood plasma by using virus to remove bag.Can be used for carrying out virus from the said method that the suspension that contains virus removes virus removal by the present invention removes.Particularly, carrying out virus by the method that may further comprise the steps removes:

With isolating blood plasma from sampled plasma mechanism (i) be incorporated at least one virus remove bag (ii), remove in (ii) first Room (c) of bag in virus and to hold isolating blood plasma;

Remove bag virus (ii) by virus and remove the isolating blood plasma of membrane filtration, thereby remove virus removal from isolating blood plasma; With

Remove the filtrate of collecting in bag second Room (d) (ii) in virus as the blood plasma that removes virus removal.

In order to prevent the blood plasma degeneration, preferably after by collection blood such as donate blood, carry out virus as early as possible and remove processing.Particularly, when temperature is 20 ℃ to 40 ℃, preferably in 10 hours, carries out the virus of blood plasma and remove, more preferably carry out in 6 hours behind blood collection.When temperature is 10 ℃ to 20 ℃, preferably carries out the virus of blood plasma in 24 hours behind blood collection and remove.

At last, in step (7), from virus remove bag discharge (ii) except that the blood plasma of virus removal to the blood plasma recovering mechanism (iii) in.The blood plasma of collecting can be used to produce blood plasma product immediately or be used for plasma transfusion.Perhaps, can be at the freezing blood plasma of collecting of storing down.

In the present invention, preferred virus is removed volume that virus in the system removes second Room (d) of bag and is enough collected by virus and remove all filtrates that membrane filtration blood plasma obtains.Therefore, in the method for the invention, in step (6), preferably remove in bag second Room (d) (ii) in virus carrying out all filtrate collections that step (7) will obtain by the blood plasma of isolated by filtration before.When will be by filtering all filtrate collections that blood plasma obtains in second Room (d) the time, being back to the incomplete filtering danger that causes in first Room (c) by filtrate.In addition, in the method for the invention, need be before filter operation is finished not remove bag from virus and reclaim a filtrate (promptly removing the blood plasma of virus removal) or be provided for collecting the additional sack of filtrate, wherein additional sack is connected in virus by tube for transfusion etc. and removes bag.Therefore, can reduce the probability of breaking aseptic condition simultaneously by being easy to operate the viral blood plasma that is removed.

In another embodiment of the invention, provide the human or animal's blood plasma that obtains by the above-mentioned method that is used to prepare except that the blood plasma of virus removal.The method of the application of the invention, removed all virus from blood plasma, comprise virus that is in window phase and the virus that is not covered by used method for detecting virus in the blood treatment field, thereby provide blood plasma, and this blood plasma that removes virus removal can be advantageously used for the raw material of blood plasma product and as blood transfusion blood plasma except that virus removal.

Implement best mode of the present invention

Hereinafter, describe the present invention in more detail with reference to following examples and reference example, it should not be considered to limitation of the scope of the invention.

In following examples and reference example, following measurement and estimate each filter and virus remove the bag multiple performance.

[average pore size of filter]

Measure the average pore size of filter according to the method for stipulating among ASTM F316-86 and the E128-61.Particularly, the following measurement of carrying out the average pore size of filter.Be that (stamped-out) annular filter of the mold pressing of 25mm is packed in the pond with diameter.Then, will join in the pond as the perfluocarbon coolant (FX 3250, produced and sold by Japanese Sumitomo 3M Ltd.) of filling liquid.Use air that one side of the filter in the pond is exerted pressure, the while is increase pressure gradually.When the flow velocity of the air penetration of measuring when the effusion meter (away from a side that applies air pressure) of the opposite side that is positioned at filter by filter reaches per minute 2.5ml, read applied pressure P (Pa).Use the value P that so obtains, calculate the average pore size of filter by following formula (1):

Average pore size (μ m)=34,320/P (1)

[[the logarithm minimizing value (LRV) of bovine viral diarrhea virus]

Infect the MDBK cell of in comprising the Dulbecco ' sMEM of 5% horse serum (the Nikken Biomedical Laboratories by Japan produces and sells), cultivating with bovine viral diarrhea virus, thereby form by the culture supernatant of the cell of viral infection, collect the culture supernatant, thereby obtain containing the suspension of virus.Pressure is that 0.1MPa and temperature are that the part of the suspension that contains virus that will obtain under 25 ℃ the condition is removed membrane filtration by virus therein, and collects the filtrate that obtains, 10 parts of the filtrate that comprises 2ml respectively done for oneself.From 10 parts every part is got the 1ml sample and is mixed, thus the suspension of the virus that is removed.Use the MDBK cell of cultivating to pass through TCID ₅₀Method is measured suspension (for the filtrate) virus concentration separately contain viral suspension (before the filtration) and to remove virus removal, and calculates logarithm minimizing value according to the virus concentration of suspension of measuring that contains virus and the suspension that removes virus removal.Logarithm minimizing value (LRV) is represented by following formula (2):

Logarithm minimizing value (LRV)=-log ₁₀(as the virus concentration of the filtrate of the suspension that removes virus removal)/(virus concentration of the suspension that contains virus before filtering) (2)

[[volume of second Room (d)]

Following mensuration virus is removed the volume of second Room (d) of bag.Clamping virus with alligator clamp removes the outlet and the contact point between second Room of bag and add pure water in second Room.Make the virus that comprises pure water that obtains remove bag and place, perhaps, make the virus that obtains remove bag, measure the volume of the pure water that second Room (d) partly comprises in (it is equivalent to the dashed area shown in Fig. 7) then with the erectility suspention with erectility.Measured value is as the volume of second Room (d).

[[transmitance of latex particle]

The waterborne suspension (the Asahi Kasei Corporation by Japan produces and sells, and is designated hereinafter simply as " latex suspension ") of the styrene latex (mean diameter is 120nm) of the 1 weight % of 100ml is joined virus remove the bags of blood that is used for whole blood in the system.Whole latex suspension are incorporated into virus removes virus in the system and removes in first Room (c) of bag.Then, the virus of using centrifuge (Model 8100, produced and sold by the Kubota Corporation of Japan) will comprise latex suspension under 25 ℃, 1000G was removed bag centrifugal 15 minutes, thereby obtained filtrate in virus is removed second Room (d) of bag.Use granularmetric analysis instrument " Particle SizeAnalyzer UPA150, Model 9230 " (by Microtrac Inc., U.S.A. produces and sells) to measure the particle size distribution of the latex particle that comprises in the filtrate.

Embodiment 1

Use kneading machine (Labo Plastomill Model C, Toyo SeikiSeisaku-sho by Japan, Ltd. produce and sell) with the polyvinylidene fluoride resin (SOLEFl012 of 40 weight %, Solvay Solexis K.K. by Japan produces and sells, crystalline melting point: 173 ℃) and the mixture of 60 weight %d dicyclohexyl phthalates (industrial goods are produced and sold by the Osaka OrganicChemical Industry LTD. of Japan) knead 200 ℃ of following fusions.The molten mixture that obtains is cooled to be up to 30 ℃ temperature, thereby obtains resinite (bulk).With resinite through under the pressure of 10MPa 200 ℃ hot pressing, under the pressure of 10MPa, cold pressing then, thereby obtain resin sheet.Subsequently, extract as extractant and remove the dicyclohexyl phthalate that comprises in the resin sheet by using isopropyl alcohol (guaranteed reagents) (by the Wako Pure Chemical Industries of Japan, Ltd. produces and sells), thereby obtain perforated membrane A.The average pore size of perforated membrane A is 83nm, and thickness is 40 μ m.

On the other hand, except the quantitative change of the polyvinylidene fluoride resin that uses is 25 weight % and uses the amount of the phthalic acid ester ethylhexyl of 75 weight % to replace the dicyclohexyl phthalate of 60 weight %, preparing perforated membrane, thereby obtain perforated membrane B with the above-mentioned same basically method of perforated membrane A for preparing.The average pore size of the perforated membrane B that obtains is 123nm, and thickness is 42 μ m.

With respect to each perforated membrane A and B, followingly give hydrophilic processing.At first, at nitrogen environment Co ⁶⁰Gamma-rays is with dosage irradiation each perforated membrane A and B of 100kGy.On the other hand, with hydroxyethyl methylacrylate (one-level reagent) (by the Wako PureChemical Industries of Japan, Ltd. produce and sell) and polyethyleneglycol diacrylate (produce and sell) by Sigma-Aldrich Corporation U.S.A. be dissolved in the 1-butanols, to obtain the hydrophilic compounds solution that the concentration of hydroxyethyl methylacrylate and polyethyleneglycol diacrylate wherein is respectively 10 weight % and 1 weight %.Each perforated membrane A behind the gamma-ray irradiation and B immersed respectively in 40 ℃ the above-mentioned hydrophilic compounds solution that obtains 2 hours, thus realization response.Reclamation film and wash from the reactant mixture that each obtains with ethanol, dry then, thus obtain exsiccant film A and B.In addition, each exsiccant film immersed in the hot water in 121 ℃ the pressure heat sterilization device 20 minutes, thereby obtain Hydrophilized porous membrane A and B.

The above-mentioned Hydrophilized porous membrane B that obtains and A are contained this order of observing on the flow direction of viral suspension lamination each other, thereby obtaining composite membrane.Measure the logarithm minimizing value of the bovine viral diarrhea virus of composite membrane, find that its logarithm minimizing value is 3.1.

The composite membrane that so obtains is clipped in two non-woven polyester fabrics, and (weight per unit area separately is 50g/m ²) between (produce and sell) by the Asahi Kasei Corporation of Japan, thus complex filter obtained, the complex filter that obtains is cut to the square of 20cm * 20cm size.The peripheral part (it is equivalent to the part of reference number 11 expressions among Fig. 5) that makes complex filter is through heat-sealing, thereby the formation width is the peripheral part of the heat-sealing of about 2mm.In the complex filter that obtains, perforated membrane B is as prefilter, and perforated membrane A removes filter as virus.

Cutting has two complex filters of 11cm * 11cm size separately in the complex filter that obtains from above.Two complex filters are overlapped each other, the perforated membrane B of two complex filters is faced with each other, thereby form laminated body.As shown in Fig. 6 (a) with laminated body heat-sealing, thereby obtain the filter bag of 11cm * 11cm size.The width of the heat seal lands of filter bag is about 4mm.Then, filter bag is placed flexible soft PVC (PVC) bag-like container (a), bag-like container (a) is of a size of 13cm * 20cm, and has conduit as outlet.In addition, PVC duct portion ground is inserted in the filter bag to form inlet.To have partly, insertion wherein places flexible PVC bag-like container (a) as the filter bag of the PVC conduit that enters the mouth, the PVC outer end of conduit portion as inlet that makes is positioned at the outside of bag-like container (a), and as shown in Fig. 9 (b), bag-like container (a) is sealed, remove bag thereby obtain having bag virus of shape barrier film (b) (being filter bag).Remove in the bag in the virus that so obtains, the membranaceous surrounding wall of filter bag all is separated into the inner space of bag-like container (a) and first Room (c) that communicates and second Room (d) that communicates with outlet of entering the mouth, first Room (c) is the inner space of filter bag, and second Room (d) removes the inner space of filter bag part for bag-like container (a).Measure virus and remove the volume of second Room (d) of bag, the volume of finding second Room (d) is 180cm ³

First conduit is connected in the inlet of filter bag, and the virus that will have a filter bag is removed bag and is connected in the bags of blood (volume: 200ml) that is used for whole blood by first conduit.In addition, second conduit is connected in the outlet of bag-like container, and virus is removed bag (having bag-like container) be connected in the bags of blood (volume: 200ml), thereby obtain removing system of the blood plasma after being used to filter by second conduit as many bags of viruses that schematically show among Figure 13.Remove in the production of system in many bags of viruses, virus is being removed second Room (d) degassing that bag is removed bag with virus before being connected in bags of blood.Make many bags of viruses remove system, remove system thereby obtain many bags of airtight viruses through 121 ℃ pressure heat sterilization 20 minutes.

The many bags of virus systems of removing as shown in Figure 13 that use so obtains are prepared as follows the blood plasma except that virus removal.

At first, obtain the 200ml whole blood and be collected in the bags of blood 20 from the blood donor.Then, pack in the centrifuge cup of centrifuge " himacModel B3 " (the Hitachi High-Technologies Corporation by Japan produces and sells) wherein virus being removed total system that bag is connected in bags of blood.Whole blood in the bags of blood 20 is carried out centrifugal 10 minutes of 4000G, thus with separation of whole blood be the supernatant formed by plasma component mutually and the precipitated phase of forming by the hemocyte component.Finish on the centrifugal time point, any virus remove bag and the bags of blood that connects in find to destroy.The above-mentioned plasma component that obtains of about 100ml volume is incorporated in first Room (c) (being filter bag) that virus removes carefully, makes the hemocyte component can not enter first Room (c) (filter bag).After in plasma component being incorporated into first Room (c), finishing, by cutting off first conduit (bags of blood that will be used for whole blood is connected in the conduit that the virus with bag-like container 1 is removed the inlet of bag) in the melting sealed/cutting of the part 19 of tube for transfusion.Thereby, many bags of virus system of removing remove bag (having bag-like container 1) by virus and be used to filter after the bags of blood 21 of blood plasma form.Then, second conduit is connected to the outlet that virus is removed bag (having bag-like container 1), wherein use alligator clamp to clamp the outlet that communicates of second Room (d) of removing bag with virus, make after all filtering plasma collection and remain on virus and remove in second Room (d) of bag.Subsequently, as shown in Figure 23, virus is removed in the packed improved centrifuge cup of going into centrifuge.Particularly, in improved centrifuge cup, be provided for virus in the inside of passing the centrifuge cup and remove the hold-down bars 30 of bag, the virus that places the centrifuge cup remove the bag the top fixation hook (being the fixation hook 29 shown in Figure 23) shown in Figure 24 is provided, and with the virus in the centrifuge cup remove the bag fixation hook 29 be engaged in hold-down bars 30 securely.In improved centrifuge cup, at the bags of blood 21 of placing the blood plasma after being used to filter on the bottom of cup.To comprise virus and remove the improved centrifuge cup of bag and be downloaded on the centrifuge (Model 8100, produced and sold by the KubotaCorporation of Japan), and under 1000G, carry out centrifugal 30 minutes at 25 ℃.The result is to have filtered the plasma component in the filter bag by filter bag, and the plasma collection after all filtrations that obtain is removed in second Room (d) of bag in virus.Measure the weight of the blood plasma after filtering.The gravimetric value of the blood plasma after the filtration that use obtains is by the yield of the blood plasma after the following formula calculating filtration.Found that yield is 95%.

Yield (%)=[the blood plasma weight (g) in (weight (g) of the blood plasma after the filtration of in second Room (d), collecting)/(being incorporated into first Room (c))] * 100

Finish centrifugal time point, any virus remove bag and the bags of blood that connects in find to destroy.

From above apparent, of the present inventionly be used to prepare the blood plasma that removes virus removal that is sterilely to obtain aequum except that the advantage of the method for the blood plasma of virus removal by a series of continued operations, and the problem of not using sterilizing room and not having film to block.

In addition, the many bags of virus systems of removing same as described above are basically carried out the measurement of latex particle transmitance.Found that remove bag for the virus that above-mentioned many bags of viruses are removed system, the transmitance of latex particle is lower than detectability.Therefore, confirm that virus of the present invention removes bag and prevented that average pore size from being the blood plasma after the particle of 120nm such as virus infiltration enter filtration.

Embodiment 2

Being used for airtight virus with similarly to Example 1 method production removes the virus of system and removes bag.The virus that use obtains is removed bag production many bags of airtight viruses as shown in Figure 21 and is removed system.Here the system of Sheng Chaning comprises leukocyte and removes unit 22.Remove unit 22 for leukocyte, use commercial articles " Sepacell " (trade name is by the Asahi MedicalCorporation production and the sale of Japan).

With similarly to Example 1 method basically from the separation of whole blood plasma component.Isolating plasma component is removed unit 22 by above-mentioned leukocyte filter, thereby be removed leukocytic blood plasma.To remove leukocytic blood plasma and be incorporated into virus and remove in first Room (c) (being filter bag) of bag (having bag-like container 1), and carry out virus with similarly to Example 1 method basically then and remove.For the blood plasma that removes virus removal that obtains (blood plasma after promptly filtering), the yield of the blood plasma after finding to filter is 97%.That is to say the yield of the blood plasma after the filtration that in embodiment 2, realizes even remove higher among the embodiment 1 of step than wherein not carrying out leukocyte.Finish centrifugal time point, any virus remove bag and the bags of blood that connects in find to destroy.

The many bags of airtight viruses of producing in embodiment 2 are removed in the system, when whole blood is centrifugal when being separated into hemocyte component and plasma component, although system exists leukocyte to remove the unit, do not cause that any virus is removed bag and the destruction of the bags of blood that connects.

Embodiment 3

Except following difference, with basically with embodiment 1 in same method produce Hydrophilized porous membrane:

Use polyethylene porous membrane (average pore size is 65nm, and thickness is 20 μ m) (the Asahi Kasei Corporation by Japan produces and sells) as perforated membrane (giving hydrophilic processing in conjunction with hydrophilic compounds) by additional;

By hydroxyethyl methylacrylate (one-level reagent, by the Wako PureChemical Industries of Japan, Ltd. produces and sells) is dissolved in the ultimate density that makes hydroxyethyl methylacrylate in the methanol is that 50 weight % prepare hydrophilic compounds solution; With

Be reflected at and carried out under 40 ℃ 15 minutes.

The average pore size of the Hydrophilized porous membrane that obtains is 58nm.

Subsequently, replace perforated membrane A to remove the filter, produce complex filter with similarly to Example 1 method basically as virus except using above-mentioned Hydrophilized porous membrane.For the complex filter that obtains, measured the logarithm minimizing value of bovine viral diarrhea virus, find that its logarithm minimizing value is 3.9.

Use the above-mentioned complex filter that obtains, with embodiment 1 in same method produce filter bag.Then, except using above-mentioned filter bag, with basically with embodiment 1 in same method production virus remove bag.Use the virus of so producing to remove bag, produce many bags of viruses with method similarly to Example 1 and remove system.

Use the many bags of viruses of so producing to remove system, with basically with embodiment 1 in same method preparation remove the blood plasma of virus removal.For the blood plasma that removes virus removal (blood plasma after promptly filtering) of preparation, the yield of the blood plasma after finding to filter is 92%.In addition, remove bag, find that the transmitance of latex particle is lower than detectability for virus.

The above results shows, removes filter (comprising Hydrophilized porous membrane) and also can be used for producing virus of the present invention and remove bag by giving virus that polyethylene porous membrane obtains with hydrophilic.

Embodiment 4

Except using Hydroxypropyl methacrylate to replace hydroxyethyl methylacrylate as the hydrophilic compounds, with basically with embodiment 3 in same method production virus remove filter (comprising Hydrophilized porous membrane).Use this virus to remove filter and produce complex filter, its average pore size is 52nm, and the logarithm minimizing value (LRV) of the bovine viral diarrhea virus of complex filter is 3.9.

Use the complex filter of above-mentioned production, with embodiment 1 in same method produce filter bag.Then, except using above-mentioned filter bag, with basically with embodiment 1 in same method production virus remove bag.Use the virus of so producing to remove bag, produce many bags of viruses with method similarly to Example 1 and remove system.

Use the many bags of viruses of so producing to remove system, with basically with embodiment 1 in same method preparation remove the blood plasma of virus removal.For the blood plasma that removes virus removal (blood plasma after promptly filtering) of preparation, the yield of the blood plasma after finding to filter is 94%.In addition, remove bag, find that the transmitance of latex particle is lower than detectability for virus.

The above results shows, removes filter (comprising Hydrophilized porous membrane) and also can be used for producing virus of the present invention and remove bag by using Hydroxypropyl acrylate to give virus that polyethylene porous membrane obtains with hydrophilic.

Embodiment 5

Except with the spongy adsorbing material (melamine foamed plastic of size, be of a size of 80mm * 80mm * 10mm) (by the Arai-Kasei Co. of Japan, Ltd. produce and sell) place in the filter bag, thereby the virus that obtains having the filter bag (i.e. first Room (c)) that comprises spongy adsorbing material is removed bag, with basically with embodiment 1 in same method production virus remove bag.

Except the virus of using above-mentioned production remove the bag and will be used for from spongy adsorbing material remove air the bag (promptly be used for from virus remove the bag remove air the bag 26) be connected in the filter bag, with basically with embodiment 1 in same method produce many bags of viruses and remove system, remove system thereby obtain many bags of viruses shown in Figure 22.Being used for removing a bag bag of removing air 26 from virus is not aeriferous empty bag.Remove in the process of first Room (c) (being filter bag) of bag blood plasma being incorporated into virus, the air that comprises in the filter bag is transferred in the bag 26.Particularly, with with embodiment 1 in same method from the separation of whole blood plasma component, and isolating plasma component is incorporated in the filter bag that comprises spongy adsorbing material, will be contained in air transfer in the spongy adsorbing material simultaneously to being used for removing the bag 26 that bag is removed air from virus.On the other hand, be included in virus remove the bag second Room (d) in air be drained.Cut off in the part shown in Figure 22 19 by sealing/cutting and to be used for plasma component is incorporated into each conduit of filter bag and filter bag is connected in being used for removing another conduit that bag is removed the bag 26 of air from virus.Then, the use alligator clamp is clamped and is connected in the duct portion that virus is removed bag, and this outlet communicates with second Room (d) that virus is removed bag, and the blood plasma after feasible whole the filtration can be collected and remain on virus and remove in second Room (d) of bag.Subsequently, use the roll-type pressue device, plasma component is filtered by filter bag gradually, thereby in second Room (d), collect the blood plasma after filtering.Use the roll-type pressue device for explanation shown in Figure 27 and carry out filtering sketch map.As a result, filtered the plasma component in the filter bag by filter bag, and the blood plasma (for the blood plasma except that virus removal) after in virus is removed second Room (d) of bag, collecting all filtrations that obtain.

For the blood plasma after filtering, the yield of the blood plasma after finding to filter is 92%.In addition, remove bag, find that the transmitance of latex particle is lower than detectability for virus.

The above results shows, in the present invention, can promote to contain the filtration of viral suspension by using the roll-type pressue device that the suspension that contains virus in first Room (c) is exerted pressure.

Embodiment 6

Except using board-like pressue device to replace the roll-type pressue device, with basically with embodiment 5 in same method preparation remove the blood plasma of virus removal.Particularly, use board-like pressue device, plasma component is filtered by filter bag gradually, thereby in second Room (d), collect the blood plasma after filtering.Use board-like pressue device for explanation shown in Figure 28 and carry out filtering sketch map.Thus, filtered the plasma component in the filter bag by filter bag, and the blood plasma (for the blood plasma except that virus removal) after in virus is removed second Room (d) of bag, collecting all filtrations that obtain.

For the blood plasma after filtering, the yield of the blood plasma after finding to filter is 94%.In addition, remove bag, find that the transmitance of latex particle is lower than detectability for virus.

The above results shows, in the present invention, can promote to contain the filtration of viral suspension by using board-like pressue device that the suspension that contains virus in first Room (c) is exerted pressure.

Embodiment 7

From thickness be the flexible soft PVC plastic sheet preparation of 0.4mm respectively do for oneself bowl-shape (highly: 1.5cm, length: 20cm, width: two outer housing equal portions 10cm) (the first and second outer housing equal portions).Prepare each outer housing equal portions, make to have retaining collar (width: 1cm) at its periphery.Use epobond epoxyn that conduit (as inlet) is connected in the first outer housing equal portions, another conduit (with for export) is connected in the second outer housing equal portions.Use the complex filter of producing among the embodiment 1 as barrier film (b).Barrier film (b) is clipped between two outer housing equal portions, makes that form the position and the retaining collar of outer housing equal portions that the diapire of outer housing equal portions wherein is positioned at away from each other is positioned at structure by the peripheral part position respect to one another of barrier film (b).Make the retaining collar of the first and second outer housing equal portions bonded to each other by heat-sealing, remove bag thereby obtain virus by the peripheral part of barrier film (b).Remove the cutaway view of bag shown in Figure 30 for the above-mentioned virus that obtains.In Figure 30, retaining collar is represented by reference number 3 as the first outer housing equal portions of first Room (c) by reference number 42 expressions, is represented by reference number 4 as the second outer housing equal portions of second Room (d).

The virus of above-mentioned preparation is removed bag, and to place diameter be on the outer surface of tubular rotor (being rotary body) of 20cm, then virus is removed bag with the screw nail on rotor, thereby it is fixed on the rotor.Remove bag sketch map of the rotary body that obtains for being connected with virus shown in Figure 25 (b).About 100ml plasma component of using among the embodiment 1 is incorporated into virus removes in first Room (c) of bag, and under 1000G, carried out centrifugal 30 minutes at 25 ℃.Plasma component in first Room (c) is by filtering as the barrier film (b) of complex filter as a result, and removes the blood plasma after all filtrations that obtain of collection in second Room (d) of bag in virus.The yield of the blood plasma after the filtration is 90%.

The above results shows and can remove bag with the be removed blood plasma of virus of high yield by the virus that use has a plate diaphragm (b).

Reference example 1

Except independent use non-woven polyester fabric (produced and sold by the Asahi Kasei Corporation of Japan) (promptly not using virus to remove filter and prefilter) replaces the complex filter, with basically with embodiment 1 in same method produce filter bag.Use the filter bag of producing to remove bag with method production virus same among the embodiment 1.The supatex fabric of Shi Yonging is equivalent to not among the unexamined patent application Hei 7-267871 disclosed leukocyte and removes filter herein.

The above-mentioned virus that obtains is removed bag carry out the measurement of latex particle transmitance.Found that, be incorporated into 78 volume % that virus removes the latex particle that comprises in the latex suspension in first Room (c) of bag and enter in second Room (d) that virus removes bag by filter bag.Therefore, the supatex fabric of being made by supatex fabric can not prevent that mean diameter from being that the particle of 120nm passes through.

Reference example 2

Except using the container shown in Figure 31 (be diameter be 3cm, length tubular hard polysulfones container) to replace virus to remove the bag as 13cm, with basically with embodiment 1 in same method produce many bags of viruses and remove system.Use the model of said vesse as conventional hollow fiber filter module.

Whole blood is incorporated into the bags of blood that is used for whole blood that the many bags of viruses of being produced are removed system, and make whole many bags of viruses remove system with embodiment 1 in carry out under the same condition centrifugal.Though many bags of viruses are removed the bags of blood that comprises in the system and serious destruction are not taken place as tearing, and have produced disadvantageous phenomenon by cylindrical container and bags of blood collision, as form scratch on the surface of bags of blood.

Embodiment 8

Except the filter bag that uses as internal diameter shown in Figure 10 (a) towards the filter bag that the leading section of filter bag reduces gradually, with basically with embodiment 1 in same method produce many bags of viruses and remove system.In Figure 32 exemplary illustration be used for the shape of the filter bag of embodiment 8.

The filtration of the plasma component in filter bag replaces carrying out under 1000G under 500G, the many bags of viruses of use producing remove system with basically with embodiment 1 in same method preparation remove the blood plasma of virus removal.For the blood plasma that removes virus removal (blood plasma after promptly filtering) of preparation, the yield of the blood plasma after finding to filter is 65%.

Even The above results shows a half that be kept to the centrifugal force that uses among the embodiment 1 when the centrifugal force that blood plasma is applied, remove to observe on the flow direction that contains viral suspension in the bag towards virus at internal diameter and can reach yield greater than the blood plasma after 60% the filtration towards the filter bag that the filter bag leading section reduces gradually.

Embodiment 9

The filtration of the plasma component in filter bag replaces carrying out under 1000G under 500G, with basically with embodiment 1 in the preparation of same method remove the blood plasma of virus removal.

For the blood plasma that removes virus removal (blood plasma after promptly filtering) of preparation, the yield of the blood plasma after finding to filter is 45%.The result shows, removing the leading section of observing filter bag on the flow direction that contains viral suspension in the bag when the filter bag internal diameter that uses in virus is not when reducing gradually, the centrifugal force that blood plasma is applied is reduced to a half of the centrifugal force that uses among the embodiment 1, and the yield of the blood plasma after the filtration sharply reduces.

Reference example 3

Except the size of the bag-like container (a) made by flexible soft PVC becomes 13cm * 13cm, with basically with embodiment 1 in same method production virus remove bag.The volume that virus is removed second Room (d) of bag is 52cm ³

Use the virus of so producing to remove bag, with embodiment 1 in same method produce many bags of viruses and remove system.Use many bags of viruses to remove system then, with basically with embodiment 1 in the preparation of same method remove the blood plasma of virus removal.For the blood plasma that removes virus removal (blood plasma after promptly filtering) of preparation, the yield of the blood plasma after finding to filter has only 41%.Therefore, find that carrying out filtering most of blood plasma still is not filtered in filter bag.

Industrial applicibility

The virus for remove virus removal from the suspension that contains virus of the application of the invention is removed Bag is removed bag internal gathering as the filtrate of the suspension that removes virus removal in virus, does not therefore need Provide independent container to be used for holding filtrate. Therefore, virus of the present invention is removed the advantage of bag Be that not only it has simple structure, and be and realize virus by being easy to operation Remove. In addition, can bag appends to for blood treatment by virus of the present invention is removed In conventional many bag systems and easily prepare virus and remove system. Use this removing from blood plasma to prevent or cure a disease The advantage that the virus of poison is removed the use of system is and can easily removes all diseases from blood plasma Poison, the virus detection that comprises the virus that is in window phase and do not used in the blood treatment field The virus that method covers, and need not to carry out complicated sterile working and use large-scale instrument. Cause This can easily prepare the blood transfusion blood plasma with extremely low risk from viral infection with low cost.

Claims

2. the virus of claim 1 is removed bag, and wherein said barrier film (b) is all forms of membranaceous surrounding wall of filter bag,

3. the virus of claim 2 is removed bag, wherein remove on the flow direction that contains viral suspension in the bag and observe in described virus, the internal diameter of described filter bag reduces gradually towards the leading section of filter bag, and wherein internal diameter reduces gradually that rearward end at described filter bag begins or begins between the leading section in the rearward end of described filter bag.

4. each virus is removed bag in the claim 1 to 3, it is complex filter that wherein said virus is removed striping, wherein at least one prefilter and at least one virus are removed filter with observed this order lamination on the flow direction of the suspension that contains virus, thereby the formation complex filter wherein provides supatex fabric at least one side of complex filter.

5. each virus is removed bag in the claim 1 to 4, and it is that average pore size is 1 to 100nm perforated membrane that wherein said virus is removed striping.

6. each virus is removed bag in the claim 1 to 5, and it is the Hydrophilized porous membrane that obtains by additional hydrophilic compounds on the surface of perforated membrane that wherein said virus is removed striping.

7. the virus of claim 6 is removed bag, and adding of wherein said hydrophilic compounds is the graft polymerization reaction of hydrophilic monomer.

8. each virus is removed bag in the claim 1 to 7, and it is flexible.

9. each virus is removed bag in the claim 1 to 8, and the volume of wherein said second Room (d) is enough collected by described virus and removed all filtrates of obtaining of suspension that membrane filtration contains virus.

10. each virus is removed bag in the claim 1 to 9, and wherein said first Room (c) comprises spongy adsorbing material.

11. each virus is removed bag in the claim 1 to 10, the volume of wherein said second Room (d) is 100 to 800cm ³

12. each virus is removed bag in the claim 1 to 11, its sterilely and liquid thickly be connected at least one and have and be different from virus and remove on the function bag of function of function, thereby provide many bags of airtight viruses to remove system.

(1) provide in the claim 1 to 12 each at least one virus to remove bag;

(4) collect filtrate in described second Room (d), this filtrate is for removing the suspension of virus removal; With

14. the method for claim 13, wherein, in step (3), the described suspension that contains virus removes striping by described virus filtration obtains promoting by the suspension that contains virus in described first Room (c) being applied centrifugal force.

15. the method for claim 13, wherein, in step (3), the described suspension that contains virus removes striping by described virus filtration obtains promoting by the suspension that contains virus in described first Room (c) is exerted pressure.

16. each method in the claim 13 to 15, the wherein said suspension that contains virus is a whole blood.

17. each method in the claim 13 to 15, the wherein said suspension that contains virus is a blood plasma.

18. the method for claim 17, wherein said blood plasma never passes through freezing processing.

19. the method for claim 17 or 18, wherein said blood plasma is for removing leukocytic blood plasma.

20. each method in the claim 13 to 19 wherein, in step (4), is removed all filtrates of obtaining of suspension that membrane filtration contains virus by described virus and is collected in before in described second Room (d) carrying out step (5).

(1) provide airtight virus to remove system, it comprises:

In the claim 1 to 11 each at least one virus remove the bag (ii) and

22. the method for claim 21 wherein, in step (6), is collected in described virus before and removes in bag described second Room (d) (ii) carrying out step (7) by filtering all filtrates that described isolating blood plasma obtains.

23. human or animal's blood plasma that the method by claim 21 or 22 obtains.