WO2006116899A1

WO2006116899A1 - The system, solid phase medium, device and method for bio-fluid treatment

Info

Publication number: WO2006116899A1
Application number: PCT/CN2005/001397
Authority: WO
Inventors: Fanglin Zou; Chunsheng Chen; Jianxia Wang
Original assignee: Chengdu Kuachang Medical Industrial Limited
Priority date: 2005-04-29
Filing date: 2005-09-05
Publication date: 2006-11-09
Also published as: CN101163510A; CN101163510B

Abstract

Treatment system for bio-fluid, which not only has the function related to inactivating virus and/or removing leukocytes effectively (e.g. viral inactivation, removing viral inactivating agents, removing viral inactivating agents derivatives, removing leukocytes, etc), but also substantially has not or only has the minimum side effect to the bio-fluid. Solid phase medium for the system of present invention, devices comprising at least the system of the present invention, and the method using the system of the present invention.

Description

System and solid phase medium and apparatus and method for treating biological fluids

Field of the Invention This invention relates generally to the treatment of biological fluids, and more particularly to systems for the inactivation/removal of infectious pathogens (e.g., viruses or/and leukocytes) containing solid-liquid phase reactions.

The invention also relates to a solid phase medium useful in the system of the invention.

The invention also relates to a device comprising the system of the invention.

The invention also relates to a biological fluid treatment method comprising the use of the system of the invention. Background technique

Since the 1970s, incidents of serious medical health consequences due to biological contamination of biological materials, such as the contamination of infectious pathogens, have become a growing concern of the public. To this end, the scientific and technological community has developed several techniques for inactivating or/or removing these infectious pathogens. In the following, the virus inactivation/removal treatment technology, particularly the virus inactivation/removal treatment technology containing the solid-liquid phase reaction, is taken as an example to illustrate the problems to be solved in the prior art.

1), solid-liquid phase reaction is a method of adsorption reaction

The method comprises two methods, one is: separating the component to be prepared in the biological liquid by the solid phase medium to separate it from the virus inactivating agent, and the first is the virus inactivating agent adsorbing the virus inactivating agent in the solid phase medium. Adsorbed to separate it from the biological fluid. Related to the present invention is the latter method, which includes an organic solvent-detergent treatment (referred to as SD treatment in the present invention), a photosensitizer treatment, an iodine treatment, and the like.

The SD treatment includes an SD treatment method invented by the New York Blood Center (U.S. Patent No. 4,540,573), and a derivative method developed by others (e.g., a virus-in addition method in which only S is added, and a virus inactivation treatment method in which S is shared with alcohol, etc.). Existing virus inactivating agent adsorbents (such as C18 chromatography gel, activated carbon, etc.) in SD treatment have side effects (such as strong protein adsorption capacity and large plasma APTT value) in addition to strong adsorption capacity to SD agents. Improve, etc.). Although the use of exogenous adsorbates (e.g., C18 chromatography gels) is often expensive, and unwanted reactivity is always present.

In the photosensitizer treatment, the photosensitizer and its derivatives are removed by a solid phase medium. Existing photosensitizer/photosensitizer derivative adsorbents (eg, carbon (PCT/US94/227; US6159375; US08/347, 564), silica and ion exchange resins (PCT/WO91/03933), etc.) It has strong adsorption capacity for photosensitizer/photosist derivatives, and also has side effects (such as strong protein adsorption capacity, substantial increase in plasma APTT value, etc.).

Existing iodine adsorbents, such as carbon, polyvinylpyrrolidone (referred to as PVPP in the present invention), and the like, In addition to its strong adsorption capacity for iodine, it also has side effects (such as strong protein adsorption capacity, a large increase in plasma APTT value, etc.).

2), solid-liquid phase reaction is a method of virus inactivation reaction

At this time, the solid phase medium. It includes immobilized SD treatment, immobilized sulfhydryl compound treatment (refer to German patent DE4001099A1), immobilized iodine treatment (refer to German Shenk company product introduction), and so on. In these methods, the solid phase medium used contains a virus inactivating agent, usually containing a virus inactivating agent adsorbate, and reacts with the solid-liquid phase to be similar to the solid phase medium in the adsorption reaction, and thus has similar disadvantages. In summary, the non-specific adsorption of the solid phase medium in the existing virus inactivation treatment system has strong side effects, so that the biological fluid processed by the system produces undesired changes, such as: protein conformational change and amount loss; platelet conformation Changes and loss of quantity; red blood cell conformational changes and loss of quantity, and so on. A similar phenomenon exists in the existing leukocyte removal technology. Thus, under current conditions, a virus inactivation or/and leukocyte removal treatment system that has both effective functions (eg, adsorption of viral inactivating agents and/or virus inactivation) with minimal side effects is developed, Still the goal pursued by science and technology. Summary of the invention

It is an object of the present invention to provide virus inactivation that has both an effective function (e.g., effective viral inactivation function, effective viral inactivating agent removal function, effective leukocyte removal function), and substantially no, or only minimal, side effects. Or / and leukocyte removal treatment system. Moreover, the present invention also provides a solid phase medium for forming the system of the present invention, a device formed by the system of the present invention, and an application method of the system of the present invention. In the present invention, the expression "function" means a virus inactivating function, or/and a virus inactivating agent removing function, or/and a leukocyte removing function; the expression "effective virus inactivating function" means making one or more of 99.9% or The function of multiple modes of virus inactivation; the expression "effective virus inactivating agent removal function" refers to the function of removing more than 90% of one or more virus inactivating agents; the expression "effective leukocyte removal function" is Refers to the function of removing more than 90% of white blood cells.

The objects of the present invention are achieved by four aspects, respectively. It is an object of a first aspect of the present invention to provide a virus inactivation or/and leukocyte removal treatment system that has both an effective function and substantially no or only minimal side effects; the second aspect is to provide a A solid phase medium useful in the system of the present invention; a third aspect is directed to providing a device comprising the system of the present invention; and a fourth aspect is directed to a biological fluid treatment method using the system of the present invention. A first aspect of the invention relates to a system for treating a biological fluid of the invention, preferably a virus Live or / and leukocyte removal treatment system. In the present invention, the term "treating a biological fluid" means treatment of a biological fluid, preferably a biological contamination treatment, such as a pathogen (e.g., virus, leukocyte, etc.) treatment, more preferably a virus inactivation treatment. The technical solution of the present invention for treating a biological fluid is based on the following idea: to improve the specific adsorption capacity of the solid phase medium in the system, particularly in the system, under the condition of ensuring effective function, or/and non-specificity The adsorption capacity is reduced to reduce its side effects. The object of the present invention can be achieved by the eight systems for treating biological fluids of the present invention, respectively: the first and second systems of the present invention, by selecting a more specific virus inactivating agent/viral inactivating agent adsorbate adsorption Reaction to improve the specific adsorption capacity of the system; Third, fourth system, reduce the non-specific adsorption capacity of the system by adding a passivating agent; Fifth system, reduce the system by controlling the adsorption capacity of the virus inactivating agent adsorbate The non-specific adsorption capacity; the sixth system, which reduces the non-specific adsorption capacity of the system by controlling the total amount of the virus inactivating agent adsorbed; the seventh system is the combination of the foregoing several systems; the eighth system, A treatment system for single blood or its derivatives. Thus, the first system for treating a biological fluid of the present invention, the smallest constituent unit of which is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, Wherein: A). The virus inactivating agent comprises a dye-based photosensitizer; B). The virus inactivating agent adsorbate comprises a dyeing seat containing at least the dye-based photosensitizer, and the biological liquid A fiber having substantially no side effects, wherein: (a) the dyeing locus does not include a terminal group containing a purine or a viral RNA or DNA imitation; (b) the fiber comprises a negative in an aqueous solution of pH 7.0. An electric charge or/and an organic fiber containing at least a hydroxyl group or/and an acidic group, or/and a glass fiber; C). said viral inactivating substance comprising at least A) said virus inactivating agent and B) said virus inactivating Agent adsorbate.

In an embodiment of the first system of the invention, the organic fibers comprise natural fibers. In another embodiment, the natural fibers comprise plant fibers. In one embodiment, the vegetable fiber comprises one or more of the following: cotton fiber, hemp fiber, wood fiber, pulp. In yet another embodiment, the natural fibers comprise animal fibers.

In one embodiment, the organic fibers comprise cellulose based derived fibers. In one embodiment, the organic fibers comprise synthetic fibers. In one embodiment, the synthetic fibers comprise one or more of the following fibers: polyester fibers, polyacrylonitrile fibers, polyamide fibers, polyurethane fibers.

In an embodiment of the first system of the invention, the solid phase medium comprises a filter material comprising at least the fibers. In one embodiment, the filter media has an average density of greater than 0.10 g/cm ³ and further has one or more of the following characteristics: A) ash less than 1%; B). the average length of the fibers is less than 1 mm; C). The fibers comprise fibrous microstructures having an average length of less than 1 mm and an average diameter of less than 50 μm. In an embodiment of the first system of the invention, the solid phase medium further comprises a leukocyte-removing material. In one embodiment, the leukocyte-removing material comprises the fiber. A second system for treating a biological fluid of the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, wherein:

A). The virus inactivating agent comprises a dye-based photosensitizer; B). The virus inactivating agent adsorbate comprises a porous particle containing a hydroxyl-containing polymer; C). the virus inactivating substance contains at least A) Said virus inactivating agent and B). said adsorbate.

In an embodiment of the second system of the invention, the hydroxy polymer comprises a polysaccharide or / and a derivative thereof. In one embodiment, the polyglycan comprises one or more of the following: cellulose, dextran, agarose, chitosan, starch.

In an embodiment of the second system of the present invention, the porous particles have one or more of the following characteristics: A) an average particle diameter of 5 to 80 μm _; Β). a specific surface area of 100 to 2000 m ² /g Dry powder; C). The average pore diameter is less than 5-500 A; D). The excluded volume is less than 50,000 molecular weight. A third system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least: A) a passivating agent and a virus inactivating agent adsorbate; B). Passivating agent and virus inactivating substance; or C). Passivating agent, virus inactivating agent and virus inactivating agent adsorbate.

In an embodiment of the third system of the present invention, the passivating agent content in the solid phase medium is greater than 0.05 pmol/cm ³ .

In an embodiment of the third system of the invention, the passivating agent comprises an organic material having a hydrophilic group or/and an oleophilic group. In one embodiment, the organic substance having an oleophilic group includes natural oils or/and derivatives thereof. In another embodiment, the organic substance having an oleophilic group comprises an organic solvent. In yet another embodiment, the organics comprise a surfactant. In yet another embodiment, the organic material comprises a hydroxy compound. In one embodiment, the hydroxy compound comprises an alcohol, a Class II, or / and a derivative thereof. In one embodiment, the saccharide comprises a monosaccharide, a polysaccharide, or/and a polysaccharide. In yet another embodiment, the organic matter comprises a biological material. In one embodiment, the biological material comprises an amino acid or/and a polypeptide.

In an embodiment of the third system of the present invention, the organic substance comprises any combination of two or more of the following: natural oils, organic solvents, surfactants, hydroxy compounds, organisms substance.

In an embodiment of the third system of the present invention, the solid phase medium contains at least a passivating agent, a virus inactivating agent and a virus inactivating agent adsorbate, and: A). the virus inactivating agent comprises an organic solvent; B). the passivating agent comprises an organic solvent; and C). the organic medium in the solid phase medium The content of the solvent is more than 0.2 μηηο1/οΐΉ ³ ο In an embodiment, the content of the organic solvent is more than 0.3 mol/cm ³ . A fourth system for treating a biological fluid of the present invention, the smallest constituent unit of which is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a leukocyte-removing material and a passivating agent.

In an embodiment of the fourth system of the invention, the leukocyte-removing material comprises the fibers of the first system of the invention. In another embodiment, the passivating agent comprises the passivating agent in a third system of the invention. A fifth system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbent, and the solid phase medium is sterilized by a virus The adsorption capacity of the active agent is less than 0.02 mmol of virus inactivating agent/cm ³ .

In an embodiment of the fifth system of the present invention, the solid phase medium has an adsorption capacity for the virus inactivating agent of less than 0.1 mmol of virus inactivating agent/cm ³ . A sixth system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a liquid inlet, a liquid outlet, and a solid phase medium, wherein the solid phase medium comprises a functional layer solid phase medium and the closest a safety layer solid phase medium having a thickness of 2-15 mm, wherein: A). the functional layer solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance; B). The safety layer solid phase medium contains a virus inactivating agent adsorbate.

In an embodiment of the sixth system of the present invention, the thickness of the safety layer solid phase medium is 3.0-6. Omm o is an embodiment of the third, fifth or sixth system of the present invention. The virus inactivating agent includes an organic solvent, a photosensitizer, or iodine. In one embodiment, the photosensitizer comprises a psoralen-type photosensitizer. In one embodiment, the photosensitizer comprises a dye-based photosensitizer.

In an embodiment of the first, second, third, fifth or sixth system of the invention, the dye-based photosensitizer comprises methylene blue. In an embodiment of the third, fifth or sixth system of the invention, the viral inactivating agent adsorbate comprises an endogenous adsorbate. In one embodiment, the endogenous adsorbate comprises one of the following One or more substances: activated carbon, silicon oxide particles, particles containing poly-polysaccharides or/polypolysaccharide derivatives. In one embodiment, the endogenous adsorbate comprises one or more of the following: plant fibers, protein fibers, synthetic fibers, glass fibers.

In an embodiment of the third, fifth or sixth system of the invention, the viral inactivating agent adsorbate comprises an exogenous adsorbate immobilized with a viral inactivating agent ligand. In one embodiment, the viral inactivating agent ligand comprises a C6-C18 carbon chain, a purine-containing end group or a viral RNA, or a DNA replica. In an embodiment of the third, fifth or sixth system of the invention, the solid phase medium comprises a porous particulate solid phase medium or a depth filter media solid phase medium. In one embodiment, the porous particle solid phase medium has a spherical protein exclusion lower molecular weight of less than 5,000. In one embodiment, the depth filter media solid phase medium has a permeability of less than 200 LJm ² min. In an embodiment of one of the first to sixth systems of the present invention, a passivating agent is bonded to a surface of the part or all of the composition other than the solid phase medium that is in contact with the biological fluid. In one embodiment, the passivating agent comprises the passivating agent in a third system of the invention. A seventh system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium is a combination of two or more solid phase mediums: A). The solid phase medium containing the virus inactivating agent adsorbate in the first system of the present invention; the virus inactivating solid phase medium in the first system of the present invention; the second type of the present invention a solid phase medium containing a virus inactivating agent adsorbate in the system; the virus inactivating solid phase medium in the second system of the present invention; the inclusion in the third system of the present invention a solid phase medium containing a virus inactivating agent adsorbent; the virus phase inactivating solid phase medium in the third system of the present invention; the solid phase medium in the fourth system of the present invention; The solid phase medium in the fifth system; the solid phase medium in the sixth system of the present invention. An eighth system of the present invention is a system for treating a single human blood or a derivative thereof, comprising the system for treating a biological fluid according to any one of the above first to seventh. Embodiments of the present invention will explain that the present invention achieves the objects of the present invention by the system of the present invention. 05 001397 A second aspect of the invention relates to a solid phase medium that can form the system of the invention. The objects of the present invention can be achieved by using the two solid phase media of the present invention, respectively. The first solid phase medium for treating a biological fluid of the present invention, which is used in the first, second, third, fourth, fifth, or seven systems of the present invention, comprising at least the virus inactivating substance Solid phase media. A second solid phase medium for treating a biological fluid according to the present invention, which is a solid phase medium used in the first three, four, or five systems of the present invention, and the solid phase medium contains at least: A) The passivating agent and virus inactivating agent adsorbate; or B). the passivating agent and the leukocyte-removing material; or C). the passivating agent, the leukocyte-removing material, and the virus inactivating agent adsorbate.

Embodiments of the present invention will explain that the present invention achieves the objects of the present invention by the solid phase medium of the present invention. The first solid phase medium of the present invention is characterized in that it is a solid phase medium containing a highly selective virus inactivating agent adsorbate, and has substantially no side effects on biological fluids. The second solid phase medium of the present invention is characterized in that it is a solid phase medium which is minimized by side effects (passivation, optimization of adsorbent adsorption capacity, optimization of space exclusion effect, etc.). A third aspect of the invention relates to a device that can be formed by the system of the invention. The object of the present invention can be achieved by using the apparatus of the present invention. Thus, the apparatus for treating a biological fluid of the present invention comprises at least the system for treating a biological fluid of the present invention. In one embodiment, the device further comprises a viral inactivating agent addition structure. In one embodiment, the device further comprises a viral inactivation reaction site. In one embodiment, the device further comprises a wash liquor. A fourth aspect of the invention relates to a method of treating a biological fluid, including the use of the system of the invention. The objects of the present invention can be achieved by three methods: '

The first method of treating a biological fluid of the present invention, comprising at least: A) providing a biological fluid; B) contacting the biological fluid with the viral inactivating agent; C) bringing the biological fluid treated by B) into the present invention a system for treating a biological fluid, and contacting the solid phase medium containing at least a virus inactivating agent adsorbate; D). collecting substantially no such virus inactivating agent from said system in C) Biological fluid.

The second method for treating a biological fluid of the present invention comprises at least: A) providing a single human blood or a derivative thereof; B) adding a photosensitizer to a single human blood or a derivative thereof to a photosensitizer concentration of 0.55 -3.0μηι _Ο 1/1 and performing virus inactivation; C). passing the biologically treated biological liquid into the system for treating biological fluid of the present invention, and the solid containing at least the virus inactivating agent adsorbate Phase medium contact; D). The biological fluid substantially free of the viral inactivating agent is collected from the system in C).

A third method of treating a biological fluid of the present invention, comprising at least: Α) providing a biological fluid; Β). bringing the biological fluid into the system for treating a biological fluid of the present invention, and inactivating the virus-containing Solid phase medium contact of the agent

It should be understood by those skilled in the art that the terms used below are merely used to describe the specific modes of the present invention and may not be limited to the definitions explained below.

In the present invention, the term "biological liquid" means a liquid containing or possibly containing biological substances, including but not limited to biological liquids containing or possibly containing proteins, such as blood and blood components, plasma and plasma derivatives, biological products, organisms. Drugs, etc.

Viruses include lipid enveloped viruses and non-lipid enveloped viruses. In the present invention, the term "viral inactivation" refers to the biological fluid (eg, by the addition of a viral inactivating agent (eg, an SD agent, a photosensitizer, etc.) or/and physical energy (eg, heat, light, etc.) The process of effectively reducing the infectious activity of at least a portion of the virus present in the blood component; the term "viral inactivation treatment" refers to the entire process of bringing the viral inactivating agent into contact with the biological fluid until the viral inactivating agent in the biological fluid is substantially removed. . The virus inactivation treatment contains a virus inactivation process, and in many cases, a virus inactivating agent removal process. In the production process, the virus inactivation treatment and other treatments are performed sequentially or/and simultaneously, and thus the above-mentioned virus inactivation treatment may also partially undergo or/and undergo other treatments other than virus inactivation (for example, purification of proteins). , and many more).

In the present invention, the system can be used independently as a device (eg, filter, chromatography column, etc.), or as a component of the device (eg, filters, chromatography columns, etc. in a single person blood or component processing device) ). In the present invention, the term "device" means a structure in which the minimum composition is the above-described system, which can be practically applied to the treatment of biological fluids, such as a filter, a chromatography column, a kit (English Kit), etc.; the term "chamber" Refers to a hollow container that can hold at least a solid phase medium, such as a hollow filter cartridge for a filter, a hollow column for a chromatography column, and the like.

In the present invention, the term "solid phase medium" means a solid phase material having a certain reaction function (for example, adsorption function, virus inactivation function, etc.); the term "viral inactivating agent adsorbate", sometimes referred to as adsorbate , means having at least, but not limited to, a function of adsorbing a virus inactivating agent or/and a virus inactivating agent derivative (for example, sometimes it may also have a filtering function, a leukocyte function, etc.), and a biological liquid The concentration of the medium virus inactivating agent or/and the virus inactivating agent derivative is finally reduced to an acceptable level (for example, a TNbP concentration of less than 10 ppm, a methylene blue concentration of less than 0.03 g / ml, etc.), a solid phase material, an adsorbate It may be pure substance (such as activated carbon powder, wood fiber, etc.) or a mixture (such as cellulose-containing filter, activated carbon-containing filter, C18 chromatography gel, etc.); the term "virus inactivation""" means a solid phase material having at least, but may not be limited to, a virus inactivating function (for example, it may also have a filtering function sometimes), such as a virus inactivating agent/adsorbate complex; the term "de-whitening cell material" means any Can be used to go white Solid phase material in the cell, where the "leukocyte" includes reducing the concentration of leukocytes by adsorption mechanism of leukocytes and size filtration Processing.

In the present invention, the term "filter material" generally means a solid phase medium which can only allow a structure below a certain size to flow. Thus, the filter media of the present invention includes, but is not limited to, well-known filter media. It is often used as a stationary phase in a solid-liquid phase reaction, such as a filter material having a function of adsorbing a virus inactivating agent (referred to as a specific adsorption filter). Whether a filter material specifically adsorbs the filter material, in addition to the information provided by the manufacturer (such as activated carbon filter plate), more importantly depends on whether it has a specific adsorption function in the virus inactivation treatment. For example, a Seitz Bio filter plate which is generally considered to have no adsorption function has been found to be a preferred dye-based photosensitizer adsorbent in the examples of the present invention. The filter media includes absolute filter media and depth filter media. A preferred embodiment of the filter material of the present invention is a depth filter media. Although not intended to be discussed in theory, the fluid flow path in the deep filter media is long and has an important impact on its function (eg adsorption, virus inactivation). Filter media come in a variety of forms, such as filters, filter plates, filter rods, filter cartridges, filter mats, and more.

In the present invention, the term "filter" means a device comprising at least a filter medium and a holder thereof, including but not limited to a known filter. The holder includes a structure that seals the periphery of the solid phase medium with pressure, such as a filter disc, a filter cartridge, a filter column, and the like. In the filter of the following embodiments of the present invention, the holder generally includes: a container for accommodating the solid phase medium, an upper end structure and a lower end structure for fixing the solid phase medium, and a pressure sealing filter for surrounding the solid phase medium The structure of the solid-state medium of the material (for example, a pressure-closed structure in which the solid phase medium is closed to avoid liquid leakage due to the contact force of the convex body which is higher on the upper end structure and the lower end structure to the periphery of the solid phase medium when closed). In addition, other functional structures may be added, such as structures having special functions (e.g., sterilizing filters, etc.) introduced on the upper structure or/and the lower structure. It will be appreciated by those skilled in the art that by using the filter apparatus of the following embodiments of the present invention, a plurality of filters having different uses can be prepared by combining with different structures.

In the present invention, the term "dyeing" means a structure which can bind a dye, including a physical structure, a physicochemical structure, a chemical structure (for example, a group), and the like; the term "fiber" means a length/diameter ratio of more than 10, and A material having an average diameter of less than 1 mm; the term "Fibrets" refers to a fiber having a large number of irregular micro branches and a large surface area formed by a special production process or special processing. Structure, this fiber microstructure is very short (less than 1 mm) and very fine (less than 50 μm), for example Seitz-BiolO, Seitz-Bio20, Seitz-bio40 filter plates contain fiber microstructure. In the present invention, the term "volume exclusion chromatography organic filler" means an organic filler which is usually used or can be used in volume exclusion chromatography.

In the present invention, the term "specific adsorption" refers to adsorption of a virus inactivating agent to a virus inactivating agent, or removal of leukocyte material to leukocytes; the term "non-specific adsorption" refers to a virus inactivating agent adsorbate pair Adsorption of substances other than viral inactivating agents, or adsorption of leukocyte-derived materials to substances other than leukocytes. Non Specific adsorption includes adsorption (e.g., degreasing) and unwanted adsorption (e.g., reduction in coagulation factor activity) that are beneficial to the desired properties of the biological fluid. Unwanted reactivity of the solid phase media includes unwanted adsorption and unwanted other reactivity (eg, catalytic activity, enzyme activation activity, activity involved in reactions in biological fluids, etc.). '

In the present invention, the adsorbate includes an endogenous adsorbate and an exogenous adsorbate. In the present invention, the term "exogenous adsorbate" means a solid phase medium which obtains an adsorption capacity for a virus inactivating agent by performing a functionalized treatment of a fixed functional group on a solid phase carrier, for example, a C18 chromatography gel, a chromatography gel to which a virus inactivating agent ligand is immobilized, and the like; the term "endogenous adsorbate" means a solidification ability to adsorb a virus inactivating agent without performing a functionalized treatment of a fixed functional group. Phase medium, such as activated carbon adsorption of organic solvents, photosensitizers, and the like.

In the present invention, the term "side effects" refers to the ability of a solid phase medium, system or device, in addition to having a useful function, which may also have an undesirable change in the biological activity of the biological fluid, such as the following Or a variety of changes: a reduction in the total amount of protein, interference with the coagulation system, changes in platelet morphology, improvement in hemolytic properties, and the like.

In the present invention, the term "functional layer" means the portion sufficient to achieve its function (e.g., virus inactivation, removal of virus inactivating agent, etc.) under normal conditions (flow rate, temperature, pH, maximum throughput of biological liquid). Solid phase medium; the term "safety layer" means to ensure that the virus inactivating agent can still be effectively removed under less normal conditions (eg, the flow rate exceeds the specified 25%, the actual processing volume of the biological liquid exceeds the maximum processing amount by 25%). That part of the solid phase medium.

In the present invention, the term "complex" means a material formed by two or more compositions joined by adsorption or other physicochemical, chemical, or biochemical interaction; the term "adsorbate/passivator complex" means a composition that is at least composed of an adsorbent of a virus inactivating agent and a passivating agent of an adsorbent; the term "viral inactivating agent/adsorbate/passivator complex" means a minimum composition of a virus inactivating agent, an adsorbate, and A composite of a passivating agent for the adsorbate.

In the present invention, the term "viral inactivating agent" means any additive which has a virus inactivating function for all or part of viruses which may be present in a biological fluid, but may not be limited to a virus inactivating function, such as in photosensitizer/light treatment. A photosensitizer, an organic solvent in an SD treatment or an organic solvent/detergent, and the like. In many cases, the virus inactivating agent may have other functions besides the virus inactivating function. For example, psoralen is inactivated in addition to viruses, and is also inactivated against some other organisms (such as bacteria), in which case the virus inactivating agent is a bacterial inactivating agent, and the like. The term "viral inactivating agent derivative" is a derivative of a virus inactivating agent formed in a virus inactivating treatment, for example, a derivative produced by photoactivation of methylene blue as a virus inactivating agent in a photosensitizer/light treatment ( For example, Azure A and B:). ' In the present invention, the organic solvent (abbreviated as S in the present invention) includes any solvent known to those skilled in the art, such as n-butyl phosphate (abbreviated as TNbP in the present invention); detergent (abbreviated as D in the present invention) includes Any detergent known to those skilled in the art, such as Tween-based detergents (such as Tween-80) and Triton-based detergents (such as Triton XI 00); photosensitizers including phthalocyanine (US Pat. No. 5,232,844), fake sapphire (Sapphyrin) (U.S. Patent 5,041,078), psoralen and analogs (U.S. Patents 4,169,204, 4,294,822, 4,328,239 and 4,727,027), Hypericin (Meruelo et al., Pro. Nat Acad. Sci. US, 85, 5230) -5234 (1988)), phenothiazine dyes (Lambrecht et al., Vox Sang. 60, 207-213, (1991), and cyanine dyes (US Pat. No. 4,915,683). Usually, these photosensitizers are There is a much higher efficiency of virus inactivation under appropriate light irradiation. In the present invention, the term "dye-based photosensitizer" means a dye-like substance which can be used for photoinitiator virus inactivation (for example, photochemical virus inactivation), such as hydrazine. Cyanine, phenothiazine dye, etc.; the term "psoralen-based photosensitizer" Refers to psoralen substances that can be used to inactivate photosensitizer virus (eg, photochemical virus inactivation), including psoralen (English Psoralen), psoralen derivatives, etc. Psoralen derivatives Examples are 8-methoxyproralen, 5-methoxy psoralen, S59 psoralen ^ trioxsalen, aminomethyltrimethylpsorale ^ and the like.

In the present invention, the term "surfactant" means a substance having a surface active function, such as a detergent; the term "passivating agent" means an undesired reaction to a solid phase medium or other composition of the system ( For example, side effects include agents that have a passivating effect but may not be limited to passivation.

In the present invention, the term "single blood component" refers to blood collected from or separated from one or more persons in the same person, including single blood, single plasma, single person. Platelets, single red blood cells, etc.; the term "single blood component processing device" refers to a biological fluid processing device in which a single blood component is a biological fluid, which typically includes a virus inactivation treatment system (eg, for Single-phase blood component virus inactivated column or/and filter containing solid phase media), may also contain viral inactivating agent addition structures, viral inactivation reaction sites, connecting conduits, and other structures that may be present (eg In addition to leukocyte filters, lotions, lotion addition devices, etc., wherein the lotion (eg, saline) is used to hold blood on the solid phase medium in the device, particularly the column device or/and the filter device. The components are washed out to reduce the loss of blood components. The single blood component processing device of the present invention comprises a single person plasma virus inactivation device and a single human platelet virus inactivation device (for example, using psoralen A toxic inactivating agent), etc. Based on the above device, several other devices can also be derived. For example, by connecting with other systems (such as a blood collection and separation system), a more integrated device can be formed. The present invention will be described in more detail, but it should be understood that the embodiments of the present invention are only given examples of the individual aspects of the specific embodiments of the present invention. The present invention is not limited to these given modes of implementation (e.g., given processes, parameters, and combinations). Because the content of the invention is clear, the specific processes, parameters and combinations can be varied. The first system for treating a biological fluid of the present invention, the smallest constituent unit of which is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, wherein -

A). The virus inactivating agent comprises a dye-based photosensitizer; B). The virus inactivating agent adsorbate comprises a dyeing seat comprising at least the dye-based photosensitizer, and the biological liquid is substantially a fiber having no side effects, wherein: (a) the dyeing locus does not include a terminal group containing hydrazine or a viral RNA or DNA imitation; (b) the fiber comprises a negative charge in an aqueous solution of pH 7.0 or And/or organic fibers having at least a hydroxyl group or/and an acidic group, or/and glass fibers; C). said virus inactivating substance comprising at least A) said virus inactivating agent and B) said virus inactivating agent adsorbing Things. Here, a preferred embodiment of the expression "system for treating biological fluids" is a virus inactivation treatment system for biological liquids.

In general, the removal of additives by a solid phase medium having an adsorption function is a well-known technique that has been used for a long time. More specifically, the removal of viral inactivating agents by a solid phase medium having an adsorption function is a technique that should be known to those skilled in the art. Since the solid phase medium with adsorption function is generally very much, and the virus inactivating agent includes many types, a clear virus inactivating agent/viral inactivating agent adsorption specific pairing relationship has been developed. The system has always been a very difficult creative job.

The first processing system of the present invention is based on an unexpected result of an embodiment of the present invention. For example, although: A) a dye (such as methylene blue) is one of the most commonly used viral inactivating agents in human blood or human blood components; B) fibers containing dyed seats (such as natural fibers) can adsorb dyes; C) even Filter media containing natural fibers have long been used in the production of biological products, but no natural fiber has been used as an adsorbent for dye-based photosensitizers. This may be familiar with the innocent, perhaps because its adsorption capacity can meet the lack of effective adsorption of dye-based photosensitizers at low concentrations (usually less than ^mol/ml) and low temperatures (usually less than 36 ° C). confidence. However, according to an embodiment of the present invention, it is surprising today that the effective removal of dyes using natural fibers, synthetic fibers, and glass fibers as a virus inactivating agent is no more difficult and even more difficult than dyeing fibers. Easier to implement. For example, methylene blue (cationic dye) is generally not used for dyeing natural fibers, but natural fibers are used to effectively remove methylene blue. According to an embodiment of the present invention, these fibers are not only adsorbable to the dye-based photosensitizer, but also have characteristic significance: the adsorption is sufficiently strong (for example, the concentration of methylene blue after adsorption falls below 0.03 g / ml); Its adsorption is kinetically stable (for example, there is no significant desorption of methylene blue adsorbed on it when the biological liquid is continuously flowing through the filter plate); its adsorption is reproducible (for example, its adsorption reproducibility under the same conditions) It is 100%); and its adsorption is sufficiently specific (for example, basically no side effects). The present invention is not intended to be discussed in theory, but only provides some observations: Since: 1). "dye up-take" of dye-based photosensitizers is usually a biological liquid containing a fiber as a stationary phase and a dye-based photosensitizer. The mobile phase is carried out under the conditions of the preferred solid-liquid phase reaction; 2) the dye-based photosensitizer is not required to be uniformly dyed; 3) the total amount of the dye-based photosensitizer to be adsorbed is not the number of fibers used. Very large; 4). The structural complexity of the fiber; etc., effective removal of the fibers in the dye-based photosensitizer may have, but does not necessarily have, the same high color fastness as the dyeing of the textile. Based on this observation of the present invention, the types of fibers that can be used to effectively remove the dye-based photosensitizer are much more, at least much more than the textiles which can be dyed by the corresponding dyes, since the latter are often limited in choice. High color fastness requirements.

In an embodiment of the first treatment system of the present invention, the fibers comprise an organic fiber having a negative charge in an aqueous solution of pH 7.0, or/and at least a hydroxyl group or/and an acidic group. The acidic group includes a carboxyl group, a sulfonic acid group, and the like. The present invention is not intended to be discussed in theory, but is to be inferred from the perspective of understanding the embodiments. In fact, most biological fluids containing dye-based photosensitizers are between pH 6.5 and 9.0. Under this pH condition, the formation of a negative charge on the surface of the fiber may be due to the ionization of certain groups (such as acidic groups) thereon, or/and the selective absorption of hydroxide ions in the solution, or/and directed sorption. Water molecules (for example by hydroxyl action), and the like. If the dye-based photosensitizer is a cationic dye, it is susceptible to adsorption due to the opposite charge of the dye to the surface of the fiber; if the dye-based photosensitizer is not a cationic dye (eg, direct. dye), or even an anionic dye, due to dye and fiber surface charge Although it is not the opposite, its adsorption activation energy is high enough to cause adsorption. In particular, it is emphasized that: 1) the above acidic group is not necessarily the main derivative group of the fiber (for example, wood fiber, silk, cotton fiber, viscose fiber is partially oxidized and contains a certain amount during the preparation process). The carboxyl group, the terminal group of the polyester group has a carboxyl group, the carboxyl group contains a carboxyl group or a sulfonic acid group, etc.); 2) The fiber may further contain a group other than the above acidic group, or even a basic group.

This system of the present invention is different from existing systems for removing dye-based photosensitizers. Despite the wide variety of viral inactivating agent adsorbents mentioned in general, the dye-based photosensitizer adsorbents supported by the prior art systems are essentially activated carbon (PCT US94/14227; US6159375; US08/347564), Silica and ion exchange resins (PCT/WO91/03933), or a combination of a photosensitizer ligand (an end group of hydrazine, or a replica of viral RNA or DNA - in particular a polythymidine, carbohydrate, or viral protein) Cellulose acetate derivatives (US Patent Nos. 08/179567, 08/204102, 08/347564).

In an embodiment of the first system of the present invention, the organic fibers comprise natural fibers, such as vegetable fibers (eg, cotton fibers, hemp fibers, wood fibers, pulp, etc.), and animal fibers (eg, silk, and many more).

In one embodiment, the organic fibers comprise cellulose based derived fibers (eg, viscose, acetate, and the like). In one embodiment, the organic fibers comprise synthetic fibers, such as one or more of the following fibers: polyester fibers, polyacrylonitrile fibers, polyamide fibers, polyurethane fibers, and the like.

In one embodiment, the fiber has one or more of the following characteristics: A). Average diameter 0.01-20 μπΐ; Β). Curl degree 1-2; C). Water absorption 25-50 g/100 g fiber. In addition, it is well known that other structural parameters of the fiber, such as the glass transition temperature of the polymer, the electrokinic layer potential of the fiber, and the isoelectric point, etc., also affect its ability to bind the dye.

In one embodiment, the solid phase medium comprises a filter material comprising at least the fibers. The filter medium may contain, in addition to the fibers, an adhesive, a reinforcing agent (e.g., polyolefin), and the like. In one embodiment, the solid phase medium comprises one of the following filters or their analogs: Seitz-Bi _O 10, Seitz-Bio 20, Seitz-bio 40 > Seitz-Supradurl 00, Seitz-Supradur 200, Seitz- Supradur500, Seitz-Supmdurl000. In one embodiment, the filter media has an average density of greater than 0.10 g/cm ³ and further has one or more of the following characteristics: A) ash less than 1%; B). the average length of the fibers is less than Lmm; C). The fibers comprise fibrous microstructures having an average length of less than 1 mm and an average diameter of less than 50 μm. In fact, the Seitz Bio Series filter plates have these features.

In an embodiment of the first system of the invention, the solid phase medium further comprises a leukocyte-removing material. In one embodiment, the leukocyte-removing material comprises the fiber. For example, the fibers can be both a leukocyte-removing material and a virus inactivating agent adsorbate. A second system for treating a biological fluid of the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, wherein: A). The virus inactivating agent comprises a dye-based photosensitizer; B). The virus inactivating agent adsorbate comprises a porous particle containing a hydroxyl-containing polymer; C). the virus inactivating substance contains at least A) Said virus inactivating agent and B). said adsorbate. Here, a preferred embodiment of the expression "system for treating biological fluids" is a virus inactivation treatment system for biological fluids.

The second processing system of the present invention is also an unexpected result based on an embodiment of the present invention. In fact, porous particles containing hydroxyl polymer are often used as volume exclusion chromatography organic fillers (e.g., polysaccharide-containing fillers). It is considered to have little adsorption capacity, particularly specific adsorption capacity, and is used in chromatographic techniques for material separation according to its volume exclusion effect. As such, their side effects on biological fluids may be small, but they should not be used as adsorbents. However, by the examples of the present invention, it has been found that the porous particles of the hydroxyl group-containing polymer have a specific adsorption effect on the virus-removing agent dye in the biological liquid.

The present invention is not intended to enter a theoretical discussion, but only one observation that can be discussed: Since: 1). Dyes PT/CN2005/001397 The adsorption of photosensitizers is usually carried out with organic filler as the stationary phase and bio-liquid containing dye-based photosensitizer as the mobile phase under the preferred solid-liquid reaction conditions; The total amount of the agent is not very large; 3) the structural complexity of the porous particles; etc., the conventional adsorption properties of the stationary phase when the dye-based photosensitizer is effectively removed (for example, lipophilic groups, ligand groups, ionic groups) The requirements are far from being as high as people think. In fact, most biological fluids containing dye-based photosensitizers are between pH 6.5 and 9.0. Under this pH condition, the formation of a negative charge on the surface of the filler may be due to ionization of certain groups thereon, or/and selective absorption of hydroxide ions in the solution, or/and directed sorption of water molecules, and the like. If the dye is a cationic dye, the shell I oil is susceptible to adsorption when the dye is opposite in charge to the organic charge. If the dye is not a cationic dye or even an anionic dye, the dye is more susceptible to adsorption only when its activation energy is sufficiently high, since the charge is not opposite to the charge of the organic substance. In addition, the hydroxyl group is also an important group for the formation of hydrogen bonds, which has an important influence on the interaction between the dye and the organic filler. Thus, the porous particles in the system of the present invention are substantially different from polar polymer particles (e.g., polystyrene-divinylbenzene, or acrylic ester particles), although these porous particles can also function as dye adsorbents (US 6348309).

In one embodiment of the second treatment system of the invention, the hydroxy polymer comprises a polydose or/and a derivative thereof. Polysaccharides, like natural fibers, have essentially no side effects on most biological fluids, but have never been disclosed as dye-based photosensitizer adsorbates. Although polyglycans have been used as carriers in addition to viral inactivating agents, for example, nitrocellulose has been used as a carrier for photosensitizer ligands in addition to photosensitizers and leukocyte-removing filters (U.S. Patent Nos. 08/179,567, 08/204,102, 08/347564), a polysaccharide containing polypolysaccharide is used as a carrier for an SD adsorbent (for example, C18) for use in addition to an SD agent, etc., another unexpected result of the embodiment of the present invention is the polysaccharide itself. Strong enough, kinetically stable, repeatable and absorbing for dyes such as methylene blue. - In one embodiment, the polyglycan comprises one or more of the following: cellulose, dextran, agarose, chitosan, starch. Examples of the cellulose derivative include nitrocellulose, cellulose acetate, methyl cellulose, carboxymethyl cellulose, and the like.

In an embodiment of the second system of the present invention, the porous particles have one or more of the following characteristics: A). Average particle diameter: 5-80 μm _; Β). Specific surface area: 100-2000 m ² /g Dry powder; C). The average pore diameter is less than 5-500 A; D). The excluded volume is less than 50,000 molecular weight. For example, the following GPC chromatography gel has the characteristics: Sephadex GlO. Sephadex G25, Sephadex G50. Sepharose. A third system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least: A) a passivating agent and a virus inactivating agent adsorbate; B). Passivating agent and virus inactivating substance; or C). Passivating agent, virus inactivating agent and virus inactivating agent adsorbate. it's here, A preferred embodiment of the expression "system for treating biological fluids" is a virus inactivation treatment system for biological fluids.

The third system of the present invention is also based on the unexpected results of the embodiments of the present invention. The general idea is that the adsorbate should not be passivated. Since the permissible residual value of the virus inactivating agent in the bioliquid product standard is usually very low (for example, the TNbP permissible residual value in the European Pharmacopoeia is less than 10 ppm), the adsorbent of the existing virus inactivating agent is not passivated with the passivating agent. Surprisingly, in embodiments of the present invention, after some of the adsorbate immobilization passivating agent forms the adsorbate/passivator complex, it can still be used to adsorb out the virus inactivating agent. Moreover, the bioactive activity of the contacted biological fluid is better preserved (e.g., human plasma APTT value) than the adsorbate/passivator complex. Thus, this embodiment of the invention is essential to existing adsorbents for the removal of viral inactivating agents (for example, PCT US94/14227; US6159375; US08/347564; PCT/WO91/03933) different.

In addition, we ourselves have thought that because of the high requirements for virus inactivation (usually requiring a virus titer to drop by more than 10 ³ ), the solid phase medium containing the virus inactivating agent (especially the virus inactivating agent is not in the external adsorption group). a solid phase medium, especially a solid phase medium that is not on a long-chain adsorption group, such as SD-activated carbon. The passivation may reduce the effect of the virus inactivating agent on the solid phase medium and adversely affect the immobilized virus. Passivation treatment was not introduced in the development of the agent (refer to the document of Chinese Patent Application No. 01104343.1 ^; International Patent Application No. W09518665). However, embodiments of the present invention will demonstrate that the use of an immobilized virus inactivating agent containing a passivating agent not only effectively protects the biological activity of the liquid medium contacted by the solid phase medium, but also effectively inactivates the virus. Thereby the object of the invention is achieved. In the present invention, the solid phase medium may contain one or more passivating agents, one or more adsorbents, and the like.

In an embodiment of the third system of the invention, the passivating agent content in the solid phase medium is greater than 0.05 mol/cm ³ , preferably greater than 1 mol/cm ³ . For the system of the present invention, the purpose of the present invention (e.g., minimizing side effects) can be met only in certain cases when the level of passivating agent is suitably large. Some unexpected results in the examples of the present invention are that the adsorption of viral inactivating agents (e.g., methylene blue) is still sufficiently strong when the amount of certain passivating agents on the activated carbon material is greater than 5 μηιο/οπι ³ . As for the upper limit of the content of the passivating agent, it should be different according to its activity (specific adsorption capacity or virus inactivation ability) and the degree of passivation required (for example, the degree of passivation of biological fluids with or without clotting factors may be different) , optimized according to known methods.

In an embodiment of the third system of the present invention, the passivating agent comprises an organic substance having a hydrophilic group or/and an oleophilic group, preferably an organic substance which can be injected into a human body. The characteristics of these passivating agents are: 1). It is a relatively inert substance; 2) It can be immobilized on the adsorbate to inhibit the side effects of the adsorbate and has no effect on its specific adsorption; 3). Even with a controlled amount of passivating agent from solid phase media or other The composition falls off into the biological fluid, which does not cause substantial damage to the safety of the use of the biological fluid. An organic substance having an oleophilic group is poorly water-soluble (for example, a natural fat or oil, an organic solvent), and a considerable amount of an organic substance having a hydrophilic group or having a hydrophilic group and a lipophilic group is considered to have poor adsorption force (for example, a surfactant, Sugar) is generally not used as a passivating agent for solid phase media for treating aqueous solutions. Surprisingly, such materials are useful as passivating agents in the practice of the present invention and are intended to serve the objectives of the present invention.

In one embodiment, the organic substance having an oleophilic group includes natural oils or/and derivatives thereof. For example, the natural oils and fats include vegetable oils and phospholipids, wherein: vegetable oils include castor oil, soybean oil, tea oil, glycerin; and phospholipids include cephalin, lecithin, and plant phospholipids. Examples of natural oil and fat derivatives include vegetable oil emulsions, fat emulsions, and the like. The dispersion of the low water-soluble organic substance deactivator can be carried out by a known technique. There are many methods for dispersing natural fats and oils in an aqueous solution, such as an emulsification method, an air removal method, and the like.

In one embodiment, the organic substance having an oleophilic group includes an organic solvent such as: tributyl phosphate (TNbP), diethyl ether, glycerin, ethyl carbonate, ethyl lactate, benzyl benzoate, and the like.

In one embodiment, the organic material having a hydrophilic group and an oleophilic group includes a surfactant. The present inventors have found that a large number of surfactants, especially those having a hydrophilic group and an oleophilic group in the molecular structure, can be adsorbed on the surface of the activated carbon and reduce the side effect of the activated carbon on the biological liquid. Hydrophilic groups include: -OH, -OS03, -(CH2CH20)3, -N(CH3)2, -N(CH3)3, -CH2COO, -NH2; lipophilic groups include: organic ring groups, -( CH2)n-, and so on. Examples of the surfactant include: Triton-based surface active materials, Tween-based surface active materials, sodium cholate, tetrahydrofurfural polyethylene glycol ether, dimethylacetamide, polyvinylpyrrolidone, and dimethyl sulfoxide. An example of a partial surfactant as a passivating agent is given in the examples.

In one embodiment, the organic substance having a hydrophilic group includes a hydroxy compound such as an alcohol (eg, ethanol, glycerin, glycerol sodium chloride, etc.), a saccharide, or/and a respective derivative thereof .

In one embodiment, the saccharide comprises a monosaccharide, a polysaccharide, or/and a polypolysaccharide, such as: glucose, mannitol ([Molecular Formula] C ₆ H ₁₄ 0 ₆ ), sorbitol, glycerol fructose, sucrose, hydroxy Ethyl starch, lentinan, etc. A surprising result of embodiments of the present invention is that various sugars can be adsorbed on the surface of the activated carbon and reduce the side effects of the activated carbon on the biological fluid.

In one embodiment, the organic substance having a hydrophilic group includes a biological substance such as an amino acid or/and a polypeptide. The amino acids include cystine, lysine, tyrosine, glycine, arginine, proline, serine, and the like. The polypeptides include albumin, serum, and milk, and their respective derivatives.

In one embodiment, the organic substance includes any two or more of the following two or more substances Any combination: natural oils, organic solvents, surfactants, hydroxy compounds, biological substances. These substances correspond to several of the above several embodiments. For example: Dextran 40/glucose, dextran 40/albumin, albumin/glucose, TN P/Tween-80/dextran, and the like.

In an embodiment of the third system of the present invention, the solid phase medium comprises at least a passivating agent, a virus inactivating agent, and a virus inactivating agent adsorbate, and: A). the virus inactivating agent comprises An organic solvent; B). The passivating agent comprises an organic solvent; and C). The content of the organic solvent in the solid phase medium is greater than 0.2 mol/cm ³ , preferably greater than 0.3 mol/cm ³ . Only when the content of organic solvent (such as TnBP) is greater than a certain level, the organic solvent can be used both as a virus inactivating agent for effective virus inactivation and as a passivator for virus inactivating agent (for example, activated carbon). Agent to minimize side effects. The embodiment of the present invention has the feature that the content of the organic solvent is greater than 0.2 μm _Ο 1/1⁄2 η ³ . In the solid phase medium, an appropriate amount of detergent (for example, in an amount greater than Ο.ΟΙμπιοΙ/cm ³ ) or other passivating agent (for example, a polysaccharide) may be contained. When the content of D is sufficiently large (e.g., greater than _{^{0.2 mol / C m 3),}} D can be as virus inactivating agent, but also for passivating agent adsorbate. A fourth system for treating a biological fluid of the present invention, the smallest constituent unit of which is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a leukocyte-removing material and a passivating agent. In fact, leukocyte-removing materials usually have more or less adsorption capacity to white blood cells. The general idea is that the addition of a passivating agent can inhibit its side effects, but it may also reduce its adsorption on white blood cells. Surprisingly, however, in one embodiment of the invention, the addition of a passivating agent inhibits its side effects, but it can still be used to effectively remove leukocytes. In a preferred embodiment, the fourth treatment system of the invention can be used to simultaneously remove viral inactivating agents (or/and viral inactivating agent derivatives) and white blood cells.

In an embodiment of the fourth system of the invention, the leukocyte-removing material comprises the fibers of the first system of the invention. In another embodiment, the passivating agent comprises the passivating agent in a third system of the invention. A fifth system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbent, and the solid phase medium is sterilized by a virus The adsorption capacity of the active agent is less than 0.02 mmol of virus inactivating agent/cm ³ , or less than 0.1 mmol of virus inactivating agent/cm ³ . Here, a preferred embodiment of the expression "system for treating biological fluids" is a virus inactivation treatment system for biological fluids.

In the adsorbent of the existing virus inactivating agent, there is no upper limit to the adsorption capacity. It is generally believed that a high adsorption capacity facilitates the removal of the viral inactivating agent. However, by the examples of the present invention, we have found that: the virus inactivating agent adsorbent has a suitably low adsorption capacity, not only for removing the virus inactivating agent, Severe effects, and can significantly reduce its side effects on biological fluids (such as changes in APTT values). In fact, the specificity of the functional group (such as activated carbon) of the virus inactivating agent adsorbate is usually not high, so the high adsorption capacity may also be favorable for the adsorption of other substances (such as blood coagulation factors) in the biological liquid to form a high side effect. A sixth system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a liquid inlet, a liquid outlet, and a solid phase medium, wherein the solid phase medium comprises a functional layer solid phase medium and the closest a safety layer solid phase medium having a thickness of 2-15 mm (preferably 3.0-6.0 mm), wherein: A). the functional layer solid phase medium contains at least a virus inactivating agent adsorbate or/and virus inactivation B). The safety layer solid phase medium contains a virus inactivating agent adsorbate. Here, a preferred embodiment of the expression "system for treating biological fluids" is a virus inactivation treatment system for biological fluids.

For safety, it is a well-known practice to use an excess of adsorbent medium. However, excessive adsorption media increases the risk of side effects. Since the diffusion of the virus inactivating agent in the solid phase medium is not necessarily uniform, the total amount of the solid phase medium in the safety layer is only used to prevent the risk. Thus, the minimization of the maximum thickness of the safety layer solid phase media is the minimization of system side effects. In the present invention, the thickness of the safety layer solid phase medium is equal to the total thickness of the solid phase medium minus the thickness of the solid phase medium before the safety layer. When the functional layer contains only the functional layer solid phase medium, the thickness of the safety layer solid phase medium is equal to the total thickness of the solid phase medium minus the thickness of the functional layer solid medium. The thickness of the functional layer solid phase medium, particularly the functional layer solid phase medium containing the virus inactivating agent adsorbate, refers to the thickness of the solid phase medium from the influent liquid to the liquid discharge direction just when the adsorption requirement is satisfied. An example of expressing "thickness just meeting the adsorption requirements" is: Under the designed adsorption conditions (flow rate, temperature, pH, maximum throughput of biological liquid), the rate of reduction of the virus inactivating agent in the biological fluid is less than or equal to 5 The thickness of the solid phase medium at %. The rate of reduction of virus inactivating agent content = (H-h) / h, where: h is the percentage of the solid phase medium that removes the virus inactivating agent when it meets the thickness required for adsorption, and H is the same as the solid phase medium. The percentage of virus inactivating agent removed when the thickness required for adsorption is increased by 3 mm. For example, in a filter containing a filter medium containing a virus inactivating agent adsorbent, the initial liquid inactivating agent (for example, an initial total amount of 1 mg) is calculated from the liquid inlet to the liquid outlet. %(h) is removed by the filter material (this is 0.2mg), and when the thickness of the same filter material is 8mm, 84% (H) of the initial virus inactivating agent (for example, the initial total amount is 1mg) is removed (this) Fashion saves 0.16mg). In this example, the total thickness of the solid phase medium is 8 mm, the thickness of the solid phase medium of the functional layer is 5 mm, and the thickness of the solid phase medium of the safety layer is 3 mm. The thickness of the solid layer solid phase medium in the present invention is safe and does not significantly increase side effects.

In an embodiment of the sixth treatment system of the present invention, the safety layer solid phase medium is selected from the virus inactivating agent adsorbate in the first to fifth treatment systems of the present invention. In an implementation In the solution, the safety layer solid phase medium is an adsorption medium different from the functional layer adsorption medium. For example, the functional layer adsorption medium is a passivated iodine-PVPP filter plate, the safety layer solid phase medium is a passivated PVPP filter plate; the functional layer adsorption medium is a plant fiber filter plate, and the safety layer solid phase medium is a passivated plant fiber. Filter plate; and so on. It should be noted that, in an embodiment of the third, fifth or sixth system of the present invention, the virus inactivating agent comprises an organic solvent, a photosensitizer, or iodine. Examples of organic solvents are: TNbP, formaldehyde, diethyl ether, and the like. Another form of the viral inactivating agent comprising an organic solvent is a combination of an organic solvent and a detergent, such as TNbP/Tween-80, TNbP/Triton X100. TNbP/sodium cholate, diethyl ether/Tween-80, and many more. Examples of photosensitizers are: phthalocyanine, pseudosapphire, psoralen and the like, hypericin, dye-based photosensitizers (e.g., phenothiazine dyes, acridines, cyanine dyes), and the like. The photosensitizer treatment includes a photosensitizer/light treatment using a specific wavelength and light intensity and a treatment that does not use a specific wavelength and light intensity.

In an embodiment of the first, second, third, fifth or sixth system of the invention, the dye-based photosensitizer comprises methylene blue.

In one embodiment, the viral inactivating agent further comprises a positively charged depth filter media. In one embodiment of the invention, the solid phase medium used is a passivator/solid phase virus inactivating agent complex. Among them, the solid phase virus inactivating agent is a solid phase virus inactivating agent based on a positive charge (e.g., Cuno Zetaplus VR filter plate). Although an example of this embodiment is exemplified in the embodiments of the present invention due to the limitation of the number of existing products, those skilled in the art should know that this method is easy to push on other solid phase virus inactivating agents. . It should be noted that, in an embodiment of the third, fifth or sixth system of the present invention, the virus inactivating agent adsorbate comprises an endogenous adsorbate. In fact, it is particularly surprising that the endogenous adsorbate is purified to obtain a more specific adsorbate.

In one embodiment, the endogenous adsorbate comprises one or more of the following: activated carbon, silicon oxide particles, polysaccharide-containing or/polypolysaccharide derivative particles. Activated carbon can be present in different forms, such as activated carbon powder, activated carbon felt, activated carbon containing filter media, and the like. The adsorbent containing activated carbon has an adsorption function for organic solvents, detergents, photosensitizers, iodine, and the like, but tends to have strong undesired reactivity. The oxides of silicon include diatomaceous earth (for example, Seitz Supradur 80P contains a large amount of diatomaceous earth), perlite (for example, Cuno Zetaplus Delipid contains a large amount of perlite), and the like. The oxide of silicon has an adsorption function for the organic solvent and the detergent in the present invention, but tends to have a strong undesired reactivity. As described in the second treatment system of the present invention, the polysaccharide-containing or poly-polysaccharide derivative particles are There is less adsorption to dye-based photosensitizers used as viral inactivating agents, and in some applications it is possible to further reduce side effects.

In one embodiment, the endogenous adsorbate comprises one or more of the following: plant fibers, protein fibers, synthetic fibers, glass fibers. For example, in the first treatment system of the present invention, these fibers have an adsorption function for at least a dye-based photosensitizer used as a virus inactivating agent, and in some applications, it is possible to further reduce side effects.

In an embodiment of the third, fifth or sixth system of the invention, the virus inactivating agent adsorbate comprises a virus inactivating agent ligand (eg: C6-C18 carbon chain, ruthenium containing) Exogenous adsorbate of end group or virus RA, or DNA imitation). It should be noted that, in an embodiment of the third, fifth or sixth system of the present invention, the solid phase medium comprises a porous particle solid phase medium (for example, activated carbon powder, gel), or a deep filtration filter. Solid phase media (for example, containing activated carbon filter plates, including PVPP filter plates). In one embodiment, the porous particle solid phase medium has a spherical protein exclusion lower molecular weight of less than 10,000, preferably 5,000. For example, Sephadex G10, Sephadex G25, Bio-gel-P-2, Bio-gel-P-4. Bio-gel-P-6, and the like, and derivatives thereof. In one embodiment, the depth filter media solid phase medium has a permeability of less than 400, preferably less than 200 L/m ² min. For example, Seitz-Bio 20, Seitz-Bio 40, Seitz-Supradur 100, and the like. In the present invention, the permeability refers to a flow rate per unit area of a filter medium having a thickness of 3 mm with water as a fluid under a pressure difference of 10 ÅPa. In fact, the virus inactivation treatment system is a well-characterized system: Most viral inactivating agents and their derivatives are small molecular substances (such as TNbP), and many biological substances are macromolecular substances. The lower limit of a smaller spherical protein exclusion is more conducive to the adsorption of small molecules rather than macromolecules. It should be noted that, in an embodiment of one of the first to sixth systems of the present invention, a surface of the part or all of the composition other than the solid phase medium that is in contact with the biological liquid is combined Deactivator. In one embodiment, the passivating agent comprises the passivating agent in a third system of the invention. A seventh system for treating a biological fluid according to the present invention, wherein the smallest constituent unit is a chamber containing a solid phase medium, wherein the solid phase medium is a combination of two or more solid phase mediums: A). The solid phase medium containing the virus inactivating agent adsorbate in the first system of the present invention; the virus inactivating solid phase medium in the first system of the present invention; the second type of the present invention The virus-containing inactivation in the system Solid phase medium for adsorbent; solid phase medium containing virus inactivating material in the second system of the present invention; solid phase containing virus inactivating agent adsorbate in the third system of the present invention The medium containing the virus inactivating solid medium in the third system of the present invention; the solid phase medium in the fourth system of the present invention; the solid in the fifth system of the present invention Phase medium; the solid phase medium in the sixth system of the invention. An eighth system of the present invention is a system for treating a single human blood or a derivative thereof, comprising the system for treating a biological fluid according to any one of the above first to seventh. A second aspect of the invention comprises the first solid phase medium for treating a biological fluid of the invention, which is used in the first, second, third, fourth, fifth, or seven systems of the invention, a solid phase medium containing at least the virus inactivating substance, for example: a dye-based photosensitizer/fiber composite, a dye-based photosensitizer/fiber-containing filter composite, a virus inactivating agent/activated carbon/passivating agent, etc. .

A second solid phase medium for treating a biological fluid according to the present invention, which is a solid phase medium used in the first three, four, or five systems of the present invention, and the solid phase medium contains at least: A) The passivating agent and virus inactivating agent adsorbate; or B). the passivating agent and the leukocyte-removing material; or C). the passivating agent, the leukocyte-removing material, and the virus inactivating agent adsorbent, for example Passivator/fiber composite, passivator/activated carbon composite, passivator/de-leukocyte material complex, passivator/de-leukocyte material/viral inactivating agent sorbate complex, and the like. A third aspect of the invention comprises a device for treating a biological fluid of the invention comprising at least a system for treating a biological fluid of the invention, for example comprising one of the first to nine treatment systems of the invention Pillars, filters, kits, and more. In one embodiment, the device further comprises a viral inactivating agent addition structure, or/and a virus inactivation reaction site, or/and a wash solution. In one embodiment, the device comprises a kit. A fourth aspect of the invention includes the method of treating a biological fluid of the invention.

A second method of treating a biological fluid of the present invention, comprising at least: A) providing a single blood separation or a derivative thereof; B). adding a photosensitizer to a single human blood or a derivative thereof to a photosensitizer concentration of 0.55-3.0 μηι _Ο 1/1 and performing virus inactivation; C). entering the biological liquid treated by hydrazine) a system for treating a biological fluid of the present invention, and in contact with said solid phase medium containing at least a virus inactivating agent adsorbate; D). collecting from said system in C) substantially free of said virus inactivation Biological fluid. A high concentration of photosensitizer is beneficial to reduce the time to virus elimination, or/and to apply a virus-killing condition (e.g., lower temperature, lower light intensity, etc.) that is beneficial for maintaining biological activity. In fact, the side effect of a solid phase medium containing a virus inactivating agent adsorbent is one factor limiting the concentration of the photosensitizer. In one embodiment, the virus inactivation is carried out at a temperature below room temperature, for example between 4-19.5 ° C, preferably between 15 and 19.5 ° C, more preferably between 15 and 17 ° C. Hey.

A third method of treating a biological fluid of the present invention, comprising at least: Α) providing a biological fluid; Β). bringing the biological fluid into the system for treating a biological fluid of the present invention, and inactivating the virus-containing The solid phase medium of the agent is in contact. According to the virus inactivation treatment method of the present invention, an embodiment comprises: a) adding a virus inactivating agent to the biological fluid and performing a virus inactivation; b) contacting the biological fluid with the solid phase medium and performing Another virus was inactivated. There are two options for this scenario. Scheme 1: a). adding a virus inactivating agent to the biological fluid and performing the first virus inactivation; b) contacting the biological fluid treated with a) with the solid phase medium containing the adsorbate to remove a) the added virus Inactivating agent; c) contacting the biological fluid treated with b) with a solid phase medium containing the virus inactivating agent and performing a second viral inactivation; and optionally present d). The liquid is contacted with a solid phase medium containing the adsorbate to remove viral inactivating agents that may be present in the biological fluid. Scheme 2: a). contacting the biological fluid to be treated with a solid phase medium containing the virus inactivating agent and performing the first virus inactivation process; b) adding the virus inactivating agent to the biological fluid and performing the second virus Inactivation process; c) contacting the biological fluid treated with b) with a solid phase medium containing the adsorbate to remove viral inactivating agents that may be present in the biological fluid. Example

In general, the detection methods used in the following examples are all known detection methods, and the raw materials used are all commercially available raw materials.

The fibers of the first system of the present invention are referred to as fibers which can be dyed without side effects. In the following examples, the non-side-effect dyeable fibers used included organic fibers, glass fibers. The organic fibers used include natural fibers, cellulose-based derived fibers, and synthetic fibers. Natural fibers used include plant fibers, animal fibers (e.g., silk). The plant fibers used include cotton fibers (such as non-fat cotton), wood fibers (in filter plates), Pulp (eg paper). The synthetic fibers used include polyester fibers, polyacrylonitrile fibers, polyamide fibers, and polyurethane fibers (all of which are nonwoven fabrics). These fibers do not contain the following dye holders: end groups of hydrazine, viral RNA, DNA imitations, and both have a negative charge in an aqueous solution of pH 7.0 or/and contain at least hydroxyl groups and/or acidic groups. The plant fiber-containing filter material has an average density of greater than 0.10 g/cm ³ and further has one or more of the following characteristics: A). ash content is less than 1%; B). the fiber has an average length of less than 1 mm; The fibers comprise fibrous microstructures having an average length of less than 1 mm and an average diameter of less than 50 μm. Filter media having these characteristics include various German Seitz products (KS80, K900, Supradur 80, P30, Eco 1000, Permadur 0/400A, T2600, Bio20, Bio40, Bio60, Supradur 100, etc.). In the present invention, the prefix Seitz- refers to the product of Seitz, Germany. These non-side-effect dyeable fibers are also used as leukocyte-removing materials.

In the following examples, the porous particles of the hydroxyl group-containing polymer used include polypolysaccharides or/and derivatives thereof such as cellulose, dextran, and agarose. The porous particles of the hydroxyl-containing polymer used are: I). Sephadex G-10, Sephadex G-25, Sephadex G50 containing dextran; II) Sepharose 4B containing agarose gel , Sagavac 10, Bio-gel A-0.5M; III). Cellulose-containing chromatography gel Cellulose ο They have one or more of the following characteristics: A). Average particle size 5-80μπι; Β). Surface area 100-2000 m ² /g _; C). Average pore diameter 5-500 A; D). Exclusion volume is less than 50,000 molecular weight.

In the following examples, the passivating agent used is an organic substance having a hydrophilic group or/and an oleophilic group, and includes: 1) an organic substance having a lipophilic group, such as a natural oil, an organic solvent, a natural oil and fat derivative; An organic substance having a hydrophilic group and an oleophilic group, such as a surfactant; 3) an organic substance having a hydrophilic group, such as a hydroxy compound, a biochemical substance. Among them, the natural oils and derivatives used are castor oil, soybean oil, tea oil, and fat emulsion; the organic solvents used are respectively tributyl phosphate (TNbP in the present invention) and diethyl ether; the surfactant used is sodium cholate, respectively. , Triton X100, Tween 80, and polyvinylpyrrolidone; the hydroxy compounds used are: glycerin, glucose, maltose, dextran (dextran), water-soluble cellulose, mannitol ([Molecular Formula] C ₆ H ₁₄ 0 ₆ ), Sorbitol, hydroxyethyl starch, lentinan; biochemical substances used include polypeptides and amino acids. The polypeptides used were human albumin (Beijing Tiantan Biological Products Co., Ltd.), Buxuekang (Biotest, Germany) and milk; the amino acids used were valine, arginine and glycine, respectively. The composite deactivators used were dextran 40/glucose, dextran 40/albumin, albumin/glucose, TNbP/Tween-80/dextran. According to this embodiment, those skilled in the art will readily use other passivating agents to achieve passivation purposes.

In the following examples, the virus inactivating agent used includes: 1) an organic solvent or an organic solvent/detergent, 2) a photosensitizer, 3) iodine; and a solid phase virus inactivating agent used as a Zetaplus VR filter (Cuno Corporation) . The organic solvents used are respectively tributyl phosphate and diethyl ether; the detergents used are sodium cholate, Triton X100, Tween 80; The photosensitizer used includes a dye-based photosensitizer and a psoralen photosensitizer. The dye-based photosensitizers used were methylene blue, methyl violet, and toluidine blue. The psoralen-based photosensitizers used were psoralen and 8-m _e tho _X ypromlen. It should be understood by the skilled person that other psoralen have almost the same adsorption properties as the psoralen used.

In the following examples, the endogenous adsorbates of the virus inactivating agent used are: activated carbon, silicon oxide particles, particles containing poly-polysaccharide or/polypolysaccharide derivative, fibers; exogenous adsorbate used as chromatography gel . In this embodiment, when the adsorbent is an endogenous adsorbate, the passivating agent is directly fixed on the adsorbent; when the adsorbent is an exogenous adsorbate, the passivating agent is mainly fixed in the adsorbent solid phase carrier. on. The activated carbon-containing materials used are activated carbon powder, activated carbon felt (ZC-1200A, China Zichuan Carbon Fiber Co., Ltd.) and activated carbon filter plates (AKS 5 and AKS 6, Seitz, Germany); The material is a perlite-containing filter plate (Zetaplus Ddipid, Cimo); the fibers used are the above-mentioned plant fiber, protein fiber, synthetic fiber, glass fiber; the chemical fiber-containing material used is Seitz PVPP filter plate (Schenk, Germany); The chromatography gel was a C-18 reverse phase gel (Waters, USA). Professionals should be aware that similar products have similar adsorption properties. Some of the porous particle solid phase media used have a spherical protein exclusion lower molecular weight of less than 5,000, which are: Sephadex G-10, Sephadex G-15, Sephadex G-25, Biogel P-2, Biogel P-4. The permeability of the partially used deep-filtration filter medium has a permeability of less than 200 L/m ² min, which are respectively: Seitz-Supradur 100, Seitz-biolO, Seitz-bio 40. Example 1. Second solid phase medium of the present invention

The solid phase medium prepared in Example 1 , which comprises at least: 钝化). the passivating agent and the virus inactivating agent adsorbate, such as an adsorbate/passivator complex; or Β). the passivating agent and A leukocyte material, such as a leukocyte-removing material/passivator complex; or C). the passivating agent, leukocyte-removing material, and viral inactivating agent adsorbate, such as an adsorbate/de-leukocyte material/passivator complex. Wherein, the passivating agent, the leukocyte-removing material and the virus inactivating agent adsorbate are respectively selected from the above-mentioned passivating agent, leukocyte-removing material and virus inactivating agent adsorbate.

1. Preparation method

In this embodiment, a preparation method of the adsorbate/passivator composite comprises the following steps:

(1). Preparation of passivator dispersion system

The passivation medium is PBS buffer, and the concentration (w/v) of the dispersion system is: natural oil: 0.2-0.5%; organic solvent 0.3-2.0%; surfactant: 1.0-3.0%; peptide: 1.0-10.0 %; Amino acid 3.0-10.0%. It should be noted, however, that other media (e.g., organic solvents) may also be used as a passivating agent dispersion medium to prepare a passivator dispersion system (e.g., solution, suspension) depending on the nature of the passivating agent used. At this time, the dispersion system concentration (w/v) may be between 0.1% and 50%. In one embodiment of this embodiment, a surfactant is also added to the dispersion medium. The use of surfactants (eg Tween 80, Triton X 100) in addition to facilitating the dispersion of the above-mentioned passivating agents, in particular natural oils or/and organic solvents in water, can sometimes also be used as an eluent to control the above passivation. Suction on the adsorbate

(2) fixing the passivating agent to the adsorbate

The immobilization of the passivating agent on the adsorbate is, or is essentially carried out by, adsorption. However, be aware that other fixed methods (such as covalent bonding) can also be selected. For example, a liquid passivating agent can also be directly contacted with an adsorbate to carry out an adsorption reaction.

All binding reactions were carried out using optimized passivator/adsorbate ratios under optimized reaction conditions. These optimizations are carried out in accordance with well-known bonding techniques (e.g., adsorption techniques). The conditions of the adsorption reaction include: reactant addition amount, pH, temperature, time, concentration of certain additives (e.g., surfactant, salt, etc.), mobile phase flow rate (during flow adsorption reaction), and the like. Those skilled in the art will recognize that by controlling these conditions, the adsorption reaction is controlled to achieve the desired result (e.g., amount of adsorption). The uniformity of the adsorption reaction is also a priority.

It is known to those skilled in the art that adsorption can also be prepared by immobilizing a virus inactivating agent adsorbent (e.g., C-18) on a solid support (e.g., chromatography gel) to form an exogenous adsorbate, and then fixing the passivating agent. / passivator complex.

(3). Cleaning the unsorbed material

Passivation agents and other substances that are not fixed or weakly adsorbed on the adsorbate, and may be cleaned or prevented by different washing liquids (for example, PBS buffer, preferably urea solution, alcohol solution, etc.) according to different needs. Deodorized washing.

In the present embodiment, a method for preparing the leukocyte-removing material/passivator complex is the same as the method for preparing the adsorbate/passivator complex described above, and the adsorption reaction is carried out between the leukocyte material and the passivating agent.

In this embodiment, a method for preparing the adsorbate/de-clear cell material/passivator complex is the same as the method for preparing the adsorbate/passivator complex, and the adsorption reaction is in the adsorbate, the leukocyte material and the passivating agent. In between.

The solid phase media prepared in this example are listed in Table 1.

The composite prepared above, especially the particulate matter, can be used alone as a solid phase medium (for example, A5-A30 in Table 1), or with other components (such as a speed increasing substance, a binder, a solubilizing agent, etc.). After mixing, it is used as a solid phase medium containing an adsorbate and a passivating agent. For example, in Table 1, A1 adsorbate/passivator complex and 10% by volume chromatographic gel (Sepharose FF, Pharmacia); A2 adsorbate/passivator complex and 10% by volume pearl rock. Other components in the solid phase medium (eg, speed increasing, binder, Solubilizers, etc., can be passivated according to actual needs according to the undesired reactivity, for example, forming other solid phase components/passivator complexes, or blunt after mixing with the adsorbate (eg, forming a solid phase media/passivator complex). Their passivation methods are the same as those in the preparation method of the above adsorbate/passivator complex. In Table 1, A1 is prepared by first forming a solid phase component/passivator complex and mixing to form a solid phase medium; A2 is first mixed to form a solid phase medium, and then a passivating agent is added to passivate the different components. Prepared.

Table 1. Part of solid phase media containing adsorbate and passivation agent

2). Identification

(1). Determination of the content of passivating agent in solid phase media

In the present invention, the passivating agent content of the solid phase medium is added to the total amount - the unfixed passivation dose / the amount of the solid phase medium.

In this embodiment, the unfixed passivation dose is obtained by well-known correlation measurement techniques. For example, the method for measuring natural oils is a spectrometer method; the method for determining an organic solvent is gas chromatography; surface activity The method for determining the agent is gas chromatography; the method for determining the polypeptide is high pressure liquid chromatography; the method for determining the amino acid is high pressure liquid chromatography; and the like. In the solid phase medium prepared in this embodiment, the content of the passivating agent is greater than Ο.05μηιο1/οηι ³ , and the individual is greater than 0.4mmol/cm ³ .

(2) . Determination of specific adsorption

In the present invention, the specific adsorption amount of the virus inactivating agent = (the total amount of the virus inactivating agent added - the unadsorbed virus inactivating dose y the volume of the solid phase medium).

In this example, the virus inactivating agent model includes an organic solvent (TNbP) and a photosensitizer (methylene blue), respectively, which are used to determine specific adsorption. The measurement of methylene blue uses a well-known spectrophotometer method. The measurement of TNbP is carried out by a known gas chromatography. The amount of adsorption of the virus inactivating agent is measured by a known method for measuring the amount of dynamic adsorption. For example, the adsorbate/passivator complex prepared in this embodiment, and the control adsorbate are respectively charged into a column container (volume 10 ml) or a filter (volume 10 ml) having substantially no side effects, and 100 ml of the virus inactivating agent solution is measured ( The flow rate of methylene blue concentration of 100 g/ml; TNbP concentration of 10 mg/ml) was 0.3 cm/min.

In Table 1: the adsorption amount of the solid phase medium A1-A35 to the photosensitizer (methylene blue) is more than 0.01 mmol/cm ³ , and the individual is more than 0.02 mmol/cm ³ , and even more than 0.04 mmol/cm ³ (Al, A2 is Activated carbon powder, methylene blue absorption capacity greater than 120mg / g or 0.36mmol / g, iodine value greater than 800mg / g or 3m mol / g); solid phase media A1-A30 and A36-A39 organic solvent (TNbP) adsorption The amount is more than 0.05mmol/cm ³ , the individual is more than 0.1mmol/cm ³ , and the individual is even more than 0.3mmol/cm ³ _; the adsorption amount of iodine on A1-A30 is more than 1mmol/cm ³ , and the adsorption amount of iodine on A40 is more than 0.2mmol/ Cm ³ (Al, A2 is activated carbon powder, iodine value greater than 800 mg / g or 3 mmol / g). In addition, some of the above-mentioned solid phase media (especially those containing activated carbon) have similar results for the specific adsorption of other photosensitizers, such as psoralen.

In Table 1, A31-A35 can also be used as a leukocyte-removing material. The amount of leukocyte-specific adsorption was measured in Example 8.

(3) Determination of side effects of solid phase media

In the present invention, the non-specific adsorption amount indicates the total amount of the reagent added - the total amount of the unadsorbed indicator reagent) / the volume of the solid phase medium.

In this example, human albumin (sample C) (Tiantan Biological Products Co., Ltd.) was used as a non-specific adsorption indicating reagent; partial prothrombin activity time of human plasma (sample D) (abbreviated as APTT in the present invention) Used as an indicator of changes in the coagulation system. The APTT kit was purchased from the Chengdu Institute of Blood Transfusion, Chinese Academy of Medical Sciences.

The measurement of side effects is also carried out in accordance with a known dynamic reaction measurement method, as in the measurement method for specific adsorption described above. Determination of human albumin (5% concentration) or human plasma (protein concentration 5.5%) and solid phase media The volume ratio is between 3:1 and 5:1.

Compared with the control adsorbate, the adsorbate/passivator composite prepared in this example has a significant decrease in side effects, which is reflected as: A). The albumin adsorption amount (mg/cm ³ ) decreases by more than 25%, and the individual decreases by more than 50%. (eg albumin/adsorbate complex, vegetable oil/adsorbate complex, sugar/adsorbate complex, etc.); B). Human blood plasma APTT (human plasma partial prothrombin activity, sec) decreased value More than 30%, individual drops by more than 100% (eg albumin/adsorbate complex, vegetable oil/adsorbate complex, sugar/adsorbate complex, etc.). Example 2. Preparation of the first solid phase medium of the present invention (1)

The solid phase medium prepared in this embodiment comprises at least a virus inactivating agent and a passivating agent, comprising: 1) at least a virus inactivating agent, an adsorbent of the virus inactivating agent, and a passivating agent for the adsorbent. a solid phase medium (eg, a virus inactivating agent/adsorbate/passivator complex); 2) a solid phase medium containing at least a passivator of a solid phase virus inactivating agent and a solid phase carrier (eg, solid phase virus inactivation) Agent/passivator complex). Wherein, the passivating agent and the virus inactivating agent adsorbate are respectively selected from the above-mentioned passivating agent and virus inactivating agent adsorbate.

1). Preparation method

A preparation method of the virus inactivating agent/adsorbent/passivator compound of the present embodiment includes the following steps

"(1). Preparation of virus inactivating agent/adsorbate complex from adsorbate

(A) Preparation of a virus inactivating agent solution or suspension

In this embodiment, a virus inactivating agent solution or suspension is prepared according to a known technique using PBS buffer as a dispersed phase, for example: TNbP/Triton X 100/water solution (TNbP concentration (w/v) is 1%, Triton X 100 Concentration (w/v) is 1%); TNbP/Tween 80/water solution (TObP concentration (w/v) is 0.3%, Tween 80 concentration (w/v) is 1%); methylene blue aqueous solution (Asia Blue concentration (w/v) is 0.5%);

(B) Fixing the virus inactivating agent to the adsorbate

In this embodiment, the immobilization of the virus inactivating agent on the adsorbate is, or substantially, carried out by adsorption. However, be aware that other fixed methods (such as covalent bonding) can also be selected.

If a powdery adsorbate (e.g., activated carbon) is used, it is added to the above-prepared virus inactivating agent solution for adsorption reaction. If a bulk adsorbate (e.g., activated carbon filter plate) is used, the virus inactivating agent solution prepared above is used as a mobile phase, and the adsorbate is used as a stationary phase for flow adsorption reaction.

The conditions of the adsorption reaction include: the amount of reactant added, pH, temperature, time, concentration of certain additives (e.g., surfactant, salt, etc.), mobile phase flow rate (at the time of flow adsorption reaction), and the like. Those skilled in the art will know that by controlling these conditions, the adsorption reaction is controlled to obtain the desired knot. Fruit (eg adsorption amount). The uniformity of the adsorption reaction is also a priority.

(2). Preparation of virus inactivating agent/adsorbate/passivation complex from virus inactivating agent/adsorbate complex This process involves preparing a passivator dispersion, fixing the passivating agent, and cleaning the non-sorbent. In the present embodiment, the method for preparing the passivator dispersion system, the method for fixing the passivating agent, and the method for cleaning the non-sorbent are the same as those for the preparation of the adsorbate/passivation compound in Example 1, respectively.

The virus inactivating agent/adsorbent/passivator complex in this embodiment can be prepared by using the above method, or the virus inactivating agent/adsorbent (for example, iodine-PVPP filter plate) can be prepared first, and then the adsorbate can be prepared. Passivation is carried out to prepare. In the latter preparation method, the preparation method of the virus inactivating agent/adsorbent and the passivating agent is the same as the preparation method of the adsorbate/passivation complex deactivator in the first embodiment.

A method for preparing a solid phase virus inactivating agent/passivator complex (for example, Cuno-Zetaplus VR virus-removing filter plate/passivator complex) in this embodiment, and an adsorbate/passivation complex in Example 1. The passivating agent is prepared in the same manner.

Some of the solid phase media prepared in this example are listed in Table 2.

Like the adsorbate/passivator complex in Example 1, the virus inactivating agent/adsorbent/passivator complex (for example, B1-B3 in Table 2) in this embodiment can also be used alone, or It is used as a solid phase medium containing a virus inactivating agent after mixing with other components such as a speed increasing substance, a binder, a solubilizing agent, and the like. The passivation method may also be first mixed to form a solid phase medium, followed by passivation to passivate, or passivate the different components and then mix them. Table 2. Part of solid phase media containing virus inactivating agent

*: SEITS PVPP iodine filter plate 2). Identification

In this embodiment, the method for determining the content of the passivating agent in the solid phase medium, the content of the virus inactivating agent in the solid phase medium, and the side effect of the solid phase medium are respectively different from the amount of the passivating agent and the amount of the virus inactivating agent in the first embodiment. (Specific adsorption) The same method as the side effect of the solid phase medium.

In the solid phase medium in Table 2, the content of the passivating agent is more than 0.05 μηιο1/η ³ , and the amount of the inactivation agent is greater than 0.4 mmol / cm ³ ; the amount of the virus inactivating agent is not significantly changed by passivation. And control virus inactivating agent/adsorbate complex (for solid phase virus inactivating agent/passivator complex), or control solid phase virus inactivating agent (for virus inactivating agent/adsorbent/passivator) For composites, the side effects are significantly reduced: A). The amount of albumin adsorption (mg/cm ³ ) decreases by more than 15%, and the individual decreases by more than 30%; B). The increase in human plasma APTT is more than 20%, individual Drop by more than 50%.

In particular, in B7 or B8 of Table 2: A) the virus inactivating agent comprises an organic solvent; B). the passivating agent comprises an organic solvent; and C). in the solid phase medium The content of the organic solvent is more than 0.1 mmol/cm or even more than 0.3 mmol/cm ³ (for example, 0.40 mmol/cm ³ ). At this time, the organic solvent can be used both as a virus inactivating agent for effective virus inactivation and as a passivator for a virus inactivating agent adsorbent (for example, activated carbon) to minimize side effects. Example 3. Preparation of the first solid phase medium of the present invention (2)

The solid phase medium prepared in this example has a minimum composition of a dye-based photosensitizer and can be dyed with no side effects. Among them, the dye-based photosensitizer and the non-side-effect dyeable fiber are respectively selected from the above-mentioned dye-based photosensitizers and non-side-effect dyeable fibers. Other dye-based photosensitizers/fiber composites are easily prepared by the production method of this embodiment.

1) . Preparation

In the present embodiment, a method for preparing a dye-based photosensitizer/no side-effect dyeable fiber composite is the same as the method for preparing a virus inactivating agent/adsorbate composite from the adsorbent in Example 2, which comprises: Preparation of a dye-based photosensitizer dispersion system; and (B). Fixing the dye-based photosensitizer to a fiber-free composite (for example, a fiber-containing filter material) without side effects. Some of the complexes prepared in this example, such as Seitz Bio 40, Seitz-Supradur 100. Seitz-T2600, Peraiadur 0/400A, and methylene blue, respectively, were designated Cl, C2, C3 and C4.

2) . Identification

In the present embodiment, the method for determining the content of the dye-based photosensitizer in the solid phase medium and the side effect of the solid phase medium, and the method for determining the side effect of the virus inactivating agent (specific adsorption) and the solid phase medium in Example 1 respectively the same. In the above composite prepared in the present embodiment, the content of the dye-based photosensitizer was more than 0.001 mmol/cm ³ . Compared with the existing solid phase media (such as dye photosensitizer / activated carbon complex), the side effects are significantly reduced: K). The amount of albumin adsorption (mg/cm ³ ) is reduced by more than 30%; B). Human plasma APTT (human) The plasma partial prothrombin activity, s) increased by more than 50%. Embodiment 4. The first system of the present invention

This example produced the first system of the present invention. Wherein: the chamber used is a hollow filter; the solid phase medium used is selected from the above-mentioned dye-free photosensitizer prepared without the side effect, the dye-based photosensitizer prepared in Example 3, or the non-side-effect dyeable fiber composite (for example, C1_C4).

1). Preparation

The above-mentioned no side effects can be dyed fibers, and can be used alone or in combination with other components (e.g., speed increasing agents, binders, solubilizers, etc.) to remove the dye-based photosensitizer. Other components in the solid phase medium (e.g., speed accelerating, binder, solubilizing agent, etc.) may be passivated according to actual needs depending on the desired reactivity (see Example 1).

1) no side effects can be dyed fiber, or 2) dye photosensitizer / no side effects can be dyed fiber complex, or 3) dye photosensitizer / no side effects can be dyed fiber complex + no side effects can be dyed fiber The system of this example was prepared by charging it into a passivated or unpassivated hollow filter in a conventional manner.

2). Identification

In the present embodiment, the method for measuring the specific adsorption of the dye-based photosensitizer and the side effect of the system is the same as the method for determining the side effects of the solid phase medium-specific adsorption and the solid phase medium in Example 1, respectively.

The dyeing system of the dye-containing photosensitizer dye (methylene blue, methyl violet, toluidine blue) prepared by the present invention has no side effects, and the adsorption amount of the dye-based photosensitizer is greater than O.Olmmol. /cm ³ , individually up to 0.02 mmol/cm ³ or more (for example, a system containing Seitz-BiolO, Seitz-Bio20, Seitz-bio40, Seitz-SupmdurlOO, or Seitz-Supradur200). Compared with systems containing existing solid phase media (eg, dye-based photosensitizer/activated carbon complex), the system produced in this example has significantly less side effects: A). Albumin adsorption capacity (mg/cm ³ ) is small 30 More than %; B). The increase in human plasma APTT (human plasma partial prothrombin activity, sec) is less than 50%.

The dye-containing photosensitizer prepared in this embodiment/the system capable of dyeing the fiber composite without side effects has an inactivating effect on the pattern virus in the biological liquid, and the determination method thereof is as follows in the relevant part of the following biological liquid treatment method embodiment. . Embodiment 5. The second system of the present invention

This example produces a second system of the invention. Wherein: the chamber used is a hollow column; the solid medium used is selected from the above porous particles containing a hydroxyl polymer.

In the present embodiment, the method of preparation and identification of the system is the same as the method of preparation and identification of the system of Example 4. The results are also roughly similar. Embodiment 6. The third system of the present invention (1)

This embodiment produces a third system of the present invention. The chambers used therein include: A) hollow columns, B). Hollow filters; the solid phase medium used is a virus inactivating agent adsorbate/passivator complex.

The system of this embodiment is obtained by two methods: A) loading the prepared adsorbate/passivator compound into the chamber; B) loading the adsorbate into the chamber and blunting it with a passivating agent The formation of an adsorbate/passivator complex. The passivation method in both methods was the same as the passivation method of the adsorbate in Example 1. In the method of A), the solid phase medium charged into the chamber is selected from the adsorbate/passivator composite prepared in Example 1 (Table 1). In the B) method, the adsorbate charged into the chamber is selected from the above adsorbates.

In this embodiment, the identification method of the system is the same as that of the system in the fourth embodiment. The specific adsorption capacity and side effects of the system of this example are consistent with the specific adsorption capacity and side effects of the adsorbate/passivator contained therein (see Example 1). Embodiment 7. The third system of the present invention (2)

This embodiment produces a third system of the present invention. Wherein: the chamber used is a passivated or unpassivated hollow column or hollow filter; the solid phase medium used is selected from the group consisting of: 1) the solid phase medium prepared in Example 2 (Table 2); or 2) the solid phase prepared in Example 2. Medium (Table 2) and solid phase medium prepared in Example 1 (Table 1); Example 2 A solid phase medium prepared (e.g., B12 in Table 2) and the above-mentioned no side effects can be dyed fibers.

In the present embodiment, the method of preparation and identification of the system is the same as that of the system of Example 4. The virus inactivating ability and side effects of the system of this example are consistent with the virus inactivating ability, virus inactivating agent adsorption ability and side effects of the solid phase medium contained therein (see Examples 1, 2 and 4). Example 8. The leukocyte-removing system of the present invention

This embodiment produces the first or fourth system of the present invention. Wherein: the chamber used is a hollow filter; the solid phase medium used is selected from the above-mentioned non-side-effect dyeable fibers, or the leukocyte-removing material/passivator complex prepared in Example 1 (A31-A35 in Table 1). In the present invention, the leukocyte removal rate is measured and calculated by a known method. The first system of the present invention prepared in this example is used for a dye-removing photosensitizer and leukocyte-removing cells. It is a filter containing three layers of solid phase media, which are respectively cotton fiber, polyester, and polyurethane nonwoven fabric. In fact, cotton fiber, polyester, polyurethane, etc., in this embodiment, both a dye-based photosensitizer adsorbent and a leukocyte-removing material. The dye-based photosensitizer of this system of this embodiment The adsorption capacity and side effects are consistent with the adsorption ability and side effects of the dye-based photosensitizer of the above system containing the corresponding fibers (refer to Example 4), and the leukocyte removal rate is over 99%.

In the fourth system of the present invention prepared in this embodiment, the filter comprises four layers of solid phase medium, respectively, glass fiber, cotton fiber, polyester, polyurethane non-woven fabric fixed with passivating agent. (See Table 1). This system can be used to remove leukocyte filters, or to remove leukocyte/dyeing-based photosensitizer filters. The adsorption capacity and side effects of the dye-based photosensitizer of this system are consistent with the adsorption capacity and side effects of the dye-based photosensitizer of the system containing the corresponding solid phase medium (refer to Example 1), and the leukocyte removal rate can reach 99% or more. Example 9. The fifth system of the present invention

This example produces a fifth system of the invention. Among them: The chamber used includes: A). Hollow column, B). Hollow filter; The solid phase medium used is a solid phase medium defined by the ability of the virus inactivating agent to adsorb. The solid phase media used in this example were: A). C-18 silica gel derivatives A and B; B) activated carbons A and B; C). Activated carbon/vegetable oil complexes A and 8. Wherein: C-18 silica gel derivatives C-18A and C-18B were prepared according to a known method; activated carbon/vegetable oil complexes A and B were prepared as in Example 1. In summary, the silica gel derivative A, activated carbon A and activated carbon/vegetable oil complex A contain more viral inactivating agents (for example, TNbP) than the silica gel derivative B, the activated carbon B and the activated carbon/vegetable oil complex B, respectively. The adsorption group is such that the adsorption capacity of the former is greater than 0.02 mmol of the virus inactivating agent/cm ^{3 of the} solid phase medium, and the adsorption capacity of the latter is less than that of the O.Olmmol virus inactivating agent/cm ³ solid phase medium.

In the present embodiment, the method of preparation and identification of the system is the same as the method of preparation and identification of the system of Example 4. In the system prepared in this example, the system containing the silica gel derivative A, the activated carbon A and the activated carbon/vegetable oil complex A is respectively higher than the system containing the silica gel derivative B, the activated carbon B and the activated carbon/vegetable oil complex B. The albumin adsorption capacity is 20% or more. The silica derivative B, activated carbon B and activated carbon/vegetable oil complex B can also effectively reduce l% TNbP in human plasma to below 10 ppm. Embodiment 10. A sixth system of the present invention

The present embodiment produces a sixth system of the present invention comprising a solid phase medium and a chamber containing a solid phase medium (e.g., a hollow filter, a hollow column, etc.). The solid phase medium is selected from the solid phase media used in the above examples (which may also be selected from other solid phase media). The solid phase medium used includes a functional layer solid phase medium and is closest to the out a safety layer solid phase medium having a thickness of 2-15 mm (individually 3.0-6.0 mm), wherein: A). The functional layer solid phase medium contains at least: a virus inactivating agent adsorbate or/and at least a virus a virus inactivating agent of the inactivating agent; B). The safety layer solid phase medium contains a virus inactivating agent adsorbate. The security layer solid phase medium is the same as, or different from, the functional layer solid phase medium. In the partial filter prepared in this embodiment, the safety layer solid phase medium is the same as or different from the other filter plate of the functional layer filter plate.

In this embodiment, the thickness of the solid phase dielectric functional layer is measured, and the thickness of the chamber of different diameters just meets the adsorption requirement is measured according to the definition of "the thickness just meeting the adsorption requirement", and then according to other geometric characteristics of the chamber. The volume of the functional layer solid phase medium is obtained.

In this embodiment, the determination of the minimum thickness of the solid layer medium of the safety layer is determined by the fact that under the abnormal condition, the larger the thickness, the more favorable the safety is to realize its function, and the larger the thickness, the larger the solid medium path through which the biological liquid flows. The longer it is, the more likely it is to increase the balance between the side effects of the solid phase media. In this embodiment, the minimum thickness of the safety layer solid phase medium required for the above-mentioned abnormal conditions for the chamber containing the solid phase medium (straight through 10 cm) is greater than 2 mm, preferably greater than 3 mm. The abnormal conditions include: 20% more methylene blue flow than the methylene blue provided in the above-mentioned thickness that satisfies the adsorption requirement, the chamber is inclined, the temperature is changed at 20-30 ° C, and the solid is installed in the chamber. The error in the phase medium. Since the adsorption specificity of the solid phase medium used in the present embodiment is high, the side effect of the solid phase medium increases with the solid phase medium passage (for example, the APTT change caused by the solid phase medium growth of 1 mm is less than 1%), and thus the safety layer The minimum thickness of the solid phase medium may be appropriately greater than 2 mm. In this embodiment, the minimum thickness of the safety layer solid phase medium is selected to be between 5 and 10 mm. Example 11. The seventh system of the present invention

The seventh system of the present invention is prepared in this embodiment. Wherein: the chamber used is a hollow filter; the solid phase medium used is a combination of two or more of the following solid phase media: A). The virus inactivating agent-containing adsorbent in the first system of the present invention Solid phase medium; the virus inactivating solid phase medium in the first system of the invention; the virus inactivating agent adsorbate-containing solid phase medium in the second system of the invention; The virus inactivating solid phase medium in the second system; the virus inactivating agent adsorbate-containing solid phase medium in the third system of the present invention; in the third system of the present invention The virus phase inactivating solid phase medium; the solid phase medium in the fourth system of the present invention; the solid phase medium in the fifth system of the present invention; the sixth system of the present invention The solid phase medium in the medium.

When a plurality of solid phase media are combined, there are a series relationship or a parallel relationship between different solid phase media. In this example, only some examples of solid-phase media in series are listed: Combination of adsorbate/passivator complex with adsorbate/passivator complex, adsorbate/passivator complex and cellulose filter Combination (see Table 3); The serial combination of solid phase media can be cascaded in the same container or in multiple vessels. Ben In the example, using the method of concatenation in the same container, Table 3 Part of the system

The side effects of the filter in this embodiment are consistent with the side effects of the solid phase medium contained therein (refer to the above related embodiment).

Embodiment 12. System of the present invention containing a steric hindrance effect solid phase medium

This example produces the first, second, third, fifth, or six systems of the present invention. Where: used The chamber includes: A). Hollow column, B). Hollow filter. The solid phase medium used is a chromatographic gel with a molecular weight exclusion lower molecular weight of less than 10,000 but greater than 5000, a spherical protein exclusion lower molecular weight of less than 5000 chromatography gel (Sephadex G10, Sephadex G25), and a permeability greater than 200 L/m ^{2 .} Min deep filter media (Seitz-Supradur 500), deep filter media (Seitz-Supradur 100) with permeability less than 200L/m ² min, and deep filter media with permeability less than 100L/m ² min (Seitz -biolO, Seitz-biol2) ₀

In the present embodiment, the method of preparation and identification of the system is the same as that of the system of Example 4. In the system prepared in this example, the system containing Sephadex G10, Sephadex G25, Seitz-biolO, Seitz-biol2, Seitz-Supradur 100 is compared with the system containing Sephadex G75, Sephadex G100, Seitz-Supradur 500, and absorbed per unit volume. The methylene blue value is 20% higher, and the albumin adsorption is lower than 5%. Example 13. A system in which a passivating agent is fixed to a portion other than a solid phase medium

The system prepared in this embodiment comprises a solid phase medium and a chamber containing a solid phase medium (e.g., a hollow filter, a hollow column, etc.). The other parts of the column or filter used except the solid phase medium are made of polypropylene plastic, which is passivated to reduce side effects (such as protein adsorption). Wherein: the solid phase medium is selected from the solid phase medium used in the above examples; the passivating agent is selected from the passivating agents (e.g., amino acids, albumin or/and vegetable oil) used in the above examples. The means of passivation include: 1) Passivating and reassembling the components that need to be passivated (such as solid phase media, or / and solid phase media contents, or / and pipes) into devices; 2) The device (eg, a device containing adsorbate and adsorbate contents is passivated; 3) the components that are required to be passivated are passivated, reassembled into a device, and then the assembled device is repassivated.

The systems prepared in this embodiment are: 1) the chamber is passivated and the solid phase medium (for example, the wood fiber-containing filter plate) is not passivated; 2) the chamber and the solid phase medium (for example, containing activated carbon) The filter plates are all passivated. In this embodiment, the surface area of the passivated chamber is reduced by more than 50% per unit area of the surface of the chamber which is not passivated. Embodiment 14. A device for treating a biological fluid

The present embodiment prepares a device for treating biological fluids of the present invention, which is a single blood component processing device: comprising: 1) a single blood component virus inactivating device, and 2) a single blood group. The leukocyte device is divided, and 3) the single-part blood component virus inactivated/de-white blood cell device. According to the undesired reactivity of the different components contained therein, the substance selected from the above-mentioned passivating agent may be added for passivation as needed. The way of passivation includes: 1) Passivating and reassembling the parts that need to be passivated into devices; 2) Assembling them The device is passivated; 3) passivating the components that need to be passivated, reassembling into a device, and then repassivating the assembled device.

1) Single blood component virus inactivation device

The single-part blood component virus inactivating apparatus of this embodiment includes a means for solid-liquid phase reaction including a virus inactivating agent adsorption reaction and a means for solid-liquid phase reaction including a virus inactivation reaction.

(1) A solid-liquid phase reaction comprising a virus inactivating agent adsorption reaction device

In this embodiment, the apparatus comprises at least: the system of the present invention having the function of adsorbing the virus inactivating agent prepared in the above embodiment, the virus inactivating agent addition device, and the virus inactivation reaction site. The working principle is as follows: a single blood component is contacted with a virus inactivating agent in a virus inactivating agent addition device, and enters a virus inactivation reaction site to carry out a virus inactivation reaction. After the reaction is completed, the biological liquid enters a virus inactivating agent. In the column container or/and filter of the adsorption function, the virus inactivating agent or/and its derivative are removed by contact with the above solid phase medium, and if necessary, the retained blood component can be washed by adding the washing liquid to the structure and adding the washing liquid. Out.

When the SD agent is used as a virus inactivating agent, the liquid phase SD agent used is added to the structure containing the liquid phase SD agent and the liquid phase SD agent (for example, a glass tube, a stainless steel tube, or an organic solvent-resistant silicone tube) and can be removed. Closed closed structure (eg glass switch, stainless steel switch, fragile organic solvent resistant polyester sheet). The concentration of the SD agent in the liquid phase SD agent is 5-10% organic solvent and 3-10% detergent.

When the photosensitizer is used as a virus inactivating agent, the virus inactivating agent is added to the structure by adding a liquid phase photosensitizer to the structure or a solid phase photosensitizer to the structure. Liquid phase photosensitizer is added to the structure containing liquid phase photosensitizer (concentration l-5mg/ml), liquid phase photosensitizer contents (such as medical polystyrene plastic tube) and deblockable closed structure (such as switch or fragile Medical polystyrene plastic sheet). The solid phase photosensitizer is added to the structure containing a solid phase photo-sensitizer (granular) and its contents (for example, a medical polystyrene plastic tube). These parts should be pre-passivated if necessary.

One of the virus inactivation treatment devices of the single-part plasma containing de-dye-based photosensitizer system prepared in this embodiment comprises: a medical polystyrene virus inactivating agent added structure; a light inactivating bag; an inner diameter of 6 cm Polypropylene plastic hollow filter; solid phase medium: upper layer is a layer of SEITZ-ECO 1000 filter plate, the lower part is 2 layers of SEITZ-Bio60 filter plate; connecting pipe;

(2). Solid-liquid phase reaction including a device for inactivating a virus

In this embodiment, the apparatus comprises at least the system of the present invention having the virus inactivating function prepared in the above embodiment. The working principle is as follows: Single blood component is subjected to virus inactivation reaction through column container or/and filter with virus inactivation function (fixed SD agent treatment, immobilized iodine treatment, immobilized ion treatment or immobilized photosensitizer) Treatment), if necessary, can also be added to the structure by adding a lotion to the wash solution. The components are washed out.

One of the immobilized SD virus inactivating devices of several single-part plasmas prepared in this embodiment comprises: a fluoroplastic hollow filter having an inner diameter of 6 cm; a solid phase medium: a layer of SEITZ-ECO 1000 filter plate at the upper portion, and a central portion 5-layer SD/AKS5/glucan complex with a layer of A S5/glucan complex in the lower part; 75 ml sterile saline bag; connecting tubing;

2) Single blood component to leukocyte device

In this embodiment, the apparatus comprises at least the system of the invention comprising at least a solid phase medium comprising a leukocyte-removing material and a passivating agent prepared in Example 8. The principle of operation is that a single human blood component passes through the system of the present invention, wherein the white blood cells are substantially intercepted by the solid phase medium.

3) Single blood component virus inactivation / de-whitening device

In the present embodiment, such a device contains at least the system of the present invention for de-dyeing photosensitizer and de-whitening cells prepared in Example 8. The working principle is a combination of the above-mentioned solid-liquid phase reaction device including the virus inactivating agent adsorption reaction and the working principle of the single human blood component de-whitening cell device.

Further, those skilled in the art can easily perform the following operations: The above-described apparatus based on the present embodiment forms a new one by combining them with each other, or by combining them with other systems (for example, a single blood fraction collecting system). s installation.

Upon examination, the functions and side effects of the above-described apparatus of the present embodiment are consistent with the functions and side effects of the system of the present invention contained therein (refer to Examples 4-13). Example 15. The first method of treating biological fluid of the present invention (1)

In the following examples, the conditions for the virus inactivation treatment are generally as follows: pH is 2.0-12.0; temperature is -5 to 60 ° C; the amount of solid phase medium and biological liquid containing the virus inactivating agent is Viral inactivation experiments are preferred (e.g., solid phase media volume/biological fluid volume between 1% and 30%); virus inactivation fluid dynamics conditions are preferred according to virus inactivation experiments (e.g., linear flow rate 0.1-lOcm/sec) , the pressure is 0.1-5 kg/cm ² ); the amount of solid phase medium and biological liquid containing the virus inactivating agent is preferred according to the virus inactivating agent removal experiment (for example, the volume of the solid phase medium / the volume of the biological liquid is 1 Between % and 30%); the determination of the solid-liquid phase adsorption reaction conditions is basically carried out according to a well-known rule, for example: the greater the flow rate of the biological liquid, the smaller the adsorption efficiency;

In a method of treating a biological fluid according to embodiments 15 to 18 of the present invention, the method comprises at least: A) providing a biological fluid; B) contacting the biological fluid with the virus inactivating agent; C) treating the biological fluid treated by B) Entering the virus inactivation treatment system for biological liquid prepared in the above embodiment, and contacting with the solid phase medium containing at least the virus inactivating agent adsorbent; D) collecting substantially no from the system in C) Inactivation of the virus Biological fluid. If necessary, the device including the solid phase medium is also washed with sputum. Although only a portion of the system of the present invention is used, it is easy to push to all of the systems of the present invention.

In the present embodiment, the biological fluid used is a single-part plasma; the virus inactivating agent used is methylene blue; and the apparatus used is selected from the apparatus for solid-liquid phase reaction prepared in Example 14 including a virus inactivating agent adsorption reaction. It contains at least the first (Example 4) or the second system (Example 5) of the present invention.

The virus inactivation treatment method in this embodiment is: single-person plasma is contacted with methylene blue in the virus inactivating agent addition device, and enters the virus inactivation reaction site for virus inactivation treatment (0.5 μ _β methylene blue/ml). , room temperature, light for 30 minutes), then enter the column container or / and filter with virus inactivating agent adsorption function, remove the virus inactivating agent or / and its derivatives by contact with the solid phase medium, and then from the system A biological fluid that is substantially free of methylene blue or methylene blue derivatives is collected.

In the method of the present example, the virus inactivating agent removal efficiency was determined by measuring residual methylene blue in plasma (Reference Example 4); the side effects were determined by measuring plasma APTT value (Reference Example 1) and blood coagulation factor (11). , VII, VIII, IX) loss to determine. Compared with the method using a similar device containing a common adsorbent (for example, activated carbon), the method of the present embodiment can also effectively remove the virus inactivating agent (for example, more than 90% of methylene blue is removed), and the APTT value is increased by 30 less. More than %, the loss of coagulation factors should be less than 15%. More than 99% of white blood cells can be removed at the same time if necessary. Embodiment 16. The first method of treating a biological fluid of the present invention (2)

In this embodiment, the biological fluid used is a single blood paddle; the virus inactivating agent used is an S/D agent (TNbP/Triton X100 TNbP/Tween 80, or diethyl ether/Triton XI 00); the device used is selected from the examples. The solid-liquid phase reaction prepared in 14 includes a device for the adsorption reaction of the virus inactivating agent. It contains at least the third, fifth, or sixth system of the present invention in which activated carbon is used as a virus inactivating agent adsorbate (Examples 5, 9, 10).

The method for inactivating the virus in this embodiment is as follows: a single person is divided into a virus inactivation reaction site in the device, and is contacted with an SD agent added by a virus inactivating agent addition device to perform SD virus inactivation treatment (1%). S, 03-l% D, 30 ° C, 4 hours), then enter the system through the same solid phase media (such as activated carbon / human albumin complex, activated carbon / vegetable oil, activated carbon / polysaccharide, etc.) The SD agent is removed by contact, and if necessary, the retained blood component can be washed out by adding the washing liquid to the structure.

In the method of the present embodiment, the virus inactivating agent removal efficiency is determined by measuring the residual SD agent in the plasma (refer to Example 1); the side effect is determined by measuring the plasma APTT value and the clotting factor loss (Reference Example 1). . Compared with the method using a similar device containing a common adsorbent (for example, activated carbon), the method of the present embodiment can also effectively remove the virus inactivating agent (for example, more than 90% of the SD agent is removed), and the APTT value is increased by 30%. Above, the loss of clotting factors is less than 15%. Embodiment 17. The first method of treating a biological fluid of the present invention (3)

In this embodiment, the biological fluid used is a single-person platelet; the virus inactivating agent used is psoralen (4'-aminomethyl-4,5', 8-trimethyl psoralen); The solid-liquid phase reaction selected from the preparation of Example 14 includes a device for the virus inactivating agent adsorption reaction. It contains at least the third, fifth, or sixth system of the present invention in which activated carbon is used as a virus inactivating agent adsorbate (Examples 5, 9, and 10).

The method for inactivating the virus in this embodiment is: the single-part platelet and the psoralen in the virus inactivating agent adding device enter the virus inactivation reaction site to perform photosensitizer virus inactivation treatment (appropriate concentration of psoralen , room temperature, light for 30 minutes), then the biological liquid enters the system, by removing the virus inactivating agent by contact with the solid phase medium (such as activated carbon / human albumin complex, activated carbon / vegetable oil, activated carbon / polysaccharide, etc.) / and its derivatives.

In the method of the present example, the virus inactivating agent removal efficiency was determined by measuring residual psoralen in plasma; the side effects were determined by measuring plasma APTT value and clotting factor loss. Compared with the method using a similar device containing a common adsorbent (for example, activated carbon), the method of the present embodiment can also effectively remove the virus inactivating agent (for example, more than 90% of psoralen is removed), and has a smaller need. Reactivity. For example, in a control method containing activated carbon adsorbate (for example, by removing psoralen by Seitz-AKS5), the protein loss is 10-20%, the platelet loss is 7%, and the platelet morphology fraction is decreased by 16%. Solid phase media for adsorbate/passivator complexes (eg Seitz-AKS5/human albumin complex, Seitz-AKS5/vegetable oil, etc.), protein loss is only 5%, platelet loss is 3%, platelet morphology The score does not decrease substantially. More than 99% of white blood cells can be removed at the same time if necessary. Embodiment 18. The first method of treating a biological fluid of the present invention (4)

In this embodiment, the biological fluids used are: 1. multi-person plasma, 2. human plasma fraction containing human fibrinogen (for example, component I or cryoprecipitate in cold alcohol precipitation), 3. Human plasma separation component of human coagulation factor (eg, cryoprecipitate), 4. Human plasma separation component containing human coagulation factor 9 (eg, DEAE-Sephadex washout component of cryoprecipitate supernatant), 5. Contains human Human plasma separation component of prothrombin complex (PCC) (eg DEAE-Sephadex washout component of cryoprecipitate supernatant), 6. Human plasma fraction containing gamma globulin (eg cold alcohol precipitation method) The components were precipitated, 7. Recombinant Alpha interferon (interferon concentration 1.15 million IU/ml, pH 7.0), 8. Positive human serum reference. In this embodiment, the system for biological fluid treatment is selected from the third system of the present invention (Example 6), wherein the solid phase medium used is selected from the passivator/adsorbate composite prepared in Example 1 (Reference) Table 1); The virus inactivating agents used are organic solvents (TNbP) and organic solvents/detergents (TNbP/Triton X100, TNbP/Tween 80, or diethyl ether/Triton) X100);

The virus inactivation treatment in the present embodiment is: adding S or SD agent to the biological liquid and performing virus inactivation according to the known S or SD agent virus inactivation method (0.3-l% S, or 0.3-l% S and 0.3). -l%D; 30 ° C; 4 hours), then with or without vegetable oil extraction, and then pumped into a column container or / and filter with virus inactivating agent adsorption function (linear flow rate 0.1-0.5cm / min) The virus inactivating agent is removed by contact with a solid phase medium. The determination of the solid-liquid phase adsorption reaction conditions is basically carried out according to well-known laws, for example: the greater the flow rate of the biological liquid, the smaller the adsorption efficiency; the low temperature and the low pH are favorable for the adsorption reaction on the activated carbon;

In the method of the present embodiment, the virus inactivating agent removal efficiency is determined by measuring the residual S/D agent in the plasma (refer to Example 1); the side effect is determined by measuring the plasma APTT value and the clotting factor loss (Reference Example) 1). Compared with the method using a similar device containing a common adsorbent (for example, activated carbon), the method of the present embodiment can also effectively remove the virus inactivating agent (for example, TNbP is removed by more than 90%), and the APTT value is increased by 30% or more. . The activated carbon is the solid medium of the SD agent, and the loss rate of fibrinogen, coagulation factor VIII and coagulation factor IX is 30% or more, 25% or more and 30% or more respectively; and the activated carbon/passivator complex ( For example, activated carbon/human albumin complex, activated carbon/vegetable oil complex, etc.), in addition to the SD solid phase medium, the loss rates of fibrinogen, coagulation factor VIII, and coagulation factor IX are less than 10% and less than, respectively. 15%, less than 15%. Embodiment 19. A second method of treating a biological fluid of the present invention

In the present embodiment, the biological fluid used is a single-part plasma; the virus inactivating agent used is methylene blue; and the apparatus used is selected from the apparatus for solid-liquid phase reaction prepared in Example 14 including a virus inactivating agent adsorption reaction. It contains at least the first (embodiment 4), the second system (embodiment 5), or the third system (embodiment 6) of the present invention.

The virus inactivation treatment method in this embodiment is: A) providing a single human blood or a derivative thereof; B) adding a photosensitizer to a photosensitizer concentration of 0.55-3.0 μm _Ο 1/1, at a virus inactivation reaction site Virus inactivation treatment (15-18 ° C and 25-30 ° C, fluorescence illumination for 30 minutes); C). Passing B) treated single blood or its derivatives into the virus for biological fluids Living the system and contacting the solid phase medium containing the virus inactivating agent adsorbate; D) collecting a single human blood or derivative thereof substantially free of the viral inactivating agent from the system in C) .

In the method of the present embodiment, the virus inactivating agent removal efficiency is determined by measuring residual methylene blue in plasma (refer to Example 4); the side effects are determined by measuring the blood plasma APTT value and the clotting factor loss (Reference Example) 1). Compared with a method using a similar device containing a common adsorbent such as activated carbon, The method of the examples can also effectively remove the virus inactivating agent (for example, more than 95% of methylene blue is removed), and the APTT value is increased by more than 30%, and the clotting factor is less than 15%. Embodiment 20. A third method of treating a biological fluid of the present invention (1)

In the following embodiments of the present invention, the virus inactivation treatment method comprises at least the following steps: A) providing a biological fluid; B) bringing the biological fluid into the virus inactivation treatment system for biological fluid of the present invention prepared in the above embodiment, And contacting the solid phase medium containing at least the virus inactivating agent; C). washing the device including the solid phase medium with sputum if necessary.

In the present embodiment, the biological fluid used is a purified human gamma globulin liquid, such as a semi-finished product in the preparation of human gamma globulin; the treatment system for biological fluid used is the seventh system of the present invention (Table 3), Contains: 1). Solid phase media selected from Table 2 (eg SD/activated carbon/human albumin complex, SD/activated carbon/vegetable oil, SD/activated carbon/polysaccharide, etc.) and existing virus inactivating agent sorbent ( For example, activated carbon); or 2) a solid phase medium selected from Table 2 and a solid phase medium selected from Table 1 (e.g., activated carbon/human albumin complex, activated carbon/vegetable oil, activated carbon/polysaccharide, etc.). In this embodiment, the number of the solid phase medium, the biological liquid, and the solid phase medium are both optimized, so that the virus inactivation can be effectively performed, and the virus inactivating agent can be effectively removed.

The method of virus inactivation treatment in the present embodiment is: the biological liquid is pushed to optimize the flow rate (for example, a linear velocity of 0.1-0.5 cm/min) to flow through the solid phase medium selected from Table 2, and the virus is inactivated therein (fixed SD virus inactivation, or / and immobilized iodine virus inactivation, or / and positively charged virus inactivation :), then pushed to optimize flow rate through existing virus inactivating agent sorbate or solid phase selected from Table 1 medium. If necessary, wash the unit including the solid phase medium with sputum.

The virus inactivation efficiency of the method of this example was studied using a model lipid enveloped virus VSV (initial titer greater than 10 ⁴ · ⁸ ) and Sendai virus (initial titer greater than 10 ⁵ · ¹ ), respectively. After inactivation by the above virus, the detection titers of both models were less than 10 ^ι , and the virus inactivation was greater than 10 ⁴ , and the corresponding immobilized virus inactivating agent containing no passivating agent was used as a control. The virus treatment (eg SD-activated carbon, iodine-PVPP filter plate, or Zetaplus VR filter plate) is consistent.

The virus inactivating agent removal efficiency of the method of this example is consistent with the use of a similar system containing a corresponding adsorbate (e.g., activated carbon) used as a control.

The method in this example is used with a corresponding solid phase medium containing a control (for example, SD-activated carbon, iodine-PVPP filter plates, or a combination thereof with activated carbon/passivator complex, PVPP filter plate) Comparing the methods of similar devices, the former has less unwanted unwanted activity than the latter, for example, the protein loss of the former can be reduced by more than 30%. Embodiment 21. A third method of treating a biological fluid of the present invention (2)

In this embodiment: the biological fluid used is a single-part plasma; the apparatus used is selected from the single-part blood component processing apparatus of the system of the present invention prepared in the following Example: 1). Blue/Seitz-Bio 40 and Seitz-Bio 40 filters; 2). Filters containing SD/activated carbon/passivator complex and activated carbon/passivator complex; 3). Containing Zetaplus VR/passivation Filter for the agent complex; 4). Filter containing iodine-PVPP filter/passivator composite and PVPP filter/passivator complex.

The virus inactivation treatment method in this embodiment is: single-person plasma is flowed through the system at an optimized flow rate (for example, a linear velocity of 0.1-0.5 cm/min) at 20-37 ° C, in which virus inactivation is performed, The virus inactivating agent that may be shed is then removed, and if necessary, the device including the solid phase medium is washed with sputum.

The study and results of virus inactivation efficiency of the method of this example are consistent with the study and results of virus inactivation efficiency in Example 20.

The method of this example has a protein loss of up to 20% compared to a method using a similar device containing a corresponding solid phase medium used as a control (for example, a combination of SD-activated carbon and activated carbon/passivator complex). Above, the increase in the APTT value can be reduced by more than 30%.

It will be apparent that various modifications and changes can be made to the preferred embodiments of the invention described herein. These modifications and variations can be made without departing from the spirit and scope of the invention and the advantages thereof. Accordingly, such modifications and variations are intended to be included within the scope of the appended claims.

Claims

Rights request

A system for treating a biological fluid, the smallest constituent unit being a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, wherein:

A). The virus inactivating agent comprises a dye-based photosensitizer;

B). The virus inactivating agent adsorbate comprises a fiber comprising at least a dyeing agent of the dye-based photosensitizer and having substantially no side effects on the biological liquid, wherein -

(a) The dyeing seat does not include a terminal group containing hydrazine or a virus R A or a DNA imitation;

(b) The fiber comprises an organic fiber having a negative charge or / and at least a hydroxyl group or / and an acidic group in an aqueous solution of pH 7.0, or / and glass fibers;

C). The virus inactivating substance comprises at least A) the virus inactivating agent and B) the virus inactivating agent adsorbate.

2. The system of claim 1 wherein the organic fibers comprise natural fibers.

3. The system of claim 2, wherein the natural fibers comprise plant fibers.

4. The system of claim 3, wherein the plant fibers comprise one or more of the following: cotton fibers, hemp fibers, wood fibers, paper pulp.

5. The system of claim 2, wherein the natural fibers comprise animal fibers.

6. The system of claim 1 wherein the organic fibers comprise cellulose based derived fibers.

7. The system of claim 1 wherein the organic fibers comprise synthetic fibers.

8. The system of claim 7, wherein the synthetic fibers comprise one or more of the following fibers: polyester fibers, polyacrylonitrile fibers, polyamide fibers, polyurethane fibers.

9. The system of claim 1 wherein the solid phase medium comprises a filter material comprising at least the fibers.

10. The system of claim 9, wherein the filter media has an average density greater than 0.10 g/cm<^3> and further has one or more of the following characteristics:

A). Ash is less than 1%;

B). The average length of the fibers is less than 1 mm;

C). The fibers comprise fiber microstructures having an average length of less than 1 mm and an average diameter of less than 50 μm.

11. The system of claim 1 wherein the solid phase medium further comprises a leukocyte-removing material.

12. The system of claim 11 wherein the leukocyte-removing material comprises the fiber.

13. A system for treating a biological fluid, the smallest constituent unit being a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance, wherein:

A). The virus inactivating agent comprises a dye-based photosensitizer; B). The virus inactivating agent adsorbate comprises porous particles comprising a hydroxyl polymer;

C). The virus inactivating substance comprises at least A) the virus inactivating agent and B) the adsorbate.

14. The system of claim 13 wherein the hydroxy polymer comprises a polysaccharide or/and a derivative thereof.

15. The system of claim 14, wherein the polyglycan comprises one or more of the following: cellulose, dextran, agarose, chitosan, starch. ·

16. The system of claim 13, wherein the porous particles have one or more of the following characteristics: A). Average particle size 5-80 μιη;

Β). Specific surface area 100-2000m ² /g thousand powder;

C). Average pore size 5-500A;

D). Exclude a volume of less than 50,000 molecular weight.

17. A system for treating a biological fluid, the smallest constituent unit being a chamber containing a solid phase medium, wherein the solid phase medium comprises at least:

A) passivating agent and virus inactivating agent adsorbate; or

B) passivation agent and virus inactivating substance; or

C) Passivator, virus inactivating agent and virus inactivating agent adsorbate.

18. The system of claim 17, wherein the passivator content of the solid phase medium is greater than 0.05 mol/cm.

19. The system of claim 17, wherein the passivating agent comprises an organic having a hydrophilic group or / and an oleophilic group.

20. The system of claim 19, wherein the organic substance having an oleophilic group comprises natural oils or/and derivatives thereof.

The system according to claim 19, wherein the organic substance having an oleophilic group comprises an organic solvent.

22. The system of claim 19, wherein the organics comprise a surfactant.

23. The system of claim 19, wherein the organic material comprises a hydroxy compound.

24. The system of claim 23, wherein the hydroxy compound comprises an alcohol, a saccharide, or/and a derivative thereof.

25. The system of claim 24, wherein the saccharide comprises a monosaccharide, a polysaccharide, or/and a polysaccharide.

26. The system of claim 19, wherein the organic matter comprises a biomass.

27. The system of claim 26, wherein the biological material comprises an amino acid or/and a polypeptide.

28. The system of claim 19, wherein the organic matter comprises two or more of the following two Any combination of several substances: natural oils, organic solvents, surfactants, hydroxy compounds, biological substances.

29. The system of claim 17 wherein the solid phase medium comprises at least a passivating agent, a virus inactivating agent, and a virus inactivating agent adsorbate, and:

A). The virus inactivating agent comprises an organic solvent;

B). The passivating agent comprises an organic solvent;

C). The content of the organic solvent in the solid phase medium is greater than 0.2 mol/cm ³ .

30. The system of claim 29, wherein the organic solvent is present in an amount greater than 0.3 m _O l / _C m ³ .

31. A system for treating a biological fluid, the smallest constituent unit being a chamber comprising a solid phase medium, wherein the solid phase medium comprises at least a leukocyte-removing material and a passivating agent.

32. The system of claim 31, wherein the leukocyte-removing material comprises the fiber of the system for treating a biological fluid of any of claims 1-11.

33. The system of claim 31, wherein the passivating agent comprises the passivating agent in a system for treating a biological fluid according to any one of claims 19-28.

34. A system for treating a biological fluid, the smallest constituent unit being a chamber containing a solid phase medium, wherein the solid phase medium contains at least a virus inactivating agent adsorbate, and the solid phase medium is a virus inactivating agent The adsorption capacity is less than 0.02 mmol of virus inactivating agent/cm ³ .

35. The system of claim 34, wherein the solid phase medium has an adsorption capacity for the virus inactivating agent that is less than 1.0 mmol of virus inactivating agent per cm<^3> .

36. A system for treating a biological fluid, the smallest constituent unit being a chamber comprising a liquid inlet, a liquid outlet, and a solid phase medium, wherein the solid phase medium comprises a functional layer solid phase medium and closest to the outlet a safety layer solid phase medium with a thickness of 2-15 mm, of which:

A). The functional layer solid phase medium contains at least a virus inactivating agent adsorbate or/and a virus inactivating substance;

B). The safety layer solid phase medium contains a virus inactivating agent adsorbate.

37. The system of claim 36, wherein the security layer solid phase medium has a thickness of from 3.0 to 6.0 mm.

38. The system of claim 17, 34 or 36, wherein the viral inactivating agent comprises an organic solvent, a photosensitizer, or iodine.

39. The system of claim 38, wherein the photosensitizer comprises a psoralen-based photosensitizer.

40. The system of claim 38, wherein the photosensitizer comprises a dye-based photosensitizer.

41. The system of claim 1, 13 or 40, wherein the dye-based photosensitizer comprises methylene blue.

42. The system of claim 17, 34 or 36, wherein the viral inactivating agent adsorbate comprises an endogenous adsorbate.

43. The system of claim 42, wherein the endogenous adsorbate comprises one or more of the following: activated carbon, silicon oxide particles, polysaccharide-containing or poly-polysaccharide derivative particles.

44. The system of claim 42 wherein the endogenous adsorbate comprises one or more of the following: plant fiber, protein fiber, synthetic fiber, fiberglass.

45. The system of claim 17, 34 or 36, wherein the viral inactivating agent adsorbate comprises an exogenous adsorbate immobilized with a viral inactivating agent ligand.

46. The system of claim 45, wherein the viral inactivating agent ligand comprises a C6-C18 carbon chain, a purine-containing end group or a viral RNA, or a DNA replica.

47. The system of claim 1, 13, 17, 34 or 36, wherein the solid phase medium comprises a porous particulate solid phase medium or a depth filter media solid phase medium.

48. The system of claim 47, wherein the porous particle solid phase medium has a spherical protein exclusion lower molecular weight of less than 5,000.

49. The system of claim 47, wherein the depth filter media solid phase medium has a permeability of less than 200 L/m ² min _o

50. The system of claim 1, 13, 17, 31, 34 or 36, wherein a passivating agent is bonded to a surface of the part or all of the composition other than the solid phase medium that is in contact with the biological fluid .

51. The system of claim 50, wherein the passivating agent comprises the passivating agent in a system for treating a biological fluid according to any one of claims 19-28.

52. A system for treating a biological fluid, the smallest constituent unit being a chamber containing a solid phase medium, wherein the solid phase medium is a combination of two or more of the following solid phase media:

A) the solid phase medium containing the virus inactivating agent adsorbate in the system of claim 1;

B) the viral inactivating solid phase medium in the system of claim 1;

C) the solid phase medium containing the virus inactivating agent adsorbate in the system of claim 13;

D) the viral inactivating solid phase medium in the system of claim 13;

E) The solid phase medium containing the virus inactivating agent adsorbate in the system of claim 17;

F). The virus inactivating solid phase medium in the system of claim 17;

G). The solid phase medium in the system of claim 31;

HQ. The solid phase medium in the system of claim 34;

I) The solid phase medium of the system of claim 36.

53. A system for treating a single human blood or a derivative thereof, comprising the system for treating a biological fluid according to any one of claims 1-52.

54. The system of claim 53 wherein the single human blood or derivative thereof comprises one of the following Or a variety of biological fluids: single-person plasma, single-platelet fluid, single-part red blood cell fluid.

55. A solid phase medium for treating a biological fluid, which is for use in a system for treating a biological fluid according to claim 1, 13, 17, 31, 34 or 52, comprising at least said virus inactivation Solid phase medium of matter.

56. A solid phase medium for treating a biological fluid, which is a solid phase medium for use in a system for treating a biological fluid according to claim 17, 31 or 34, and wherein the solid phase medium comprises at least:

A) the passivating agent and the virus inactivating agent adsorbate; or

B) the passivating agent and leukocyte-removing material; or

C). The passivating agent, leukocyte-removing material and virus inactivating agent adsorbate.

57. Apparatus for treating a biological fluid, comprising at least the system for treating a biological fluid of any of claims 1-54.

58. The device of claim 57 further comprising a viral inactivating agent addition structure.

59. The device of claim 57, further comprising a viral inactivation reaction site.

60. Apparatus according to claim 57 further comprising a wash liquor.

61. A method of treating a biological fluid, comprising at least:

A) providing biological fluids;

B) contacting the biological fluid with the virus inactivating agent;

C) bringing the biological fluid treated by B) into a system for treating a biological fluid according to any one of claims 1-54, and contacting the solid phase medium containing at least the virus inactivating agent adsorbate;

D). The biological fluid substantially free of the viral inactivating agent is collected from the system in C).

62. A method of treating a biological fluid, comprising at least:

A) providing a single person's blood or its derivatives;

B) adding a photosensitizer to the single blood or its derivative to a photosensitizer concentration of 0.55-3.0 μηιο / 1 and performing virus inactivation;

C) passing the biological liquid treated by the hydrazine into a system for treating a biological liquid according to any one of claims 1-54, and contacting the solid phase medium containing at least the virus inactivating agent adsorbate;

63. A method of treating a biological fluid, comprising at least:

Α). providing biological fluids;

生物). The biological fluid is introduced into the system for treating a biological fluid according to any one of claims 1-54, and is contacted with the solid phase medium containing at least the virus inactivating agent.