Method for evaluating the coating state of silicone compounds

Abstract

The purpose of the present invention is to provide a means for easily evaluating the formation state of a coating layer containing, inter alia, a silicone compound on an inner surface of a hollow fiber membrane.　The present invention relates to an evaluation method for the covering state of a silicone compound, the method including: dissolving a silicone compound and a dyeing agent in an organic solvent to prepare a coating solution; feeding the coating solution to the inner surface of the hollow fiber membrane and forming a coating layer including, on the inner surface thereof, the silicone compound and / or a crosslinked product of the silicone compound and the dyeing agent; and observing the dyeing state of a coating solution start-of-flow-side hollow fiber membrane end surface 1 and a coating solution end-of-flow-side hollow fiber membrane end surface 2 of the hollow fiber membrane in which the coating layer has been formed, and thereby evaluating the covering state of the silicone compound / cross-linked product.

Description

[Technical Field]

[0001] The present invention relates to a method for evaluating the state of coating with a silicone compound. [Background technology]

[0002] Oxygenators with porous hollow fiber membranes can experience a decline in gas exchange performance over time. Wet lunging and plasma leakage are considered to be the main causes. Wet lunging restores gas exchange performance by blowing high-pressure air into the hollow fiber membrane to remove condensation. On the other hand, plasma leakage is believed to cause an irreversible decline in the performance of the oxygenator. Solving the problem of plasma leakage is essential for long-term use of oxygenators, and many studies have been conducted to date. Among these, methods of improving plasma leakage resistance have been adopted, such as blocking the micropores in the hollow fiber membrane or making the micropores of the hollow fiber membrane extremely small.

[0003] For example, Japanese Patent Application Laid-Open No. 2002-035116 describes that applying a silicone coating to the outer surface of a porous hollow fiber membrane made of polypropylene makes plasma leakage less likely to occur and enables long-term use. Summary of the Invention

[0004] However, according to the method described in JP 2002-035116 A, a continuous hollow fiber membrane is moved at 0.5 to 50 m / min in a silicone monomer atmosphere undergoing plasma discharge under high vacuum, and silicone coating is carried out by polymerizing the silicone monomer on the outer surface of the hollow fiber membrane. Therefore, the coating process has the problem of requiring complicated equipment and a long time.

[0005] With the aim of providing an oxygenator with plasma leakage resistance using a simpler method, we are conducting research into methods for forming a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane (e.g., Patent Application No. 2020-035292). In this research, there was a need for a means to easily evaluate the state (degree of coverage) of the coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane.

[0006] Therefore, an object of the present invention is to provide a means for easily evaluating the state of formation of a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane.

[0007] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by observing the end surface of a hollow fiber membrane after contacting the inner surface of the hollow fiber membrane with a coating liquid containing a silicone compound and a dye.

[0008] That is, the above-mentioned object can be achieved by a method for evaluating the coating state of a silicone compound, which comprises: dissolving a silicone compound and a dye in an organic solvent to prepare a coating liquid; passing the coating liquid over the inner surface of the hollow fiber membrane to form a coating layer on the inner surface containing the silicone compound and / or a crosslinked product of the silicone compound and the dye; and observing the dyeing state of the hollow fiber membrane end face 1 on the side where the coating liquid starts to pass and the hollow fiber membrane end face 2 on the side where the coating liquid ends to pass the coating liquid, on which the coating layer has been formed, to evaluate the coating state of the silicone compound / crosslinked product. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 is a cross-sectional view of a hollow fiber membrane external hemoperfusion oxygenator according to one embodiment of the present invention. In Figure 1, 1 denotes the hollow fiber membrane external hemoperfusion oxygenator; 2 denotes the housing; 3 denotes the porous hollow fiber membrane for gas exchange; 4 and 5 denote diaphragms; 6 denotes the blood inlet; 7 denotes the blood outlet; 8 denotes the gas inlet; 9 denotes the gas outlet; 10 denotes the gas inlet header; 11 denotes the gas outlet header; 12 denotes the blood chamber; 13 denotes the gas inlet chamber; and 14 denotes the gas outlet chamber. [Figure 2] Figure 2 is an enlarged cross-sectional view of a porous hollow fiber membrane for gas exchange used in a hollow fiber membrane external hemoperfusion oxygenator according to one embodiment of the present invention. In Figure 2, 3 indicates the porous hollow fiber membrane for gas exchange; 3a indicates the outer layer; 3a' indicates the outer surface; 3b indicates the inner layer; 3c indicates the inner layer; 3c' indicates the inner surface; 3d indicates the passage (lumen); 3e indicates the opening on the outer surface; 3f indicates the opening on the inner surface; 16 indicates the coating layer; and 18 indicates the coating. [Figure 3] Figure 3 is a cross-sectional view of a hollow fiber membrane external hemoperfusion oxygenator according to another embodiment of the present invention. In Figure 3, 20 denotes the hollow fiber membrane external hemoperfusion oxygenator; 3 denotes the porous hollow fiber membrane for gas exchange; 17 denotes the blood chamber; 17a and 28 denote blood inlets; 17b denotes the first blood chamber; 17c denotes the second blood chamber; 22 denotes the tubular hollow fiber membrane bundle; 23 denotes the housing; 24 denotes the gas inlet; 25 denotes the first partition; 26 denotes the second partition; 27 denotes the gas outlet; 29a and 29b denote the blood outlet; 31 denotes the inner tubular member; 32 denotes the blood circulation opening; 33 denotes the outer tubular member; 35 denotes the inner tubular body; 41 denotes the gas inlet member; and 42 denotes the gas outlet member. [Figure 4] Figure 4 is a cross-sectional view taken along line AA in Figure 3. In Figure 4, 3 indicates a porous hollow fiber membrane for gas exchange; 17a indicates a blood inlet; 17b indicates a first blood chamber; 17c indicates a second blood chamber; 22 indicates a tubular hollow fiber membrane bundle; 29a and 29b indicate blood outlets; 31 indicates an inner tubular member; 32 indicates openings for blood circulation; 33 indicates an outer tubular member; and 35 indicates an inner tubular body. [Figure 5] Fig. 5 is a front view showing an example of an inner tubular member used in the hollow fiber membrane external hemoperfusion oxygenator according to the present invention, in which 31 denotes the inner tubular member and 32 denotes the blood circulation opening. [Figure 6] Fig. 6 is a central longitudinal cross-sectional view of the inner tubular member shown in Fig. 5. In Fig. 6, 31 denotes the inner tubular member, and 32 denotes the blood circulation opening. [Figure 7] Fig. 7 is a cross-sectional view taken along line BB in Fig. 5. In Fig. 7, 31 denotes the inner cylindrical member, and 32 denotes the blood circulation opening. [Figure 8]Fig. 8 is a circuit diagram used when forming a coating layer on the inner cavity of the hollow fiber membrane in Examples 1 and 2 and Comparative Example 1. In Fig. 8, 50 denotes a circuit, 51 denotes a porous hollow fiber membrane, 52 denotes a liquid inlet, 53 denotes a diaphragm pump, and 55 denotes a trap. [Figure 9] FIG. 9 shows images under visible light (color images), images illuminated with green excitation light (color images), binarized images, and binarized image contrasts of the inlet and outlet samples of Example 1 and Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to a method for evaluating the coating state of a silicone compound, comprising: dissolving a silicone compound and a dye in an organic solvent to prepare a coating liquid; passing the coating liquid over the inner surface of the hollow fiber membrane to form a coating layer on the inner surface containing the silicone compound and / or a crosslinked product of the silicone compound and the dye; and evaluating the coating state of the silicone compound / crosslinked product by observing the dyeing state of the hollow fiber membrane end face 1 at the start of the coating liquid passage and the end face 2 at the end of the coating liquid passage of the hollow fiber membrane on which the coating layer has been formed. This method makes it possible to easily evaluate the formation state of a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane. In this specification, "silicone compound and / or a crosslinked product of the silicone compound" is also collectively referred to as "silicone compound / crosslinked product" or "silicone compound or the like."

[0011] While researching methods for forming a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane (e.g., Patent Application No. 2020-035292), the inventors recognized the need for a means for evaluating whether a coating layer containing a silicone compound or the like has been formed over the entire lumen (inner surface) of a hollow fiber membrane. To this end, the inventors conducted extensive research into a means for easily evaluating the state of formation of a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane (the coating state of the silicone compound / crosslinked product). As a result, they discovered that the state of formation of the coating layer (the coating state of the silicone compound or the like) can be easily evaluated by adding a dye to a coating liquid containing a silicone compound, passing this through the lumen of the hollow fiber membrane, and observing the dyed state of the hollow fiber membrane end surfaces at the start and end of the coating liquid flow (e.g., calculating the ratio of the number of hollow fiber membranes dyed on the end of the coating liquid flow to the number of hollow fiber membranes dyed on the start side of the coating liquid flow). Specifically, when a liquid containing a silicone compound and a dye is passed through the hollow fiber membrane lumen, the silicone compound and the dye pass through the hollow fiber membrane lumen in almost the same manner. Therefore, the number of hollow fiber membranes dyed at the coating liquid passage start side corresponds to the total number of hollow fiber membranes, and when the hollow fiber membrane end surface 2 at the coating liquid passage end side is dyed, it can be assumed that the silicone compound, etc. has also passed through to the hollow fiber membrane end surface. Therefore, according to the method of the present invention, whether a coating layer containing a silicone compound, etc. has been formed throughout the entire lumen of the hollow fiber membrane can be easily evaluated by the presence or absence of dyeing at both end surfaces of the hollow fiber membrane (for example, the ratio of the number of hollow fiber membranes dyed at the coating liquid passage end side to the number of hollow fiber membranes dyed at the coating liquid passage start side).

[0012] Preferred embodiments of the present invention will be described below. However, the present invention is not limited to the following embodiments and can be modified in various ways within the scope of the claims. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of any conflict, the present specification (including definitions) shall prevail. Furthermore, the dimensional proportions in the drawings may be exaggerated for illustrative purposes and may differ from the actual proportions.

[0013] In this specification, the term "X to Y" indicating a range includes both X and Y and means "X or more and Y or less." Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20 to 25°C) and a relative humidity of 40 to 50% RH. "A and / or B" means both A and B, or either A or B.

[0014] The method for evaluating the coating state of the silicone compound of the present invention will be described in detail below.

[0015] The method for evaluating the coating state of the silicone compound of the present invention comprises: (i) dissolving a silicone compound and a dye in an organic solvent to prepare a coating liquid (step (i)); (ii) passing the coating liquid through the inner surface of the hollow fiber membrane to form a coating layer containing the silicone compound and / or a crosslinked product of the silicone compound and a dye on the inner surface (step (ii)); (iii) The state of coating of the silicone compound / crosslinked product is evaluated by observing the dyeing state of the hollow fiber membrane end surface 1 on the side where the coating liquid starts to pass and the dyeing state of the hollow fiber membrane end surface 2 on the side where the coating liquid passes through, on which the coating layer has been formed (step (iii)). It has the following.

[0016] [Step (i)] In step (i), a silicone compound and a dye are dissolved in an organic solvent to prepare a coating solution. In this specification, a coating layer containing a silicone compound or the like (a coating made of a silicone compound or the like) has the function of suppressing plasma leakage from the outer surface side to the inner surface side of the hollow fiber membrane (plasma leak resistance). Furthermore, in hollow fiber membrane oxygenators, a phenomenon known as wet lunging, in which vaporized water from blood accumulates in the lumen of the hollow fiber membrane, can cause a problem of reduced gas exchange performance. The silicone compound also has the function of suppressing this wet lunging.

[0017] The silicone compound can be any polymeric compound having a siloxane bond (Si-O-Si) in the main skeleton. Among them, the silicone compound is preferably a silicone compound represented by the following formula (1) because it can form a coating layer with excellent plasma leakage resistance. That is, according to a preferred embodiment of the present invention, the silicone compound is represented by the following formula (1):

[0018] [ka]

[0019] In the above formula (1), R 1 ~R 8 each independently represents a reactive group selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, an aromatic hydrocarbon group having from 6 to 30 carbon atoms, or an ethylenically unsaturated bond-containing group having from 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxy group-containing group, a maleimide group-containing group, a thiol group-containing group, and a halogen group.

[0020] In the above formula (1), n ​​is 1 or more and 100,000 or less.

[0021] In the silicone compound represented by the above formula (1), R 1 ~R 8 may each independently be an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 30 carbon atoms, but R 1 ~R 8 At least one of R is preferably a reactive group selected from the group consisting of an ethylenically unsaturated bond-containing group having from 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxyl group-containing group, a maleimide group-containing group, a thiol group-containing group, and a halogen group. 1 ~R 3 At least one of the following and R 6 ~R 8 and at least one of R is independently a reactive group selected from the group consisting of an ethylenically unsaturated bond-containing group having from 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxyl group-containing group, a maleimide group-containing group, a thiol group-containing group, and a halogen group; 1 ~R 3 The remainder of R 4 ~R 5 and R 6 ~R 8 The remainders in each of the above groups independently represent an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 30 carbon atoms. 1 ~R 3 One of the R 6 ~R 8 each independently represents a reactive group selected from the group consisting of an ethylenically unsaturated bond-containing group having from 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxyl group-containing group, a maleimide group-containing group, a thiol group-containing group, and a halogen group; R 1 ~R 3 The remaining two of these, and R 4 ~R 5 and R 6 ~R 8The remaining two of these independently represent an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 30 carbon atoms. Since the silicone compound represented by formula (1) has a reactive group, a crosslinking reaction can proceed during the process of forming a coating layer (for example, during the process of drying an organic solvent), and a crosslinked product of the silicone compound can be produced. This can improve the adhesion and durability of the coating layer.

[0022] When the silicone compound (preferably a silicone compound represented by formula (1)) used in preparing the coating liquid does not have a reactive group, the silicone compound can be contained as is in the coating layer formed on the inner surface of the hollow fiber membrane. On the other hand, when the silicone compound (preferably a silicone compound represented by formula (1)) used in preparing the coating liquid has a reactive group as described above, the coating layer formed on the inner surface of the hollow fiber membrane can contain the silicone compound (i.e., an uncrosslinked silicone compound) used in preparing the coating liquid and / or a crosslinked product of the silicone compound. In other words, the coating layer formed on the inner surface of the hollow fiber membrane can contain the silicone compound (i.e., an uncrosslinked silicone compound) used in preparing the coating liquid and / or a crosslinked product of the silicone compound.

[0023] In formula (1), examples of the alkyl group having 1 to 6 carbon atoms or the aromatic hydrocarbon group having 6 to 30 carbon atoms include a methyl group, an ethyl group, an n-propyl group, a phenyl group, and groups derived from fluorescein and its derivatives. Examples of fluorescein derivatives include fluorescein isothiocyanate, N-hydroxysuccinimide fluorescein, Oregon Green, Tokyo Green, SNAFL, carboxyfluorescein, carboxyfluorescein diacetate, and aminofluorescein. Among these, from the viewpoints of fluidity and Young's modulus after curing, a methyl group or an ethyl group is preferred, and a methyl group is more preferred. Examples of ethylenically unsaturated bond-containing groups having 1 to 6 carbon atoms include a vinyl group, a vinyloxy group, an allyl group, an allyloxy group, a propenyl group, and a propenyloxy group. Examples of functional groups containing an amino group (amino group-containing groups) include an amino group and an aminophenyl group. Examples of functional groups containing a hydroxyl group (hydroxyl group-containing groups) include a hydroxyl group, a phenol group, and a catechol group. Examples of functional groups containing a carboxy group (carboxy group-containing groups) include a carboxy group and a maleic acid group. Examples of functional groups containing a maleimide group (maleimide group-containing groups) include a maleimide group. Examples of functional groups containing a thiol group (thiol group-containing groups) include a thiol group, a thiophenyl group, and a thiophenol group. Examples of halogen groups include a fluoro group, a chloro group, a bromo group, and an iodo group. Among these, due to their good crosslinking reactivity, a vinyloxy group (-O-CH=CH2), an allyloxy group (-O-CH2CH=CH2), and an allyl group (-CH2CH=CH2) are preferred, with a vinyloxy group being more preferred.

[0024] In one embodiment of the present invention, the silicone compound is R 1 ~R 3 At least one of, and R 6 ~R 8 at least one of R is independently a vinyloxy group (-O-CH=CH), an allyloxy group (-O-CHCH=CH), or an allyl group; 1 ~R 3 The remainder of R 4 ~R5 , and R 6 ~R 8 wherein the remainder of the formula (1) is independently a methyl group or an ethyl group.

[0025] In one embodiment of the present invention, the silicone compound is R 1 ~R 3 One of the following, and R 6 ~R 8 are each independently a vinyloxy group (-O-CH=CH), an allyloxy group (-O-CHCH=CH), or an allyl group, and R 1 ~R 3 The remaining two of these, R 4 ~R 5 , and R 6 ~R 8 wherein the remaining two of the groups are independently a methyl group or an ethyl group.

[0026] In one embodiment of the present invention, the silicone compound is R 1 ~R 3 One of the following, and R 6 ~R 8 One of the groups is a vinyloxy group (-O-CH=CH2), and R 1 ~R 3 The remaining two of these, R 4 ~R 5 , and R 6 ~R 8 The remaining two of the groups are methyl groups, and the silicone compound is represented by formula (1).

[0027] In formula (1), n ​​is not particularly limited, but is preferably from 1 to 100,000, and more preferably from 1 to 10,000. When n is within the above range, the coating liquid can be easily passed through the lumen of the hollow fiber membrane.

[0028] The silicone compound may be either a commercially available product or a synthetic product, such as SYLGARD (registered trademark) 184 and 186 manufactured by Dow Corning Corporation.

[0029] The silicone compounds may be used alone or in combination of two or more.

[0030] The concentration of the silicone compound in the coating solution is not particularly limited, but from the viewpoint of improving the liquid permeability of the coating solution through the lumen of the hollow fiber membrane, it is preferably 10 mg / mL or more and less than 800 mg / mL, more preferably 20 to 400 mg / mL, and particularly preferably 100 to 300 mg / mL. When the coating layer is formed in a single coating solution application step, from the viewpoint of forming a coating layer of sufficient thickness, the concentration is preferably 100 to 400 mg / mL, more preferably 100 to 300 mg / mL, and particularly preferably 100 mg / mL or more and less than 200 mg / mL. When the coating layer is formed in multiple coating solution application steps, a coating layer of sufficient thickness can be formed even at a low concentration, so it is preferably 10 mg / mL or more and less than 100 mg / mL, more preferably 20 to 70 mg / mL. Note that when two or more silicone compounds are used, the concentration of the silicone compounds refers to the total concentration of the silicone compounds used.

[0031] The dye is not particularly limited as long as it can dye the hollow fiber membrane. Specific examples include rhodamine dyes (e.g., rhodamine B, rhodamine 6G, rhodamine 6GP, rhodamine 3GO, and rhodamine 123), fluorescein dyes (e.g., fluorescein, fluorescein isothiocyanate, N-hydroxysuccinimide fluorescein, Oregon Green, Tokyo Green, SNAFL, carboxyfluorescein, carboxyfluorescein diacetate, and aminofluorescein, and derivatives thereof), indocyanine green, and polymers having these molecules at at least one of their side chains and terminals. Among these, from the viewpoints of the dyeability, visibility, and availability of hollow fiber membranes, rhodamine B, rhodamine 6G, rhodamine 6GP, rhodamine 3GO, rhodamine 123, fluorescein and its derivatives, and polymers having these molecules on at least one of their side chains and termini are preferably used, with rhodamine B being more preferred. That is, according to a preferred embodiment of the present invention, the staining agent is selected from rhodamine B, rhodamine 6G, rhodamine 6GP, rhodamine 3GO, rhodamine 123, fluorescein and its derivatives, and polymers having these molecules on at least one of their side chains and termini. In a more preferred embodiment of the present invention, the staining agent is selected from rhodamine B, rhodamine 6G, rhodamine 6GP, rhodamine 3GO, and rhodamine 123. In an even more preferred embodiment of the present invention, the staining agent is rhodamine B.

[0032] The dye may be either a commercially available product or a synthetic product.

[0033] The dyes may be used alone or in combination of two or more.

[0034] The concentration of the dye in the coating solution is not particularly limited, but from the viewpoint of the degree of dyeing (ease of visibility) of the hollow fiber membrane, it is preferably 0.025 to 0.5 mg / mL, more preferably 0.05 to 0.1 mg / mL. When two or more dyes are used, the concentration of the dye means the total concentration of the dyes used.

[0035] The organic solvent is used for the purpose of dispersing or dissolving the silicone compound and the dye. In the method of this embodiment, the organic solvent is not particularly limited as long as it can achieve the above purpose, but it is preferable that the surface tension is less than 70 dyn / cm. That is, according to a preferred embodiment of the present invention, the surface tension of the organic solvent is less than 70 dyn / cm. When the surface tension of the organic solvent is less than 70 dyn / cm, the silicone compound dissolves more easily and the coating liquid can easily pass through, thereby forming a good coating layer (as a uniform coating film). From the viewpoint of further improving the solubility of the silicone compound and further improving the liquid permeability of the coating liquid in the lumen of the hollow fiber membrane, the surface tension of the organic solvent is preferably 50 dyn / cm or less, more preferably 40 dyn / cm or less, and even more preferably 30 dyn / cm or less. The lower limit of the surface tension is not particularly limited, but is preferably 15 dyn / cm or more from the viewpoint of smoothly flowing through the hollow fiber membrane and preventing the coating liquid from permeating through the pores of the hollow fiber membrane. The surface tension of the organic solvent is preferably in a range of 15 dyn / cm or more and less than 70 dyn / cm, more preferably 15 dyn / cm or more and 50 dyn / cm or less, even more preferably 15 dyn / cm or more and 40 dyn / cm or less, and particularly preferably 15 dyn / cm or more and 30 dyn / cm or less, where 1 dyn / cm is 0.001 N / m.

[0036] In this specification, the surface tension of an organic solvent (when a mixture of two or more organic solvents is used, the surface tension of the mixed organic solvents) is measured at 20°C using a Dunouy surface tensiometer (manufactured by Ito Seisakusho). Specifically, a platinum ring is hung from the end of a thin rod attached to the center of a steel wire, which is brought into contact with the liquid surface of the organic solvent in a horizontal position, and the knob is turned to twist the steel wire to pull up the platinum ring. The moment it separates from the liquid surface is read using the scale and pointer, and this value is taken as the surface tension (dyn / cm) of the organic solvent.

[0037] Examples of organic solvents include aromatic hydrocarbons such as toluene (28.5 dyn / cm), xylene (28.4 dyn / cm), cyclohexane (25.3 dyn / cm), n-hexane (18.4 dyn / cm), n-heptane (20.1 dyn / cm), diethyl ether (16.96 dyn / cm), diisopropyl ether (17.1 dyn / cm), methyl hexyl ether (23.5 dyn / cm), ethyl acetate (24.0 dyn / cm), butyl acetate (25.2 dyn / cm), isopropyl laurate (30.1 dyn / cm), isopropyl myristate (28.3 dyn / cm), methyl ethyl ketone (24.6 dyn / cm), methyl isobutyl ketone ( 23.9 dyn / cm), lauryl alcohol (24.0 dyn / cm), acetone (23.3 dyn / cm), butyl alcohol (25.4 dyn / cm), 1-propanol (23.7 dyn / cm), isopropanol (23.0 dyn / cm), 2-ethylhexanol (26.9 dyn / cm), chloroform (26.7 dyn / cm), hydrofluoroether (13.6 dyn / cm), hydrofluoroolefin (17.9 dyn / cm), hydrofluorocarbon (13.6 dyn / cm), hydrochlorofluoroolefin (14.6 dyn / cm), hydrochlorofluorocarbon (12.7 dyn / cm). Among these, n-hexane, cyclohexane, acetone, butyl alcohol, 1-propanol, isopropanol, chloroform, diethyl ether, aromatic hydrocarbons, and fluorine-based solvents are preferred, with n-hexane and acetone being more preferred, from the viewpoint of their ability to dissolve silicone compounds and dyes (especially silicone compounds) well and their low boiling points making the organic solvent easy to remove. These solvents may be used alone or in combination of two or more. That is, according to a preferred embodiment of the present invention, the organic solvent is at least one selected from the group consisting of n-hexane, cyclohexane, acetone, butyl alcohol, 1-propanol, isopropanol, chloroform, diethyl ether, aromatic hydrocarbons, and fluorine-based solvents.That is, according to a more preferred embodiment of the present invention, the organic solvent is n-hexane, acetone, or a combination of n-hexane and acetone. However, as long as the surface tension of the solvent that dissolves the silicone compound is less than 70 dyn / cm, an organic solvent with a surface tension of 70 dyn / cm or more may be included.

[0038] In addition to the silicone compound and organic solvent, the coating liquid may contain additives such as carnauba wax, PDMS-PEG, and a crosslinking agent, if necessary.

[0039] In this process, the order of mixing the silicone compound, dye, and organic solvent is not particularly limited. It is possible to add the silicone compound and dye to the organic solvent all at once; add the silicone compound and dye separately (silicone compound followed by dye, or dye followed by silicone compound) to the organic solvent; mix the silicone compound and dye in separate organic solvents; dissolve the dye in an organic solvent first, and then add the silicone compound to the same or a different organic solvent; or dissolve the silicone compound in an organic solvent first, and then add the dye in the same or a different organic solvent. The mixing order can be appropriately selected taking into account the ease of solubility of the silicone compound and dye. When dissolving or dissolving the dye and silicone compound in different organic solvents, these organic solvents may be the same or different, but it is preferable that both have a surface tension of less than 70 dyn / cm.

[0040] [Step (ii)] In step (ii), the coating liquid prepared in step (i) above is passed through the inner surface of the hollow fiber membrane (the inner surface of the hollow fiber membrane is brought into contact with the coating liquid prepared in step (i) above), and a coating layer containing a silicone compound and / or a crosslinked product of the silicone compound (silicone compound / crosslinked product) and a dye is formed on the inner surface.

[0041] Here, the hollow fiber membrane can be the same as the hollow fiber membrane typically used in oxygenators. Therefore, the hollow fiber membrane can be used in the form of an oxygenator having a plurality of porous hollow fiber membranes for gas exchange. In the form of an oxygenator, the hollow fiber membrane has an inner surface forming a lumen and an outer surface, and a coating layer containing a silicone compound (a silicone compound used in preparing the coating liquid and / or a crosslinked product of the silicone compound) is formed on the inner surface, and a coating containing an antithrombogenic polymer compound is formed on the outer surface. Here, as long as the antithrombogenic polymer compound has antithrombogenicity and biocompatibility, known antithrombogenic polymer compounds described in JP-A-57-039851, JP-A-63-154180, JP-A-02-305575, JP-A-04-152952, JP-A-2018-149270, etc. can be used in the same manner. Furthermore, the method for forming a coating containing an antithrombogenic polymer compound on the outer surface is not particularly limited, and known methods can be used in the same manner or with appropriate modifications.

[0042] The details of the hollow fiber membrane oxygenator are described below with reference to the drawings.

[0043] FIG. 1 is a cross-sectional view of a hollow fiber membrane external hemoperfusion oxygenator according to one embodiment of the present invention. FIG. 2 is an enlarged cross-sectional view of a gas-exchange porous hollow fiber membrane used in a hollow fiber membrane external hemoperfusion oxygenator according to one embodiment of the present invention. In this specification, the hollow fiber membrane external hemoperfusion oxygenator is also simply referred to as a "hollow fiber membrane oxygenator" or "oxygenator." In this specification, the gas-exchange porous hollow fiber membrane is also simply referred to as a "porous hollow fiber membrane" or "hollow fiber membrane."

[0044] In the embodiment shown in FIG. 1, the hollow fiber membrane external hemoperfusion oxygenator 1 contains a number of porous hollow fiber membranes 3 for gas exchange housed within a housing 2. As shown in FIG. 2, the hollow fiber membrane 3 has a passage (lumen) 3d that forms a central gas chamber. Additionally, the hollow fiber membrane 3 has openings 3e and 3f that connect its outer surface 3a' to its inner surface 3c'. A coating layer 16 containing a silicone compound or the like is formed on the inner surface 3c' of the hollow fiber membrane 3, through which oxygen-containing gas flows. Furthermore, a coating 18 containing an antithrombotic polymer compound is formed on the outer surface 3a' (or, in some cases, the outer surface 3a' and the outer surface layer 3a) of the hollow fiber membrane 3, which is the blood-contacting portion. The coating layer 16 may contain other components in addition to the silicone compound or the like. Examples of such other components include, but are not limited to, polyolefins, aliphatic hydrocarbons, inorganic fine particles, and crosslinking agents. Preferably, the coating layer 16 is composed solely of a silicone compound or the like. Similarly, coating 18 may contain other components in addition to the antithrombotic polymer compound. Here, the other components are not particularly limited, but include other antithrombotic substances (e.g., heparin), crosslinking agents, thickeners, preservatives, pH adjusters, etc.

[0045] The coating layer 16 containing a silicone compound or the like may be formed on at least a portion of the inner surface 3c' of the hollow fiber membrane 3 through which the oxygen-containing gas flows. However, from the viewpoint of maintaining gas exchange performance during long-term use (improving plasma leakage resistance and suppressing wet lagging), it is preferably formed on the entire inner surface 3c'. In the embodiment shown in FIG. 2, the coating layer 16 containing a silicone compound or the like is formed over the entire inner surface 3c' so as to block the openings 3f of the pores on the inner surface 3c' side. However, since the coating layer 16 containing a silicone compound or the like has high gas permeability, it can have sufficient gas exchange performance. Furthermore, the coating layer 16 containing a silicone compound or the like may be present on the inner surface layer 3c of the hollow fiber membrane 3 (or, in some cases, on the inner surface layer 3c and the inner layer 3b).

[0046] Similarly, the coating 18 containing an antithrombogenic polymer compound may be formed on at least a portion of the outer surface 3a', which is the blood-contacting portion of the hollow fiber membrane 3. However, from the viewpoints of antithrombogenicity and biocompatibility (the effect of inhibiting and preventing platelet adhesion / adhesion and the effect of inhibiting and preventing platelet activation), it is preferably formed on the entire outer surface 3a'. In the embodiment shown in FIG. 2, the coating 18 containing an antithrombogenic polymer compound may be present on the inner layer 3b (or, in some cases, the inner layer 3b and the inner surface layer 3c) of the hollow fiber membrane 3, but is preferably not substantially present in the inner layer 3b (or, in some cases, the inner layer 3b and the inner surface layer 3c) of the hollow fiber membrane 3. The substantial absence of the antithrombogenic polymer compound allows the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane to retain the hydrophobic properties of the membrane substrate itself, effectively preventing leakage of plasma components. In this specification, "the coating 18 containing the antithrombotic polymer compound is substantially absent from the inner layer 3b of the hollow fiber membrane 3 (or, in some cases, the inner layer 3b and the inner surface layer 3c)" means that no penetration of the antithrombotic polymer compound is observed near the inner surface 3c' of the hollow fiber membrane 3 (the surface on the side through which the oxygen-containing gas flows).

[0047] The hollow fiber membrane oxygenator 1 of this embodiment comprises a housing 2 having a blood inlet 6 and a blood outlet 7, a hollow fiber membrane bundle consisting of a number of gas exchange porous hollow fiber membranes 3 contained within the housing 2, and a pair of partitions 4 and 5 that support both ends of the hollow fiber membrane bundle in a liquid-tight manner in the housing 2. The hollow fiber membrane oxygenator 1 also comprises a blood chamber 12 formed between the partitions 4 and 5 and the inner surface of the housing 2 and the outer surface of the hollow fiber membranes 3, a gas chamber formed inside the hollow fiber membranes 3, and a gas inlet 8 and a gas outlet 9 that communicate with the gas chamber.

[0048] Specifically, the hollow fiber membrane oxygenator 1 of this embodiment has a cylindrical housing 2, an assembly of gas exchange hollow fiber membranes 3 housed within the cylindrical housing 2, and partitions 4 and 5 that hold both ends of the hollow fiber membranes 3 liquid-tightly in the housing 2. The inside of the cylindrical housing 2 is partitioned into a blood chamber 12, which is a first fluid chamber, and a gas chamber, which is a second fluid chamber. The cylindrical housing 2 is provided with a blood inlet 6 and a blood outlet 7 that communicate with the blood chamber 12.

[0049] A cap-shaped gas inlet header 10 is attached above the partition wall 4, which is the end of the cylindrical housing 2. The cap-shaped gas inlet header 10 has a gas inlet 8, which is a second fluid inlet, that communicates with the gas chamber, which is the internal space of the hollow fiber membranes 3. Therefore, a gas inlet chamber 13 is formed by the outer surface of the partition wall 4 and the inner surface of the gas inlet header 10. This gas inlet chamber 13 communicates with the gas chamber formed by the internal space of the hollow fiber membranes 3.

[0050] Similarly, a cap-shaped gas outlet header 11 is attached below the partition wall 5 and has a gas outlet 9, which is a second fluid outlet, communicating with the internal space of the hollow fiber membrane 3. Therefore, a gas outlet chamber 14 is formed by the outer surface of the partition wall 5 and the inner surface of the gas outlet header 11.

[0051] The hollow fiber membrane 3 is a porous membrane made of a hydrophobic polymer material, and is not particularly limited, and may be the same as the hollow fiber membrane used in known artificial lungs. By making the hollow fiber membrane (particularly the inner surface of the hollow fiber membrane) from a hydrophobic polymer material, leakage of plasma components can be suppressed. The porous membrane may be made of the same hydrophobic polymer material as the hollow fiber membrane used in known artificial lungs. Specific examples include polyolefin resins such as polypropylene, polyethylene, and polymethylpentene, as well as polymer materials such as polysulfone, polyacrylonitrile, polytetrafluoroethylene, and cellulose acetate. Among these, polyolefin resins are preferred, with polypropylene and polymethylpentene being more preferred, and polypropylene being even more preferred. That is, according to a preferred embodiment of the present invention, at least a portion of the hollow fiber membrane (preferably the entire hollow fiber membrane) is formed from a polyolefin resin. In a more preferred embodiment of the present invention, at least a portion of the hollow fiber membrane (preferably the entire hollow fiber membrane) is formed from polypropylene or polymethylpentene. In a more preferred embodiment of the present invention, at least a portion of the hollow fiber membrane (preferably the entire hollow fiber membrane) is made of polypropylene.

[0052] The inner diameter of the hollow fiber membrane is not particularly limited, but is preferably 50 to 300 μm, more preferably 80 to 200 μm. The outer diameter of the hollow fiber membrane is not particularly limited, but is preferably 100 to 400 μm, more preferably 130 to 200 μm. The thickness (membrane thickness) of the hollow fiber membrane is preferably 20 μm or more but less than 50 μm, more preferably 25 μm or more but less than 50 μm, even more preferably 25 to 45 μm, even more preferably 25 to 40 μm, even more preferably 25 to 35 μm, and particularly preferably 25 to 30 μm. In this specification, the "thickness (membrane thickness) of the hollow fiber membrane" refers to the thickness between the inner and outer surfaces of the hollow fiber membrane, and is calculated by the formula: [(outer diameter of the hollow fiber membrane) - (inner diameter of the hollow fiber membrane)] / 2. By setting the lower limit of the hollow fiber membrane thickness as described above, sufficient strength of the hollow fiber membrane can be ensured. Furthermore, it is also preferable from the viewpoint of mass production, as it is satisfactory in terms of labor and cost involved in production. The porosity of the hollow fiber membrane is preferably 5 to 90% by volume, more preferably 10 to 80% by volume, and particularly preferably 30 to 60% by volume. The pore diameter of the hollow fiber membrane is preferably 0.01 to 5 μm, more preferably 0.05 to 1 μm. There are no particular limitations on the method for producing the hollow fiber membrane, and known methods for producing hollow fiber membranes can be used in the same manner or with appropriate modifications. For example, it is preferable that the hollow fiber membrane has micropores formed in the wall by a stretching method or a solid-liquid phase separation method.

[0053] In this specification, the "pore diameter of the hollow fiber membrane" refers to the average diameter of the openings on the side (outer surface side) coated with the antithrombotic polymer compound. The pore diameter of the hollow fiber membrane is measured by the method described below.

[0054] First, the side of the hollow fiber membrane that is coated with the antithrombogenic polymer compound (outer surface) is photographed using a scanning electron microscope (SEM). Next, the obtained SEM image is processed to invert the pores (openings) to white and the rest to black, and the number of pixels in the white area is counted. The binarization boundary level is the midpoint between the difference between the whitest and darkest areas.

[0055] Next, the number of pixels of the pores (openings) displayed in white is measured. The pore area is calculated based on the number of pixels of each pore thus obtained and the resolution (μm / pixel) of the SEM image. From the obtained pore area, the diameter of each pore is calculated assuming that the pores are circular. A statistically significant number of diameters, for example, 500 pores, are randomly selected, and the arithmetic average of these diameters is taken as the "pore diameter of the hollow fiber membrane."

[0056] The cylindrical housing 2 can be made of the same materials as those used for housings of known oxygenators. Specific examples include hydrophobic synthetic resins such as polycarbonate, acrylic-styrene copolymer, and acrylic-butylene-styrene copolymer. The shape of the housing 2 is not particularly limited, but it is preferably cylindrical and transparent. By forming the housing from a transparent material, the interior can be easily inspected.

[0057] The number of hollow fiber membranes stored in this embodiment is not particularly limited, and the same number as that used in known oxygenators can be applied. For example, approximately 5,000 to 100,000 porous hollow fiber membranes 3 are stored in parallel in the axial direction of the housing 2. The hollow fiber membranes 3 are fixed in a liquid-tight state by partition walls 4 and 5 at both ends of the housing 2, with both ends of the hollow fiber membranes 3 open. The partition walls 4 and 5 are formed of a potting agent such as polyurethane or silicone rubber. The area within the housing 2 sandwiched between the partition walls 4 and 5 is partitioned into a gas chamber inside the hollow fiber membranes 3 and a blood chamber 12 outside the hollow fiber membranes 3.

[0058] In this embodiment, a gas inlet header 10 having a gas inlet 8 and a gas outlet header 11 having a gas outlet 9 are attached liquid-tight to the housing 2. These headers may also be formed of any material, for example, the hydrophobic synthetic resin used for the housings described above. The headers may be attached to the housing 2 by any method, for example, by fusion bonding using ultrasound, high frequency, or induction heating, bonding with an adhesive, or mechanical fitting. A clamping ring (not shown) may also be used. It is preferable that all of the blood-contacting parts of the hollow fiber membrane oxygenator 1 (the inner surface of the housing 2 and the outer surface of the hollow fiber membranes 3) be formed of a hydrophobic material.

[0059] In this embodiment, the coating (membrane) of the antithrombogenic polymer compound is selectively formed on the outer surface (external perfusion type) of the hollow fiber membrane. Therefore, blood (particularly plasma components) is unlikely to penetrate into the pores of the hollow fiber membrane, or does not penetrate at all. This effectively suppresses or prevents leakage of blood (particularly plasma components) from the hollow fiber membrane. In particular, when the antithrombogenic polymer compound is substantially absent from the inner layer 3b of the hollow fiber membrane and the inner surface layer 3c of the hollow fiber membrane, the inner layer 3b of the hollow fiber membrane and the inner surface layer 3c of the hollow fiber membrane maintain the hydrophobic state of the material, thereby more effectively suppressing or preventing leakage of blood (particularly plasma components). Therefore, the oxygenator obtained by the method of the present invention can maintain a high gas exchange capacity for a long period of time.

[0060] The coating of the antithrombogenic polymer compound according to the present embodiment is necessarily formed on the outer surface of the hollow fiber membrane of the oxygenator, but may also be formed on other components (e.g., the entire blood-contacting portion) in addition to the outer surface. This configuration can more effectively suppress or prevent platelet adhesion / adhesion and activation throughout the entire blood-contacting portion of the oxygenator. Furthermore, the contact angle of the blood-contacting surface is reduced, facilitating the priming process. In this case, the coating of the antithrombogenic polymer compound according to the present invention is preferably formed on other components that come into contact with blood, but the hollow fiber membrane other than the blood-contacting portion or other portions of the hollow fiber membrane (e.g., portions embedded in the septum) may not be coated with the antithrombogenic polymer compound. Since these portions do not come into contact with blood, there is no particular problem if they are not coated with the antithrombogenic polymer compound.

[0061] The oxygenator obtained by the method of the present invention may be of the type shown in Fig. 3. Fig. 3 is a cross-sectional view showing another embodiment of the oxygenator obtained by the method of the present invention. Fig. 4 is a cross-sectional view taken along line AA in Fig. 3.

[0062] In Figure 3, an oxygenator (hollow fiber membrane external hemoperfusion type oxygenator) 20 comprises an inner tubular member 31 having a blood flow opening 32 on its side, a tubular hollow fiber membrane bundle 22 consisting of a number of gas exchange porous hollow fiber membranes 3 wrapped around the outer surface of the inner tubular member 31, a housing 23 that houses the tubular hollow fiber membrane bundle 22 together with the inner tubular member 31, partitions 25 and 26 that secure both ends of the tubular hollow fiber membrane bundle 22 to the housing with both ends of the hollow fiber membranes 3 open, a blood inlet 28 and blood outlets 29a and 29b that communicate with a blood chamber 17 formed in the housing 23, and a gas inlet 24 and gas outlet 27 that communicate with the interior of the hollow fiber membranes 3.

[0063] As shown in Figures 3 and 4, in the oxygenator 20 of this embodiment, the housing 23 includes an outer cylindrical member 33 that houses an inner cylindrical member 31, and the cylindrical hollow fiber membrane bundle 22 is housed between the inner cylindrical member 31 and the outer cylindrical member 33. Furthermore, the housing 23 includes one of a blood inlet and a blood outlet that communicates with the interior of the inner cylindrical member, and the other of a blood inlet and a blood outlet that communicates with the interior of the outer cylindrical member.

[0064] Specifically, in the oxygenator 20 of this embodiment, the housing 23 is housed within the outer cylindrical member 33 and the inner cylindrical member 31 and includes an inner cylindrical body 35 whose tip opens within the inner cylindrical member 31. A blood inlet 28 is formed at one end (lower end) of the inner cylindrical body 35, and two blood outlets 29a, 29b extending outward are formed on the side surface of the outer cylindrical member 33. The number of blood outlets may be one or more.

[0065] The tubular hollow fiber membrane bundle 22 is wound around the outer surface of the inner tubular member 31. In other words, the inner tubular member 31 serves as the core of the tubular hollow fiber membrane bundle 22. The inner cylindrical body 35 housed inside the inner tubular member 31 has an opening at its tip near the first partition wall 25. A blood inlet 28 is formed at the lower end protruding from the inner tubular member 31.

[0066] The inner cylindrical body 35, the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound, and the outer cylindrical member 33 are arranged approximately concentrically. The concentric positional relationship between one end (upper end) of the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound and one end (upper end) of the outer cylindrical member 33 is maintained by the first partition wall 25, and the space formed inside the inner cylindrical member and between the outer cylindrical member 33 and the outer surface of the hollow fiber membranes is liquid-tight and does not communicate with the outside.

[0067] Furthermore, the concentric positional relationship between the part of the inner cylindrical body 35 slightly above the blood inlet 28, the other end (lower end) of the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound, and the other end (lower end) of the outer cylindrical member 33 is maintained by the second partition wall 26, and the space formed between the inner cylindrical body 35 and the inner cylindrical member 31 and the space formed between the outer cylindrical member 33 and the outer surface of the hollow fiber membranes are liquid-tight and do not communicate with the outside. Furthermore, the partition walls 25, 26 are formed from a potting agent such as polyurethane or silicone rubber.

[0068] Therefore, the artificial lung 20 of this embodiment is provided with a blood inlet 17a formed by the interior of the inner cylindrical body 35, a first blood chamber 17b which is essentially a cylindrical space formed between the inner cylindrical body 35 and the inner cylindrical member 31, and a second blood chamber 17c which is essentially a cylindrical space formed between the hollow fiber membrane bundle 22 and the outer cylindrical member 33, and these form the blood chamber 17.

[0069] Then, blood flowing in through blood inlet 28 flows into blood inlet 17a, rises inside inner cylindrical body 35 (blood inlet 17a), flows out from upper end 35a (open end) of inner cylindrical body 35, flows into first blood chamber 17b, passes through opening 32 formed in inner cylindrical member 31, comes into contact with the hollow fiber membrane, undergoes gas exchange, then flows into second blood chamber 17c, and flows out from blood outlets 29a, 29b.

[0070] A gas inflow member 41 having a gas inflow port 24 is fixed to one end of the outer cylindrical member 33, and a gas outflow member 42 having a gas outflow port 27 is fixed to the other end of the outer cylindrical member 33. The blood inflow port 28 of the inner cylindrical body 35 passes through the gas outflow member 42 and protrudes to the outside.

[0071] The outer cylindrical member 33 is not particularly limited, but may be a cylinder, a polygonal cylinder, or one with an elliptical cross section. A cylinder is preferred. The inner diameter of the outer cylindrical member is not particularly limited and may be the same as the inner diameter of outer cylindrical members used in known oxygenators, with a preferred range of approximately 32 to 164 mm. The effective length of the outer cylindrical member (the length of the portion of the total length not buried in the bulkhead) is also not particularly limited, and may be the same as the effective length of outer cylindrical members used in known oxygenators, with a preferred range of approximately 10 to 730 mm.

[0072] The shape of the inner cylindrical member 31 is not particularly limited, but may be, for example, a cylinder, a polygonal tube, or one with an elliptical cross section. A cylinder is preferred. The outer diameter of the inner cylindrical member is not particularly limited, and may be the same as the outer diameter of inner cylindrical members used in known oxygenators, with a preferred range of approximately 20 to 100 mm. The effective length of the inner cylindrical member (the length of the portion of the total length that is not buried in the partition wall) is also not particularly limited, and may be the same as the effective length of inner cylindrical members used in known oxygenators, with a preferred range of approximately 10 to 730 mm.

[0073] The inner cylindrical member 31 has a large number of openings 32 for blood circulation on its side surface. The size of the openings 32 is preferably large in total area as long as the required strength of the cylindrical member is maintained. For example, as shown in FIG. 5, which is a front view, FIG. 6, which is a central longitudinal cross-sectional view of FIG. 5, and FIG. 7, which is a cross-sectional view along line B-B of FIG. 5, a preferred configuration is one in which a plurality of annularly arranged openings (e.g., 4 to 24 openings, e.g., 8 openings in the longitudinal direction in the figure) are arranged at equal angular intervals on the outer peripheral surface of the cylindrical member, with multiple sets of openings arranged at equal intervals in the axial direction of the cylindrical member (e.g., 8 sets per circumference in the figure). Furthermore, the opening shapes may be round, polygonal, elliptical, etc., but an oval shape as shown in FIG. 5 is preferred.

[0074] The shape of the inner cylindrical body 35 is not particularly limited, but may be, for example, a cylinder, a polygonal cylinder, or one with an elliptical cross section. A cylinder is preferred. The distance between the distal end opening of the inner cylindrical body 35 and the first partition wall 25 is not particularly limited, and may be the same as that used in known oxygenators, with a preferred range being approximately 20 to 50 mm. The inner diameter of the inner cylindrical body 35 is also not particularly limited, and may be the same as that used in known oxygenators, with a preferred range being approximately 10 to 30 mm.

[0075] The thickness of the tubular hollow fiber membrane bundle 22 is not particularly limited and can be the same as that of tubular hollow fiber membrane bundles used in known oxygenators, but is preferably 5 to 35 mm, and more preferably 10 to 28 mm. The filling rate of the hollow fiber membranes in the tubular space formed between the outer and inner surfaces of the tubular hollow fiber membrane bundle 22 is also not particularly limited and can be the same as that of known oxygenators, but is preferably 40 to 85%, and more preferably 45 to 80%. The outer diameter of the hollow fiber membrane bundle 22 can be the same as that of hollow fiber membrane bundles used in known oxygenators, but is preferably 30 to 170 mm, and more preferably 70 to 130 mm. The gas exchange membranes used are those described above.

[0076] The hollow fiber membrane bundle 22 can be formed by winding hollow fiber membranes around the inner tubular member 31, specifically by forming a hollow fiber membrane bobbin using the inner tubular member 31 as a core, fixing both ends of the formed hollow fiber membrane bobbin with partition walls, and then cutting both ends of the hollow fiber membrane bobbin together with the inner tubular member 31 as the core. Note that this cutting leaves openings in the hollow fiber membranes on the outer surfaces of the partition walls. Note that the method for forming hollow fiber membranes is not limited to the above method, and other known methods for forming hollow fiber membranes may be used in the same manner or with appropriate modifications.

[0077] In particular, it is preferable that one or more hollow fiber membranes are wound around the inner tubular member 31 at the same time so that they are substantially parallel and adjacent hollow fiber membranes are spaced at substantially constant intervals. This more effectively suppresses uneven blood flow. Furthermore, the distance between adjacent hollow fiber membranes is preferably 1 / 10 to 1 / 1 of the outer diameter of the hollow fiber membrane, although this is not limited thereto. Furthermore, the distance between adjacent hollow fiber membranes is preferably 30 to 200 μm.

[0078] Furthermore, the hollow fiber membrane bundle 22 is preferably formed by winding one or more (preferably 2 to 16) hollow fiber membranes simultaneously around the inner tubular member 31 so that all adjacent hollow fiber membranes are spaced at substantially constant intervals, and is preferably formed by winding the hollow fiber membranes around the inner tubular member 31 by moving a rotor for rotating the inner tubular member 31 and a winder for weaving the hollow fiber membranes under the conditions of the following formula (1).

[0079]

number

[0080] By satisfying the above conditions, the formation of a blood drift can be reduced. In this case, n, which is the relationship between the rotation speed of the winding rotor and the number of reciprocating movements of the winder, is not particularly limited, but is usually 1 to 5, and preferably 2 to 4.

[0081] Also in the hollow fiber membrane oxygenator 20, as shown in Fig. 2, a coating layer 16 containing a silicone compound or the like is formed on the inner surface 3c' of the hollow fiber membrane 3, through which the oxygen-containing gas flows. Also, a coating 18 containing an antithrombotic polymer compound is formed on the outer surface 3a' (or, in some cases, the outer surface 3a' and the outer surface layer 3a) of the hollow fiber membrane 3, which is the blood-contacting portion. Here, the preferred configuration of the hollow fiber membrane (inner diameter, outer diameter, wall thickness, porosity, pore size, etc.) is not particularly limited, and the same configuration as that described in Fig. 1 above can be used.

[0082] In this step, the inner surface of the hollow fiber membrane (or hollow fiber membrane of an oxygenator; the same applies hereinafter) is brought into contact with the coating liquid. The method for bringing the coating liquid into contact with the inner surface of the hollow fiber membrane is not particularly limited as long as it allows the coating liquid to pass through the lumen of the hollow fiber membrane. From the viewpoint of ease of passing the coating liquid through the lumen of the hollow fiber membrane, it is preferable to bring the inner surface of the hollow fiber membrane into contact with the coating liquid (pass the coating liquid through the lumen of the hollow fiber membrane) under a negative pressure of 50 hPa or more and 150 hPa or less. Note that this step may include other operations as necessary.

[0083] When the coating liquid is passed through the inner surface of the hollow fiber membrane, the lumen of the hollow fiber membrane is placed under a negative pressure of 50 hPa to 150 hPa, preferably 50 hPa to 100 hPa. The method for creating a negative pressure is not particularly limited. For example, a vacuum pump (e.g., a diaphragm pump) can be airtightly connected to one end of the hollow fiber membrane, and the vacuum pump can be operated to create a negative pressure. As described in the examples below, the atmospheric pressure is determined by the indicated pressure of the vacuum pump.

[0084] In this way, the coating liquid is passed through the inner surface of the hollow fiber membrane while the lumen of the hollow fiber membrane is under a predetermined negative pressure (the inner surface of the hollow fiber membrane is brought into contact with the coating liquid). The method for passing the coating liquid (the method for contacting the coating liquid) is not particularly limited, but examples include a method in which the coating liquid is poured into the other end of the hollow fiber membrane (the end not connected to the vacuum pump) while the hollow fiber membrane is connected to a vacuum pump. In this method, the coating liquid moves toward the end connected to the vacuum pump, thereby coming into contact with the inner surface of the hollow fiber membrane. The time for passing the coating liquid (the contact time between the inner surface of the hollow fiber membrane and the coating liquid) is not particularly limited, but is preferably 5 to 180 seconds, more preferably 15 to 120 seconds, and even more preferably 30 to 60 seconds.

[0085] The amount of coating solution brought into contact with the lumen of the hollow fiber membrane (the amount of coating solution passing through) is 10 to 10,000 mL / m per membrane area in order to form a coating layer of the desired thickness. 2 is preferably 30 to 1000 mL / m2 More preferably, it is 40 to 200 mL / m 2 It is more preferable that:

[0086] Thereafter, if necessary, the organic solvent contained in the coating film is dried. The drying method is not particularly limited, but examples thereof include vacuum drying and high-temperature drying at normal pressure. The drying temperature in high-temperature drying is preferably 45 to 80°C. The drying time in high-temperature drying is preferably 1 to 48 hours. The drying device used in this step may be a commonly used device, such as an oven or a hot-air dryer. A combination of these drying devices may also be used.

[0087] The thickness of the coating layer after drying is not particularly limited, but is preferably 0.1 to 10 μm, more preferably 0.5 to 7 μm, and even more preferably 1 to 5 μm. When the coating layer thickness is 0.1 μm or more, sufficient resistance to plasma leakage can be obtained. When the coating layer thickness is 10 μm or less, a decrease in gas exchange performance can be prevented.

[0088] The liquid passing operation (contacting the inner surface of the hollow fiber membrane with the coating liquid, preferably contacting the inner surface of the hollow fiber membrane with the coating liquid under a negative pressure of 50 hPa to 150 hPa) may be performed once or multiple times. As mentioned above, when the concentration of the silicone compound in the coating liquid is low, a coating layer of sufficient thickness can be formed by performing this operation multiple times. When this operation is performed multiple times, it is preferable to repeat this cycle multiple times, with one cycle consisting of this operation followed by drying the organic solvent. Note that when the above operation is performed multiple times, the number of times is not particularly limited, but is preferably 2 to 5 times, more preferably 2 to 4 times, and even more preferably 2 or 3 times.

[0089] [Step (iii)] In step (iii), the state of coating with the silicone compound / crosslinked product is evaluated by observing the dyeing state of the hollow fiber membrane end face 1 on the side where the coating liquid starts to pass and the hollow fiber membrane end face 2 on the side where the coating liquid ends to pass, on which a coating layer has been formed in step (ii) above.

[0090] In the above step (ii), a coating liquid containing a silicone compound and a dye is passed through the hollow fiber membrane lumen. Both the silicone compound and the dye are uniformly present in the coating liquid. That is, the silicone compound and the dye are present in the hollow fiber membrane lumen after the coating liquid is passed through (i.e., wherever the dye is present, the silicone compound is also present). Therefore, the dyed hollow fiber membrane portion can be considered to correspond to the location where a coating of the silicone compound or the like is formed. Therefore, a hollow fiber membrane in which the entire hollow fiber membrane end surface 2 on the end side of the coating liquid passage is dyed can be determined to have a coating of the silicone compound or the like formed on the entire inner surface of the hollow fiber membrane. Furthermore, because all hollow fiber membranes on the start side of the coating liquid passage come into contact with the coating liquid, the number of hollow fiber membranes in which the hollow fiber membrane end surface 1 on the start side of the coating liquid passage is dyed corresponds to the total number of hollow fiber membranes. The ratio of the number of hollow fiber membranes in which the hollow fiber membrane end surface 2 on the coating liquid passage termination side (preferably the entire cross-section of the hollow fiber membrane at the end surface) is dyed to the total number of hollow fiber membranes (the number of hollow fiber membranes in which the hollow fiber membrane end surface 1 on the coating liquid passage initiation side (preferably the entire cross-section of the hollow fiber membrane at the end surface) is dyed (hereinafter simply referred to as the "dyeing ratio") can be used as an index for evaluating the formation state of the coating layer containing a silicone compound or the like (determining the pass / fail of the product). Here, the dyeing ratio can be appropriately set by the manufacturer (e.g., 90% or more, more than 95%, 99% or more, etc.) depending on the required performance of the oxygenator (hollow fiber membrane). In this process, the ratio of the number of hollow fiber membranes in which the hollow fiber membrane end surface 2 on the coating liquid passage termination side is dyed to the number of hollow fiber membranes in which the hollow fiber membrane end surface 1 on the coating liquid passage initiation side (total number of hollow fiber membranes) can be used as an index. This is because the hollow fiber membrane end face 1 on the side where the coating liquid starts to pass comes into direct contact with the coating liquid, and so substantially the entire hollow fiber membrane is dyed with the dye. On the other hand, the hollow fiber membrane end face 2 on the side where the coating liquid finishes passing is the part where the coating liquid passes completely in the longitudinal direction of the hollow fiber membrane. Therefore, by measuring the hollow fiber membrane with the dyed hollow fiber membrane end face 1 on the side where the coating liquid starts to pass and the dyed hollow fiber membrane end face 2 on the side where the coating liquid finishes passing, the coating state of the coating layer over the entire surface of the hollow fiber membrane lumen can be evaluated.

[0091] The method for counting the number of hollow fiber membranes whose end face 2 on the coating liquid passage end side is dyed is not particularly limited. Specifically, the hollow fiber membrane is cut at a location 0.5 to 3 mm away from the hollow fiber membrane end face 1 on the coating liquid passage start side and the hollow fiber membrane end face 2 on the coating liquid passage end side, and then sliced ​​0.5 to 3 mm wide from the newly exposed end face to prepare hollow fiber membrane sections (samples) on the coating liquid passage start side and the coating liquid passage end side. Next, these hollow fiber membrane sections (samples) are examined under visible light, if necessary, using a microscope, to count the number of stained hollow fiber membranes (preferably hollow fiber membranes whose entire cross section is stained) (the number of stained hollow fiber membranes on the coating liquid passage start side = A; the number of stained hollow fiber membranes on the coating liquid passage end side = B). The number of dyed hollow fiber membranes (B) at the end of the coating liquid passage divided by the number of dyed hollow fiber membranes (A) at the start of the coating liquid passage can be expressed as a percentage (B x 100 / A (%)), and this ratio can be used as an index. Alternatively, the number of dyed hollow fiber membranes (B) at the end of the coating liquid passage divided by the total number of hollow fiber membranes (A') can be expressed as a percentage (B x 100 / A' (%)), and this ratio can be used as an index. Note that the above "B x 100 / A (%)" and "B x 100 / A' (%)" are essentially the same. Alternatively, if the staining agent is a fluorescent dye, after observation under visible light as described above if necessary, the hollow fiber membrane section (sample) is irradiated with light of a predetermined wavelength (e.g., 550 nm green excitation light for rhodamine B) and the number of hollow fiber membranes that emit fluorescence (preferably across the entire cross section of the hollow fiber membrane) is counted (the number of fluorescent hollow fiber membranes at the coating liquid passage start side = X1; the number of fluorescent hollow fiber membranes at the coating liquid passage end side = Y1). The number of fluorescent hollow fiber membranes at the coating liquid passage end side (Y1) divided by the number of fluorescent hollow fiber membranes at the coating liquid passage start side (X1) can be expressed as a percentage (Y1 × 100 / X1 (%)), and this ratio can be used as an index. Alternatively, the number of fluorescent hollow fiber membranes at the coating liquid passage end side (Y1) divided by the total number of hollow fiber membranes (X') can be expressed as a percentage (Y1 × 100 / X' (%)), and this ratio can be used as an index. It should be noted that the above "Y1×100 / X1(%)" and "Y1×100 / X'(%)" are substantially the same.Alternatively, if the dye is a fluorescent dye, fluorescence may be generated as described above if necessary, and the image under the fluorescence may then be binarized. A brightness threshold may be set to obtain a binarized image contrast, and the number of dyed hollow fiber membranes may be counted by measuring the black rings based on the binarized image contrast (number of dyed hollow fiber membranes at the coating liquid passage start side = X2; number of dyed hollow fiber membranes at the coating liquid passage end side = Y2). The number of dyed hollow fiber membranes at the coating liquid passage end side (Y2) divided by the number of dyed hollow fiber membranes at the coating liquid passage start side (X2) may be expressed as a percentage (Y2 × 100 / X2 (%)), and this ratio may be used as an index. Alternatively, the number of dyed hollow fiber membranes at the coating liquid passage end side (Y2) divided by the total number of hollow fiber membranes (X') may be expressed as a percentage (Y2 × 100 / X' (%)), and this ratio may be used as an index. It should be noted that the above "Y2×100 / X2(%)" and "Y2×100 / X'(%)" are substantially the same.

[0092] The above-described method makes it possible to easily evaluate the state of formation of a coating layer containing a silicone compound or the like on the inner surface of a hollow fiber membrane (state of coating with a silicone compound or the like). [Example]

[0093] The effects of the present invention will be explained using the following examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, unless otherwise specified, operations were performed at room temperature (25°C). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[0094] [Examples 1 and 2, Comparative Example 1] (Preparation of hollow fiber membrane) As shown in FIG. 8, a porous hollow fiber membrane 51 made of polypropylene (outer diameter: 170 μm, inner diameter: 112 μm, thickness: 29 μm, pore size: 0.05 μm, porosity: 30% by volume, total number: 300, membrane area: 0.05 m) was used. 2 A liquid inlet 52 was connected to one end of the diaphragm pump 53, and a circuit 50 was assembled.

[0095] (Preparation of coating liquid) Rhodamine B (staining agent) was dissolved in acetone to a concentration of 10 mg / mL to prepare a staining solution (saturated solution).

[0096] Polydimethylsiloxane (vinyl-terminated PDMS, SYLGARD (registered trademark) 184) (silicone compound) was added to n-hexane (surface tension: 18.4 dyn / cm) to give a concentration of 100 mg / mL, and the staining solution prepared above was added to n-hexane to give a concentration of rhodamine B of 0.075 mg / mL, to prepare coating solution (1) (Example 1). Note that the silicone compound and rhodamine B were uniformly dispersed in coating solution (1). Furthermore, polydimethylsiloxane (vinyl-terminated PDMS, SYLGARD (registered trademark) 184 ... to give a concentration of 100 mg / mL. 1 , R 3 , R 4 , R 5 , R 6 and R 8 is a methyl group, and R 2 , R 7 has the structure of the above formula (1) in which is a vinyloxy group (-O-CH=CH2).

[0097] Polydimethylsiloxane (vinyl-terminated PDMS, SYLGARD (registered trademark) 184) (silicone compound) was added to and dissolved in n-hexane (surface tension: 18.4 dyn / cm) to a concentration of 200 mg / mL, and the staining solution prepared above was added to and dissolved in rhodamine B to a concentration of 0.075 mg / mL to prepare coating liquid (2) (Example 2). Note that the silicone compound and rhodamine B were uniformly dispersed in coating liquid (2).

[0098] Polydimethylsiloxane (vinyl-terminated PDMS, SYLGARD (registered trademark) 184) (silicone compound) was added to and dissolved in n-hexane (surface tension: 18.4 dyn / cm) to a concentration of 100 mg / mL to prepare coating liquid (3) (Comparative Example 1). The silicone compound was uniformly dispersed in coating liquid (3).

[0099] (Formation of coating layer) In the circuit 50 of Figure 8, the coating solutions (1) to (3) prepared above were each poured into the liquid inlet 52, and the pressure was reduced so that the indicated pressure of the diaphragm pump 53 became 50 hPa. As a result, the inner cavity of the hollow fiber membrane 51 was brought to a negative pressure of 50 hPa, and each coating solution was passed through the inner cavity for 30 seconds. After passing through, the coating solutions were collected in a trap 55. As a result, the coating solutions (1) to (3) were passed through the inner cavity of the hollow fiber membrane 51 at a rate of 40 mL / m per membrane area. 2 The amount of was applied.

[0100] After the liquid was passed through, the hollow fiber membrane 51 was removed from the circuit and left in an oven at 60°C for 12 hours to dry the solvent remaining in the lumen of the hollow fiber membrane and to cause a crosslinking reaction of the silicone compound, thereby obtaining hollow fiber membranes (1) to (3) having a coating layer with a thickness of 4 μm.

[0101] The resulting hollow fiber membranes (1) to (3) were each cut 1 mm from both end faces, and sliced ​​1 mm from the newly exposed end faces to prepare a section on the coating solution inlet side (inlet sample) and a section on the coating solution outlet side (outlet sample). These samples (inlet sample and outlet sample) were observed under visible light. The results are shown in Figure 9 (visible light). Furthermore, these inlet and outlet samples were irradiated with green excitation light (wavelength: 550 nm) in a darkroom to confirm the presence or absence of fluorescence. The results are shown in Figure 9 (fluorescence). Next, the images obtained under fluorescence were binarized (fluorescence image binarization in Figure 9), and the binarized image contrast was obtained by setting a brightness threshold (binarized image contrast in Figure 9).

[0102] For hollow fiber membranes (1) and (2), the number of black rings was counted based on the binary image contrast of the outlet sample to count the number of hollow fiber membranes whose entire cross section at the coating solution outlet (outlet) was dyed (X1). This number (X1) was divided by the number of hollow fiber membranes whose entire cross section at the coating solution inlet (inlet) was dyed (X0) to determine the percentage of the number of hollow fiber membranes whose entire cross section at the coating solution outlet (X1) was dyed relative to the total number of hollow fiber membranes (X0) constituting the hollow fiber membranes (X1 x 100 / X0 (%); X1 / X0 ratio). As a result, the X1 / X0 ratio of hollow fiber membrane (1) was 100%, and the X1 / X0 ratio of hollow fiber membrane (2) was lower than the X1 / X0 ratio of hollow fiber membrane (1). Furthermore, at the coating liquid inlet portion (inlet portion) of each of the hollow fiber membranes (1) and (2), the entire cross section of all the hollow fiber membranes was stained.

[0103] Rhodamine B and the silicone compound were uniformly dispersed in the coating solutions (1) and (2). Therefore, like rhodamine B, the silicone compound also permeated the entire membrane, right up to the coating solution outlet. Therefore, hollow fiber membranes in which the entire cross section of the coating solution outlet was stained were judged to have a coating of the silicone compound or the like formed throughout the entire lumen of the hollow fiber membrane. From the above discussion, it can be concluded that hollow fiber membrane (1) was stained all the way to the coating solution outlet, and therefore a coating of the silicone compound or the like was formed throughout the entire lumen of the entire hollow fiber membrane (pass). On the other hand, hollow fiber membrane (2) showed no visible dyeing in some hollow fiber membranes, indicating uneven coating (there were hollow fiber membranes in which the coating of the silicone compound or the like was formed only partially within the lumen; failed). Based on these results, the X1 / X0 ratio can be used as an indicator for evaluating the coating condition of the silicone compound or the like (the pass / fail status of the product).

[0104] On the other hand, in the hollow fiber membrane (3) through which the coating liquid (3) containing only a silicone compound was passed, neither end surface of the hollow fiber membrane was visualized under irradiation with green excitation light (a binarized fluorescent image was not obtained), as shown in Figure 9. For this reason, it was impossible or very difficult to determine whether or not a coating of the silicone compound had formed in the hollow fiber membrane lumen (pass / fail).

[0105] From the above results, it is expected that the method of the present invention will be an effective indicator for determining whether a coating of a silicone compound or the like has formed in the lumen of a hollow fiber membrane, and that this indicator will be useful for determining the performance of an artificial lung.

[0106] This application is based on Japanese Patent Application No. 2021-034251, filed on March 4, 2021, the disclosure of which is incorporated by reference in its entirety. [Explanation of symbols]

[0107] 1, 20 Hollow fiber membrane external blood perfusion oxygenator, 2, 23 Housing, 3, 50 Porous hollow fiber membrane for gas exchange, 3a outer layer, 3a' outer surface, 3b inner layer, 3c inner layer, 3c' inner surface, 3D passage (lumen), 3e Opening on the outer surface side, 3f Opening on the inner surface side, 4,5 bulkhead, 6, 17a, 28 blood inlet; 7, 29a, 29b blood outlet; 8,24 gas inlet, 9,27 gas outlet, 10 Gas inlet header, 11 Gas outlet header, 12, 17 blood chamber, 13 gas inlet chamber, 14 gas outflow chamber, 16 coat layers, 17b First blood chamber, 17c Second blood chamber, 18 Coating; 22 tubular hollow fiber membrane bundle, 25 First bulkhead, 26 Second bulkhead, 31 inner tubular member; 32 Blood circulation opening; 33 outer tubular member, 35 inner cylinder, 35a top end; 41 gas inlet member, 42 Gas outlet member, 50 circuits, 52 filling port, 53 Diaphragm pump, 55 Trap.

Claims

1. A coating liquid is prepared by dissolving a silicone compound and a dye in an organic solvent. the coating liquid is passed through the inner surface of the hollow fiber membrane to form a coating layer containing the silicone compound and / or a crosslinked product of the silicone compound and a dye on the inner surface; The state of coating of the silicone compound / crosslinked product is evaluated by observing the dyeing state of the hollow fiber membrane end surface 1 on the side where the coating liquid starts to pass and the dyeing state of the hollow fiber membrane end surface 2 on the side where the coating liquid passes through, on which the coating layer is formed. The method for evaluating the coating state of a silicone compound comprises:

2. 2. The method according to claim 1, wherein the staining agent is selected from rhodamine B, rhodamine 6G, rhodamine 6GP, rhodamine 3GO, rhodamine 123, fluorescein and its derivatives, and polymers having these molecules at at least one of their side chains and ends.

3. 3. The method of claim 1, wherein the organic solvent has a surface tension of less than 70 dyn / cm.

4. 4. The method according to claim 3, wherein the organic solvent is at least one selected from the group consisting of n-hexane, cyclohexane, acetone, butyl alcohol, 1-propanol, isopropanol, chloroform, diethyl ether, aromatic hydrocarbons, and fluorinated solvents.

5. The method according to any one of claims 1 to 4, wherein at least a portion of the hollow fiber membrane is formed of polypropylene or polymethylpentene.

6. The silicone compound is represented by the following formula (1): 【Chemistry 1】 In the above formula (1), R １ ~R ８ each independently represents a reactive group selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, an aromatic hydrocarbon group having from 6 to 30 carbon atoms, an ethylenically unsaturated bond-containing group having from 1 to 6 carbon atoms, an amino group-containing group, a hydroxyl group-containing group, a carboxy group-containing group, a maleimide group-containing group, a thiol group-containing group, and a halogen group; and n is from 1 to 100,000. The method according to any one of claims 1 to 5, wherein

Images