JP6956169B2 - Manufacturing method of artificial lung - Google Patents

Description

The present invention relates to a method for producing an artificial lung. More specifically, the present invention relates to a method for producing a hollow fiber membrane type artificial lung for removing carbon dioxide in blood and adding oxygen to blood in extracorporeal blood circulation, particularly a method for producing a hollow fiber membrane external blood perfusion type artificial lung.

Hollow fiber membrane oxygenation using a porous membrane is generally widely used as an extracorporeal circulatory device and a circulatory assisting artificial heart-lung machine at the time of open heart surgery for heart disease. Membrane-type artificial lungs mainly use a hollow fiber membrane, and exchange blood gas through the hollow fiber membrane. Blood perfusion methods for artificial lungs include an internal perfusion method in which blood is flowed inside the hollow fiber membrane and gas is flowed outside the hollow fiber membrane, and conversely, blood is flowed outside the hollow fiber membrane and gas is flowed through the hollow fiber. There is an external perfusion method that flows inside the membrane.

In the hollow fiber membrane oxygenation, the inner or outer surface of the hollow fiber membrane comes into contact with blood, so the inner or outer surface of the hollow fiber membrane that comes into contact with blood affects the adhesion (adhesion) and activation of platelets. There is a risk of giving. In particular, the extracorporeal perfusion type artificial lung in which the outer surface of the hollow fiber membrane comes into contact with blood causes turbulence in the blood flow, and thus tends to affect the adhesion (adhesion) and activation of the platelet system.

In consideration of such problems, the effect of suppressing / preventing the adhesion and activation of the platelet system of alkoxyalkyl (meth) acrylate is utilized, and conventionally, alkoxyalkyl (meth) acrylate is used as an antithrombotic material and is an extracorporeal membrane oxygenation type. It was used to coat hollow fiber membranes for artificial lungs. For example, in Japanese Patent Application Laid-Open No. 11-114056 (corresponding to US Pat. No. 6,495,101), the outer surface or outer surface layer of the hollow fiber membrane is mainly composed of alkoxyalkyl (meth) acrylate in a mixed solvent of water, methanol and ethanol. It is described that the polymer is coated with a coating solution prepared by dissolving the polymer, and then dried.

As a technique capable of suppressing leakage of plasma components (plasma leak) after blood circulation, International Publication No. 2016/143752 includes a technique of coating a hollow fiber membrane with a colloidal solution of a polymer material having antithrombotic properties. Proposed. According to the technique, by adjusting the average particle size of the colloid so as to be equal to or more than a specific ratio with respect to the diameter of the opening of the hollow fiber membrane, the leakage of plasma components is effective regardless of the perfusion method. An artificial lung that can be suppressed is obtained.

On the other hand, for the purpose of further reducing the burden on the patient, a technique capable of increasing the amount of the antithrombotic polymer material (antithrombotic polymer compound) coated on the hollow fiber membrane in order to improve the antithrombotic property. Is required.

Therefore, the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a means capable of increasing the coating amount of the antithrombotic polymer compound on the hollow fiber membrane.

As a result of diligent research to solve the above problems, the present inventor solves the above problems by further adding a water-soluble cationic polymer to a colloidal solution of an antithrombotic polymer compound. Knowing what he could do, he completed the present invention.

That is, the above object is to have a plurality of gas exchange porous hollow fiber membranes having an outer surface, an inner surface forming an inner cavity, and an opening for communicating the outer surface and the inner surface. A method for producing a lung, which comprises applying a solution containing a colloid of an antithrombotic polymer compound and a water-soluble cationic polymer to either the outer surface or the inner surface. This can be achieved by the method of manufacturing an artificial lung.

FIG. 1 is a cross-sectional view showing an embodiment of an extracorporeal blood perfusion type artificial lung obtained by the production method of the present invention. In FIG. 1, reference numeral 1 is a hollow thread membrane external blood perfusion type artificial lung; reference numeral 2 is a housing; reference numeral 3 is a hollow thread membrane; reference numerals 4 and 5 are partition walls; and reference numeral 6 is blood flow. Inlet; reference numeral 7 is a blood outlet; reference numeral 8 is a gas inlet; reference numeral 9 is a gas outlet; reference numeral 10 is a gas inflow side header; reference numeral 11 is a gas outflow side header; Reference numeral 12 represents a blood chamber; reference numeral 13 represents a gas inflow chamber; and reference numeral 14 represents a gas outflow chamber. FIG. 2 is an enlarged cross-sectional view of a hollow fiber membrane used in an extracorporeal blood perfusion type artificial lung obtained by the manufacturing method of the present invention. In FIG. 2, reference numeral 3 is a hollow fiber membrane; reference numeral 3a is an outer surface layer; reference numeral 3a'is an outer surface; reference numeral 3b is an inner layer; reference numeral 3c is an inner surface layer; reference numeral 3c'is an inner surface layer. , Inner surface; reference numeral 3d represents passage; reference numeral 3e represents opening; reference numeral 18 represents antithrombotic material. FIG. 3 is a cross-sectional view showing another embodiment of the hollow fiber extracorporeal blood perfusion type artificial lung obtained by the production method of the present invention. In FIG. 3, reference numeral 3 is a hollow thread membrane; reference numeral 17 is a blood chamber; reference numeral 17a is a blood inflow portion; reference numeral 17b is a blood chamber; reference numeral 17c is a second blood chamber; reference numeral 17c. Reference numeral 20 is a hollow thread membrane external blood perfusion type artificial lung; reference numeral 22 is a tubular hollow thread membrane bundle; reference numeral 23 is a housing; reference numeral 24 is a gas inlet; reference numerals 25 and 26 are partition walls. Reference numeral 27 is a gas outlet; reference numeral 28 is a blood inlet; reference numerals 29a and 29b are blood outlets; reference numeral 31 is an inner tubular member; reference numeral 32 is a blood flow opening; Reference numeral 33 represents an outer tubular member; reference numeral 35 represents an inner tubular body; reference numeral 35a represents an upper end of the inner tubular body 35; reference numeral 41 represents a gas inflow member. FIG. 4 is a cross-sectional view taken along the line AA of FIG. In FIG. 4, reference numeral 3 is a hollow fiber membrane; reference numeral 17a is a blood inflow portion; reference numeral 17c is a second blood chamber; reference numeral 22 is a tubular hollow fiber membrane bundle; reference numerals 29a and 29b are , Blood outlet; reference numeral 31 represents an inner tubular member; reference numeral 32 represents a blood flow opening; reference numeral 33 represents an outer tubular member; reference numeral 35 represents an inner tubular body. FIG. 5 is a front view showing an example of an inner tubular member used in the hollow fiber extracorporeal blood perfusion type artificial lung obtained by the production method of the present invention. In FIG. 5, reference numeral 31 represents an inner cylindrical member; reference numeral 32 represents a blood circulation opening. FIG. 6 is a central vertical cross-sectional view of the inner cylindrical member shown in FIG. In FIG. 6, reference numeral 31 represents an inner cylindrical member; reference numeral 32 represents a blood circulation opening. FIG. 7 is a cross-sectional view taken along the line BB of FIG. In FIG. 7, reference numeral 31 represents an inner cylindrical member; reference numeral 32 represents a blood circulation opening.

The present invention relates to an artificial lung having a plurality of gas exchange porous hollow fiber membranes having an outer surface, an inner surface forming an inner cavity, and an opening communicating the outer surface and the inner surface. An artificial lung, which comprises applying a solution containing a colloid of an antithrombotic polymer compound and a water-soluble cationic polymer to either the outer surface or the inner surface. Regarding the manufacturing method of. According to the method for producing an artificial lung of the present invention, there is provided a means capable of increasing the amount of the antithrombotic polymer compound coated on the hollow fiber membrane.

In the method for producing an artificial lung according to the present invention, the solution containing colloidal particles of an antithrombotic polymer compound may be further referred to as a water-soluble cationic polymer (also simply referred to as "cationic polymer" in the present specification). Yes) is included. Then, the artificial lung is manufactured by coating (applying) the solution on the outer surface or the inner surface of the hollow fiber membrane. In the artificial lung obtained by this method, the coating amount of the antithrombotic polymer compound is dramatically improved. Here, the mechanism of exerting the above-mentioned action and effect according to the configuration of the present invention is presumed as follows. The present invention is not limited to the following mechanism.

According to the technique of WO 2016/143752, the hollow fiber membrane is coated with a colloidal solution of an antithrombotic polymer compound. At this time, it is presumed that the colloidal particles (particle surface) of the antithrombotic polymer compound contained in the colloidal solution are negatively charged. Here, since the solution (colloidal solution) according to the present invention further contains a cationic polymer, it is considered that the negative charge of the antithrombotic polymer compound and the positive charge of the cationic polymer are attracted to each other. Be done. That is, it is presumed that the cationic polymer is adsorbed on the surface of the colloidal particles. The positive charge of the cationic polymer plays a role of adsorbing the colloidal particles to the surface of the hollow fiber membrane charged with a negative charge.

On the other hand, the cationic polymer adsorbed on the colloidal particles of the antithrombotic polymer compound can also be adsorbed on the colloidal particles of other antithrombotic polymer compounds. Therefore, it is considered that the colloidal particles are likely to aggregate as a result of the form in which a plurality of colloidal particles of the antithrombotic polymer compound are crosslinked.

From the above, when the solution according to the present invention is used, colloidal particles are likely to be adsorbed on the surface of the hollow fiber membrane, and further, other colloidal particles are likely to be aggregated with respect to the colloidal particles adsorbed on the surface of the hollow fiber membrane. , It is presumed that the coating amount of the antithrombotic polymer compound increases. In addition, it is considered that the coating amount is increased by adsorbing the colloidal particles in the colloidal solution in a state of being aggregated on the surface of the hollow fiber membrane. Therefore, the artificial lung produced by the method according to the present invention has excellent antithrombotic properties.

Hereinafter, preferred embodiments of the present invention will be described. The present invention is not limited to the following embodiments. Hereinafter, the hollow fiber extracorporeal blood perfusion type artificial lung will be specifically described as a preferred embodiment, but the artificial lung produced by the method of the present invention may be a hollow fiber membrane internal blood perfusion type artificial lung. Even in this case, it can be applied by appropriately changing the following embodiment. In addition, the dimensional ratios in the drawings are exaggerated for convenience of explanation and may differ from the actual ratios.

In the present specification, "X to Y" indicating a range includes X and Y and means "X or more and Y or less". Unless otherwise specified, the operation and physical properties are measured under the conditions of room temperature (20 to 25 ° C.) / relative humidity of 40 to 50% RH.

[Manufacturing method of artificial lung]
In the method for producing an artificial lung according to the present invention, a solution (colloidal solution) containing a colloid of an antithrombotic polymer compound and a water-soluble cationic polymer is applied to the outer surface or the inner surface of the hollow fiber membrane. do. Hereinafter, a preferred embodiment of the method for producing an artificial lung according to the present invention will be described. The present invention is not limited to the following preferred forms except that the outer surface or inner surface of the hollow fiber membrane is coated with the above solution.

In the method of the present invention, first, a solution (colloidal solution) containing a colloid of an antithrombotic polymer compound and a water-soluble cationic polymer is prepared, and the colloidal solution is applied to the outer surface or the inner surface of the hollow fiber membrane. Apply (coat) to the surface. Then, if necessary, the coating film formed on the outer surface or the inner surface of the hollow fiber membrane may be washed for the purpose of removing the water-soluble cationic polymer. Hereinafter, the steps will be described as (1) a step of preparing the colloidal solution, (2) a step of applying (coating) the colloidal solution, and (3) a washing step.

(1) Preparation step of colloidal solution In this step, a colloidal solution for application to the outer surface or inner surface of the hollow fiber membrane is prepared.

(Preparation of colloidal solution)
As described above, the colloidal solution used in the method according to the present invention contains an antithrombotic polymer compound and a water-soluble cationic polymer. By including the cationic polymer, the colloidal particles of the antithrombotic polymer compound are likely to aggregate, and as a result, the coating amount of the antithrombotic polymer compound can be increased.

The "water-soluble cationic polymer" contained in the colloidal solution according to the present invention means a polymer compound that is water-soluble and has a cationic group in the molecule. Here, "water-soluble" means that the solubility in water (25 ° C.) is 0.1 g / 100 mL or more, and "polymer" means that the weight average molecular weight is 1,000 or more. ..

The water-soluble cationic polymer can be removed by coating the hollow fiber membrane with an antithrombotic polymer compound and then washing with water. Therefore, it is possible to suppress the elution of these cationic polymers into the blood by performing sufficient washing with water during the production of the artificial lung.

The water-soluble cationic polymer according to the present invention is not particularly limited as long as it satisfies the above definition.

The cationic group contained in the cationic polymer represents a group capable of producing a cation in water, and specifically represents a group dissociable to a cation or a group dissociated to a cation. The cationic group is not particularly limited, and is, for example, an amino group (primary, secondary, tertiary amino group), a quaternary ammonium group, an imino group, a guanidino group, an amidino group, a pyridyl group, or Examples thereof include these salts. Among them, the cationic group is preferably an amino group, a quaternary ammonium group, an imino group, a guanidino group or a salt thereof, and particularly preferably an amino group, a guanidino group or a salt thereof. A cationic polymer having these cationic groups easily adsorbs to the antithrombotic polymer compound and easily promotes aggregation of colloidal particles. As a result, the amount of the antithrombotic polymer compound coated can be further increased. The cationic group in the cationic polymer may be one type alone or a combination of two or more types.

The cationic polymer used in the present invention may be either a natural polymer polymer or a synthetic polymer polymer, and these may be mixed and used. Synthetic polymer-based polymers include structural units derived from monomers having cationic groups as all or part of the structural units. The cationic polymer may be either a polymer or a copolymer. The natural polymer-based polymer may be a natural polymer or a modified natural polymer in which a cationic group is introduced.

Specific examples of cationic polymers include polyethyleneimine, polyvinylamine, polyvinylpyridine, polyaminesulfone, polyallylamine, polypyridine, polyamino acid, polyacrylamide, polyamidepolyamine, polyaminoalkylacrylamide, polyepoxyamine, and polydialyldimethylammonium. Halides, polyvinylbenzyltrimethylammonium halides, polydiacrylicdimethylammonium halides, polydimethylaminoethylmethacrylate hydrochlorides, polycationic peptides and proteins (eg, histone polypeptides, and poly-L-lysine, poly-D-lysine, poly- L, D-lysine, poly-L-arginine, poly-D-arginine, poly-D, L-arginine, poly-L-ornithin, poly-D-ornithin, poly-L, including poly-L, D-ornithine, lysine, (Homopolymers and copolymers containing arginine, ornithine, and combinations thereof, etc.), gelatin, albumin, protamine and protamine sulfate, and polycationic polysaccharides such as cationic starch and chitosan, salts of these polysaccharides, and Derivatives can be mentioned.

Among them, the cationic polymer is preferably selected from the group consisting of protamine sulfate, protamine, polyethyleneimine, polyallylamine, poly-L-lysine, albumin and gelatin. These cationic polymers tend to promote colloidal aggregation of the antithrombotic polymer compound and tend to increase the coating amount. Further, the cationic polymer is preferably protamine sulfate or protamine. Since these cationic polymers have good biocompatibility, the washing step can be omitted or the washing step can be simplified after coating the hollow fiber membrane with the antithrombotic polymer compound. .. Therefore, it is also preferable from the viewpoint of productivity. The above-mentioned cationic polymer may be used alone or in combination of two or more.

The weight average molecular weight of the cationic polymer (molecular weight when the cationic polymer is a protein) varies depending on the cationic polymer used, but is preferably 1,000 to 1,000,000. , 2,000 to 100,000, more preferably 3,000 to 10,000. When the weight average molecular weight of the cationic polymer (molecular weight when the cationic polymer is a protein) is 1,000 or more, aggregation of colloidal particles is promoted and the coating amount is likely to increase, which is preferable. Further, when the weight average molecular weight of the cationic polymer (molecular weight when the cationic polymer is a protein) is 1,000,000 or less, the viscosity of the colloidal solution does not become too high, and the coating is applied to the hollow fiber membrane. Is easy and operability is improved.

In the present specification, the “weight average molecular weight” (“molecular weight” for proteins) shall be a value measured by gel permeation chromatography (GPC). Specifically, the polymer to be analyzed is dissolved in an appropriate solvent such as THF to prepare a 10 mg / ml solution. For the polymer solution prepared in this way, a suitable solvent such as THF is flowed as a mobile phase, and polystyrene is used as a standard substance to measure the GPC of the polymer to be analyzed. After preparing a calibration curve with standard polystyrene, the weight average molecular weight (molecular weight) of the polymer to be analyzed is calculated based on this curve.

The solvent used to prepare the solution (colloidal solution) containing the antithrombotic polymer compound and the cationic polymer dissolves the cationic polymer, and the antithrombotic polymer compound is appropriately dispersed to be colloidal. It is preferable to use one that can prepare a solution. The solvent preferably contains water from the viewpoint of more effectively preventing the permeation of the colloidal solution to the outer surface or inner surface (the surface on the side through which the oxygen-containing gas flows) of the pores of the hollow fiber membrane. Here, the water is preferably pure water, ion-exchanged water or distilled water, and more preferably distilled water.

The solvent other than water used for preparing the colloidal solution is not particularly limited, but methanol and acetone are preferable in consideration of ease of control such as dispersibility of the antithrombotic polymer compound. The solvent other than water may be used alone or in the form of a mixture of two or more. Of these, methanol is preferable in consideration of further controllability such as dispersibility of the antithrombotic polymer compound. That is, the solvent is preferably composed of water and methanol. Here, the mixing ratio of water and methanol is not particularly limited, but considering the dispersibility of the antithrombotic polymer compound and the ease of further control of the average particle size of the colloid, the mixing ratio of water: methanol (mass ratio). The ratio) is preferably 6 to 32: 1, more preferably 10 to 25: 1. That is, the solvent is preferably composed of water and methanol in a mixing ratio (mass ratio) of 6 to 32: 1, and is composed of water and methanol in a mixing ratio (mass ratio) of 10 to 25: 1. Is more preferable.

As described above, when preparing a colloidal solution using a mixed solvent of water and a solvent other than water, the order in which the solvent, the antithrombotic polymer compound and the cationic polymer are added is not particularly limited. It is preferable to prepare a colloidal solution by the following procedure. That is, an antithrombotic polymer compound is added to a solvent other than water (preferably methanol) to prepare an antithrombotic polymer compound-containing solution, and subsequently, separately prepared water is added to the water while stirring. On the other hand, it is preferable to add the antithrombotic polymer compound-containing solution and further prepare a colloidal solution by a method of adding a cationic polymer. According to such a method, the antithrombotic polymer compound can be easily dispersed. Further, according to the above method, it is possible to form a colloid having a uniform particle size, and there is an advantage that a uniform film can be easily formed.

In the above method, the rate of addition of water to the antithrombotic polymer compound-containing solution is not particularly limited, but it is preferable to add the antithrombotic polymer compound-containing solution to water at a rate of 5 to 100 g / min.

The stirring time and stirring temperature when preparing the colloidal solution are not particularly limited, but from the viewpoint that colloids having a uniform particle size can be easily formed and the colloids can be uniformly dispersed, the antithrombotic polymer compound-containing solution is added to water. After the addition, stirring for 1 to 30 minutes is preferable, and stirring for 5 to 15 minutes is more preferable. The stirring temperature is preferably 10 to 40 ° C, more preferably 20 to 30 ° C.

Further, in the above method, the cationic polymer may be mixed as it is with the solution after adding the antithrombotic polymer-containing solution or the antithrombotic polymer-containing solution to water, but it is previously dissolved in another solvent. It may be mixed in the form of the prepared solution. In the latter case, the other solvent is not particularly limited as long as it can dissolve the cationic polymer, and examples thereof include the same solvent as the solvent used in the above colloidal solution. The other solvent may be the same as or different from the solvent of the colloidal solution, but is preferably the same solvent as the solvent of the colloidal solution from the viewpoint that a uniform solution can be easily prepared. Further, the concentration of the cationic polymer in the other solvent in this case is not particularly limited, but in consideration of ease of mixing and the like, the amount of the cationic polymer added is based on 100 parts by mass of the other solvent. It is preferably 0.01 to 20 parts by mass, more preferably 0.1 to 10 parts by mass, and even more preferably 0.5 to 5 parts by mass.

The concentration of the antithrombotic polymer compound in the colloidal solution is not particularly limited, but is preferably 0.01% by mass or more from the viewpoint of easily increasing the coating amount. Further, from the above viewpoint, the colloidal solution preferably contains the antithrombotic polymer compound at a concentration of 0.05% by mass or more, and particularly preferably at a concentration of 0.1% by mass or more. On the other hand, the upper limit of the concentration of the antithrombotic polymer compound in the colloidal solution is not particularly limited, but is preferably 0.5% by mass or less in consideration of the ease of forming a film, the effect of reducing coating unevenness, and the like. , 0.4% by mass or less is more preferable, and 0.35% by mass or less is particularly preferable. Further, within such a range, a decrease in gas exchange ability due to an excessively thick coating of the antithrombotic polymer compound can be suppressed.

Therefore, the concentration of the antithrombotic polymer compound in the colloidal solution is preferably 0.01 to 0.5% by mass, more preferably 0.05 to 0.4% by mass, and 0.1 to 0% by mass. It is particularly preferable that it is .35% by mass.

The concentration of the cationic polymer in the colloidal solution is not particularly limited, but is preferably 0.001% by mass or more from the viewpoint of promoting the aggregation of colloids and easily increasing the coating amount. The higher the concentration of the cationic polymer, the more the coating amount can be increased. Further, from the above viewpoint, the colloidal solution preferably contains the cationic polymer at a concentration of 0.01% by mass or more, and particularly preferably at a concentration of 0.02% by mass or more. On the other hand, the upper limit of the concentration of the cationic polymer in the colloidal solution is not particularly limited, but is preferably 0.05% by mass or less, preferably 0.04% by mass, in consideration of the ease of removal of the cationic polymer. % Or less is more preferable, and 0.03% by mass or less is particularly preferable. Further, within such a range, a decrease in gas exchange ability due to an excessively thick coating of the antithrombotic polymer compound can be suppressed.

Therefore, the concentration of the cationic polymer in the colloidal solution is preferably 0.001 to 0.05% by mass, more preferably 0.01 to 0.04% by mass, and 0.02 to 0.03. It is particularly preferable to be% by mass.

Further, the mixing ratio of the antithrombotic polymer compound contained in the colloidal solution and the cationic polymer is not particularly limited, but the colloid of the antithrombotic polymer compound is more easily aggregated and the coating amount is effectively applied. From the viewpoint of easy increase, the mixing ratio (mass ratio) of the antithrombotic polymer compound: cationic polymer is preferably 1: 0.01 to 0.10. It is more preferably 09. Further, within such a range, a decrease in gas exchange ability due to an excessively thick coating of the antithrombotic polymer compound can be suppressed.

Further, the mixing ratio of the antithrombotic polymer compound contained in the colloidal solution and the cationic polymer may be in the following range. That is, from the viewpoint that the colloid of the antithrombotic polymer compound is more easily aggregated and the coating amount is easily increased, the mixing ratio (molar ratio) of the antithrombotic polymer compound: cationic polymer is 1. It is preferably 1 to 10 and more preferably 1: 1.3 to 8. Further, within such a range, a decrease in gas exchange ability due to an excessively thick coating of the antithrombotic polymer compound can be suppressed.

Next, the antithrombotic polymer compound used in the preparation of the colloidal solution according to the present invention will be described.

(Antithrombotic polymer compound and its manufacturing method)
The antithrombotic polymer compound used in the present invention is a compound that imparts antithrombotic properties to an artificial lung by being applied to a hollow fiber membrane. The antithrombotic polymer compound is distinguished from the cationic polymer described above in that it does not have a cationic group.

Here, the weight average molecular weight of the antithrombotic polymer compound is not particularly limited, but is preferably 80,000 or more. In the method for producing an artificial lung according to the present invention, the antithrombotic polymer compound is applied to the outer surface or inner surface of the hollow fiber membrane in the form of a colloidal solution. Therefore, the weight average molecular weight of the antithrombotic polymer compound is preferably less than 800,000 from the viewpoint of facilitating the preparation of a desired colloidal solution. Within the above range, a stable colloidal solution can be prepared by suppressing aggregation or precipitation of the compound in a solution containing an antithrombotic polymer compound. Further, the weight average molecular weight of the antithrombotic polymer compound is preferably more than 200,000 and less than 800,000, more preferably 210,000 to 600,000, and 220,000 to 500,000. It is even more preferable to have it, and it is particularly preferable to have it in the range of 230,000 to 450,000.

By increasing the molecular weight of the antithrombotic polymer compound, the content of the polymer having a relatively small molecular weight contained in the coating (coating) can be reduced, and as a result, the polymer having a relatively small molecular weight becomes blood. It is presumed that the effect of suppressing / preventing elution into the inside can also be obtained. Therefore, when the weight average molecular weight of the antithrombotic polymer compound is included in the above range, the elution of the coating (particularly the low molecular weight polymer) into the blood can be more effectively suppressed / prevented. It is also preferable from the viewpoint of antithrombotic property and biocompatibility. Further, in the present specification, the “low molecular weight polymer” means a polymer having a weight average molecular weight of less than 60,000. The method for measuring the weight average molecular weight is as described above.

The antithrombotic polymer compound can be used without particular limitation as long as it has antithrombotic properties and biocompatibility. Among them, the antithrombotic polymer compound has the following formula (I): from the viewpoint of being excellent in the above characteristics.

However, R ³ represents a hydrogen atom or a methyl group, R ¹ represents an alkylene group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms. It is preferable to have a structural unit derived from meta) acrylate. The compound having the structural unit represented by the above formula (I) has antithrombotic biocompatibility (effect of suppressing / preventing adhesion / adhesion of platelets and effect of suppressing / preventing activation of platelets), particularly adhesion of platelets. / Excellent effect of suppressing / preventing adhesion. Therefore, by using the compound having the above-mentioned structural unit, antithrombotic biocompatibility (effect of suppressing / preventing adhesion / adhesion of platelets and effect of suppressing / preventing activation of platelets), particularly adhesion / adhesion of platelets It is possible to manufacture an artificial lung having an excellent inhibitory / preventive effect.

In addition, in this specification, "(meth) acrylate" means "acrylate and / or methacrylate". That is, "alkoxyalkyl (meth) acrylate" includes all cases of alkoxyalkyl acrylate only, alkoxyalkyl methacrylate only, and alkoxyalkyl acrylate and alkoxyalkyl methacrylate.

In the above formula (I), R ¹ represents an alkylene group having 1 to 4 carbon atoms. Here, the alkylene group having 1 to 4 carbon atoms is not particularly limited, and includes a linear or branched alkylene group of methylene group, ethylene group, trimethylene group, tetramethylene group and propylene group. Of these, an ethylene group and a propylene group are preferable, and an ethylene group is particularly preferable in consideration of further improving the antithrombotic property and biocompatibility. R ² represents an alkyl group having 1 to 4 carbon atoms. Here, the alkyl group having 1 to 4 carbon atoms is not particularly limited, and may be a linear group of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. There is an alkyl group of the branched chain. Of these, a methyl group and an ethyl group are preferable, and a methyl group is particularly preferable in consideration of further improving the antithrombotic property and biocompatibility. R ³ represents a hydrogen atom or a methyl group. When the antithrombotic polymer compound according to the present invention has two or more kinds of alkoxyalkyl (meth) acrylate-derived structural units, each structural unit may be the same or different. good.

Specific examples of the alkoxyalkyl (meth) acrylate include methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, and butoxyethyl acrylate. Examples thereof include methoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate and the like. Of these, methoxyethyl (meth) acrylate and methoxybutyl acrylate are preferable, and methoxyethyl acrylate (MEA) is particularly preferable, from the viewpoint of further improving the antithrombotic property and biocompatibility. That is, it is preferable that the antithrombotic polymer compound according to the present invention is polymethoxyethyl acrylate (PMEA). The above-mentioned alkoxyalkyl (meth) acrylate may be used alone or in combination of two or more.

In particular, when the antithrombotic polymer compound is polymethoxyethyl acrylate (PMEA), its weight average molecular weight is not particularly limited, but is preferably 80,000 or more. On the other hand, the weight average molecular weight of PMEA is preferably less than 800,000 from the viewpoint that a desired colloidal solution can be easily prepared. Within the above range, it is possible to prevent the compound from agglutinating or precipitating in a solution containing PMEA, and to prepare a stable colloidal solution. Further, the weight average molecular weight of PMEA is preferably more than 200,000 and less than 800,000, more preferably 210,000 to 600,000, and even more preferably 220,000 to 500,000. , 230,000 to 450,000 is particularly preferable.

The antithrombotic polymer compound according to the present invention preferably has a structural unit derived from alkoxyalkyl (meth) acrylate, and is composed of one or more structural units derived from alkoxyalkyl (meth) acrylate. One or more kinds of structural units derived from one or more kinds of alkoxyalkyl (meth) acrylates and one or more kinds which can be copolymerized with the alkoxyalkyl (meth) acrylate even if it is a polymer (monopolymer). It may be a polymer (copolymer) composed of a monomer-derived structural unit (another structural unit). When the antithrombotic polymer compound according to the present invention is composed of two or more kinds of structural units, the structure of the polymer (copolymer) is not particularly limited, and a random copolymer or an alternating copolymer is used. It may be a coalescence, a periodic copolymer, or a block copolymer. The end of the polymer is not particularly limited and is appropriately defined depending on the type of raw material used, but is usually a hydrogen atom.

Here, a monomer copolymerizable with the alkoxyalkyl (meth) acrylate when the antithrombotic polymer compound according to the present invention has another structural unit in addition to the structural unit derived from the alkoxyalkyl (meth) acrylate. The (copolymerizable monomer) is not particularly limited. For example, methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, 2-ethylhexyl methacrylate, hexyl acrylate, hexyl methacrylate, ethylene, propylene, acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, diaminoethyl acrylate, diaminobutyl acrylate, metaacrylamide, N, N-dimethylmethacrylate, N, N − Diethylmethacrylate, aminomethylmethacrylate, aminoethylmethacrylate, diaminomethylmethacrylate, diaminoethylmethacrylate and the like. Of these, the copolymerizable monomer preferably has no hydroxyl group or cationic group in the molecule. The copolymer may be a random copolymer, a block copolymer, or a graft copolymer, and can be synthesized by a known method such as radical polymerization, ionic polymerization, or polymerization using a macromonomer. Here, the ratio of the constituent units derived from the copolymerizable monomer to all the constituent units of the copolymer is not particularly limited, but the copolymerizable monomer is considered in consideration of antithrombotic property, biocompatibility and the like. It is preferable that the structural unit (other structural unit) derived from the above is more than 0 mol% and 50 mol% or less of all the structural units of the copolymer. If it exceeds 50 mol%, the effect of the alkoxyalkyl (meth) acrylate may be reduced.

Further, the antithrombotic polymer compound containing a structural unit derived from the alkoxyalkyl (meth) acrylate represented by the above formula (I) can be produced by a known method. Specifically, the following formula (II):

One or more of the alkoxyalkyl (meth) acrylate represented by (1) and a monomer (copolymerizable monomer) capable of copolymerizing with the above alkoxyalkyl (meth) acrylate added as needed. A monomer solution is prepared by stirring with a polymerization initiator in a polymerization solvent, and the monomer solution is heated to obtain an alkoxyalkyl (meth) acrylate or an alkoxyalkyl (meth) acrylate and, if necessary, an alkoxyalkyl (meth) acrylate. A method of (co) polymerizing the added copolymerizable monomer is preferably used. In the above formula (II), the substituents R ¹ , R ² and R ³ are the same as the definition of the above formula (I), and thus the description thereof will be omitted here.

The polymerization solvent that can be used in the preparation of the monomer solution is particularly one that can dissolve the alkoxyalkyl (meth) acrylate of the above formula (II) used and the copolymerizable monomer added as needed. Not limited. For example, water, alcohols such as methanol, ethanol, propanol and isopropanol, aqueous solvents such as polyethylene glycol; aromatic solvents such as toluene, xylene and tetraline; and halogens such as chloroform, dichloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene. Examples include system solvents. Of these, methanol is preferable in consideration of the ease of dissolving the alkoxyalkyl (meth) acrylate and the ease of obtaining a polymer having a weight average molecular weight as described above.

The monomer concentration in the monomer solution is not particularly limited, but the weight average molecular weight of the obtained antithrombotic polymer compound can be increased by setting the concentration to be relatively high. Therefore, considering the ease of obtaining a polymer having a weight average molecular weight as described above, the monomer concentration in the monomer solution is preferably less than 50% by mass, more preferably 15% by mass. It is more than 50% by mass. Further, the monomer concentration in the monomer solution is more preferably 20% by mass or more and 48% by mass or less, and particularly preferably 25% by mass or more and 45% by mass or less. The monomer concentration means the total concentration of these monomers when two or more kinds of monomers are used.

The polymerization initiator is not particularly limited, and known ones may be used. It is preferably a radical polymerization initiator in that it is excellent in polymerization stability, and specifically, persulfate such as potassium persulfate (KPS), sodium persulfate, ammonium persulfate; hydrogen peroxide, t-butylper. Azobisisobutyronitrile (AIBN), 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis (2,) 4-Dimethylvaleronitrile), 2,2'-azobis [2- (2-imidazolin-2-yl) propane] dihydrochloride, 2,2'-azobis [2- (2-imidazolin-2-yl) propane] Disulfate dihydrate, 2,2'-azobis (2-methylpropion amidine) dihydrochloride, 2,2'-azobis [N- (2-carboxyethyl) -2-methylpropion amidine)] hydrate, 3 -Hydroxy-1,1-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, 1,1,3,3-tetrabutylperoxyneodecanoate, t-butylperoxyneodeca Noate, t-butylperoxyneoheptanoate, t-butylperoxypivalate, t-amylperoxyneodecanoate, t-amylperoxypivalate, di (2-ethylhexyl) peroxydicarbonate, Examples thereof include azo compounds such as di (secondary butyl) peroxydicarbonate and azobisisobutyric acid. Further, for example, a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or ascorbic acid may be combined with the radical polymerization initiator to be used as a redox-based initiator. The amount of the polymerization initiator to be blended is 0.0001 to 1 mol with respect to the total amount of the monomers (alkoxyalkyl (meth) acrylate and copolymerizable monomer added as needed; the same applies hereinafter). % Is preferable, 0.001 to 0.8 mol% is more preferable, and 0.01 to 0.5 mol% is particularly preferable. Alternatively, the blending amount of the polymerization initiator is preferably 0.005 to 2 parts by mass with respect to 100 parts by mass of the monomer (when a plurality of types of monomers are used, the whole thereof), which is more preferable. Is 0.05 to 0.5 parts by mass. With such a compounding amount of the polymerization initiator, a polymer having a desired weight average molecular weight can be produced more efficiently.

The above-mentioned polymerization initiator may be mixed with the monomer and the polymerization solvent as it is, or may be mixed with the monomer and the polymerization solvent as it is in the form of a solution previously dissolved in another solvent. In the latter case, the other solvent is not particularly limited as long as it can dissolve the polymerization initiator, but the same solvent as the above-mentioned polymerization solvent can be exemplified. The other solvent may be the same as or different from the above-mentioned polymerization solvent, but is preferably the same solvent as the above-mentioned polymerization solvent in consideration of ease of control of polymerization and the like. The concentration of the polymerization initiator in the other solvent in this case is not particularly limited, but the amount of the polymerization initiator added is preferably more than 100 parts by mass of the other solvent in consideration of ease of mixing and the like. Is 0.1 to 10 parts by mass, more preferably 0.15 to 5 parts by mass, and even more preferably 0.2 to 1.8 parts by mass.

Next, the monomer solution is heated to (co) polymerize the alkoxyalkyl (meth) acrylate or the alkoxyalkyl (meth) acrylate and other monomers. Here, as the polymerization method, for example, a known polymerization method such as radical polymerization, anionic polymerization, or cationic polymerization can be adopted, and radical polymerization which is easy to produce is preferably used.

The polymerization conditions are not particularly limited as long as the above-mentioned monomers (alkoxyalkyl (meth) acrylate or alkoxyalkyl (meth) acrylate and copolymerizable monomer) can be polymerized. Specifically, the polymerization temperature is preferably 30 to 60 ° C, more preferably 40 to 55 ° C. The polymerization time is preferably 1 to 24 hours, preferably 3 to 12 hours. Under such conditions, a polymer having a high molecular weight as described above can be produced more efficiently. In addition, gelation in the polymerization step can be effectively suppressed / prevented, and high production efficiency can be achieved.

Further, if necessary, a chain transfer agent, a polymerization rate adjusting agent, a surfactant, and other additives may be appropriately used at the time of polymerization.

The atmosphere in which the polymerization reaction is carried out is not particularly limited, and the polymerization reaction can be carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas. Further, the reaction solution may be stirred during the polymerization reaction.

The polymer after polymerization can be purified by a general purification method such as a reprecipitation method, a dialysis method, an ultrafiltration method, or an extraction method. Among the above, purification by the reprecipitation method is preferable because a (co) polymer suitable for preparing a colloidal solution can be obtained. At this time, it is preferable to use ethanol as the poor solvent used for reprecipitation.

The purified polymer can be dried by any method such as freeze-drying, vacuum-drying, spray-drying, or heat-drying, but from the viewpoint of having a small effect on the physical properties of the polymer, it is freeze-dried or vacuum-dried. Is preferable.

(2) Coating (coating) step of the colloidal solution Next, the colloidal solution prepared as described above is coated (coated) on the outer surface or the inner surface of the hollow fiber membrane. Specifically, after assembling an artificial lung (for example, one having a structure as shown in FIG. 1 or FIG. 3 described later), the colloidal solution prepared in the above step (1) is brought into contact with (or circulated). The outer or inner surface of the hollow fiber membrane (ie, the blood contact area) is coated with an antithrombotic polymer compound. Further, the application of the colloidal solution to the hollow fiber membrane may be performed before assembling the artificial lung.

In the present invention, the outer surface or inner surface of the hollow fiber membrane is brought into contact with the colloidal solution (the colloidal solution is circulated to the blood flow side of the artificial lung), and the outer surface or inner surface of the hollow fiber membrane is highly antithrombotic. A coating film of a molecular compound is formed. Here, the amount of the colloidal solution applied to the outer surface or the inner surface of the hollow fiber membrane is not particularly limited.

A preferred embodiment of the artificial lung produced by the method according to the present invention is an extracorporeal membrane oxygenation in which the outer surface of the hollow fiber membrane is coated with an antithrombotic polymer compound. Therefore, in this step, in order to produce an artificial lung having the above configuration, it is preferable to apply a colloidal solution to the outer surface of the hollow fiber membrane. That is, in the production method according to the present invention, the hollow fiber membrane has the inner surface forming the lumen through which the oxygen-containing gas flows and the outer surface in contact with blood, and the outer surface has the outer surface. The method of applying the colloidal solution is preferable.

The coating method of the antithrombotic polymer compound is not particularly limited, but filling, dip coating (immersion method), spraying, spin coating, dripping, blade coating, brush coating, roll coating, air knife coating, curtain coating, etc. Conventionally known methods such as wire bar coating, gravure coating, and mixed solution impregnated sponge coating can be applied. Of these, filling and dip coating (immersion method) are preferable in order to increase the coating amount of the antithrombotic polymer compound.

Further, the conditions for forming the coating film of the antithrombotic polymer compound are not particularly limited. For example, the contact time between the colloidal solution and the hollow fiber membrane (the circulation time of the colloidal solution to the blood circulation side of the artificial lung) is determined by considering the coating amount, the ease of forming a coating film, the effect of reducing coating unevenness, and the like. 1 to 5 minutes is preferable, and 1 to 3 minutes is more preferable. In addition, the contact temperature between the colloidal solution and the hollow fiber membrane (the temperature at which the colloidal solution flows to the blood flow side of the artificial lung) is determined by considering the amount of coating, the ease of forming a coating film, the effect of reducing coating unevenness, and the like. 5 to 40 ° C. is preferable, and 15 to 30 ° C. is more preferable. It is preferable that the colloidal solution is allowed to stand at the time of contact between the colloidal solution and the hollow fiber membrane. By allowing the colloidal solution to stand, a sufficient amount of antithrombotic polymer compound can be coated.

After contact with the colloidal solution, the coating film is dried to form a coating film with the antithrombotic polymer compound according to the present invention on the outer surface or inner surface of the hollow fiber membrane. Here, the drying condition is a condition that the coating (coating) with the antithrombotic polymer compound according to the present invention can be formed on the outer surface (further, the outer surface layer) or the inner surface (further, the inner surface layer) of the hollow fiber membrane. If there is, there is no particular limitation. Specifically, the drying temperature is preferably 5 to 50 ° C, more preferably 15 to 40 ° C. The drying time is preferably 60 to 300 minutes, more preferably 120 to 240 minutes. Alternatively, the coating film may be dried by continuously or stepwise flowing a gas at preferably 5 to 40 ° C., more preferably 15 to 30 ° C. through the hollow fiber membrane. Here, the type of gas is not particularly limited as long as it does not affect the coating film and can dry the coating film. Specific examples thereof include air and an inert gas such as nitrogen gas and argon gas. The amount of gas flowing is not particularly limited as long as the coating film can be sufficiently dried, but is preferably 5 to 150 L, more preferably 30 to 100 L.

(3) Cleaning Step This step is a step of cleaning the coating film made of the antithrombotic polymer compound, and is optionally provided. By cleaning the coating film made of the antithrombotic polymer compound in this step, the cationic polymer present in the coating film can be removed. On the other hand, if the cationic polymer contained in the colloidal solution has high biocompatibility, this step may not be provided.

The cleaning method is not particularly limited, but a method of immersing and extracting a film made of an antithrombotic polymer compound in a cleaning solvent, a method of pouring the cleaning solvent over, or a combination thereof may be used. The cleaning solvent used at this time is not particularly limited as long as it does not dissolve the film made of the antithrombotic polymer compound and can remove impurities containing a cationic polymer, but water or warm water is used. It is preferably used. The temperature of the washing water is not particularly limited, but is preferably 20 ° C to 100 ° C, and more preferably 25 to 80 ° C. The cleaning time (time for bringing the cleaning solvent into contact with the coating film) is not particularly limited, but is preferably 1 to 10 minutes, more preferably 2 to 5 minutes. According to the above conditions, the cationic polymer can be sufficiently removed.

Further, a drying step may be performed after the washing step. The drying method is not particularly limited, and a conventionally known method can be used.

[Artificial lung]
According to the method for producing an artificial lung according to the present invention, a sufficient amount of antithrombotic polymer compound can be coated on the outer surface side or the inner surface side of the hollow fiber membrane. Specifically, in the artificial lung produced by the method of the present invention, the coating amount of the antithrombotic polymer compound on the hollow fiber membrane (membrane area) ^{is preferably 20 mg / m 2} or more, preferably 30 mg / m ^2. The above is more preferable. With such a coating amount, an artificial lung having excellent antithrombotic properties can be obtained. On the other hand, the upper limit of the coating amount is not particularly limited, but ^{is preferably 60 mg / m 2} or less. With such a coating amount, a decrease in gas exchange ability due to an excessively thick coating of the antithrombotic polymer compound is suppressed, and an artificial lung having excellent gas exchange ability can be obtained. As the coating amount, a value measured by the method described in the following Examples is adopted. Further, in the present specification, the "membrane area" of the hollow fiber membrane means the area of the outer surface or the area of the inner surface of the hollow fiber membrane. When the outer surface of the hollow fiber membrane is coated with an antithrombotic polymer compound (that is, when the artificial lung is an extracorporeal blood perfusion type hollow fiber membrane artificial lung), the "membrane area" is the outside of the hollow fiber membrane. The area of the surface, which is calculated from the product of the outer diameter, circumference, number, and effective length of the hollow fiber membrane. On the other hand, when the inner surface of the hollow fiber membrane is coated with an antithrombotic polymer compound (that is, when the artificial lung is an internal perfusion type hollow fiber membrane artificial lung), the "membrane area" means the hollow fiber. The area of the inner surface of the membrane, which is calculated from the product of the inner diameter, circumference, number, and effective length of the hollow fiber membrane.

Further, as described above, the artificial lung produced by the method of the present invention is coated with an antithrombotic polymer material in a sufficient amount, so that the antithrombotic property of the surface side or the inner surface side of the hollow fiber membrane is improved. improves. Therefore, when the artificial lung is incorporated into an extracorporeal circulation circuit and blood is circulated, the platelet count maintenance rate of the circulating blood is improved. Specifically, the platelet count maintenance rate after circulating blood for 30 minutes is preferably more than 70%, more preferably 80% or more, and particularly preferably 90% or more (upper limit: 100%). .. As the platelet count maintenance rate, a value measured by the method described in the following Examples is adopted.

In the artificial lung produced by the method according to the present invention, an antithrombotic polymer compound (polymer) coats the outer surface or the inner surface by applying a colloidal solution to the outer surface or the inner surface of the hollow fiber membrane. Has a configuration. At this time, the cationic polymer contained in the colloidal solution may remain in the coating film made of the antithrombotic polymer compound. In such a case, it is determined that the artificial lung was manufactured by the method according to the present invention. The presence or absence of such a cationic polymer in the coating can be confirmed by any analytical means. For example, it can be confirmed by a method such as Size Exclusion Chromatography (SEC), a method combining SEC and a multi-angle light scattering detector (SEC-MALS), and elemental analysis. Further, even when the cationic polymer does not remain in the coating film made of the antithrombotic polymer compound, even when the coating amount of the antithrombotic polymer compound is within the above coating amount, the present invention is also performed. It is determined that the product was produced by the method according to the invention.

Details of the artificial lung produced by the method of the present invention will be described below with reference to the drawings.

FIG. 1 is a cross-sectional view of an embodiment of an extracorporeal blood perfusion type artificial lung obtained by the production method of the present invention. FIG. 2 is an enlarged cross-sectional view of a porous hollow fiber membrane for gas exchange used in an extracorporeal blood perfusion type artificial lung obtained by the manufacturing method of the present invention. FIG. 3 is a cross-sectional view of another embodiment of the artificial lung obtained by the production method of the present invention.

In FIG. 1, in the artificial lung 1, a large number of porous hollow fiber membranes 3 for gas exchange are housed in a housing 2, blood flows to the outer surface side of the hollow fiber membrane 3, and oxygen-containing gas is contained inside the hollow fiber membrane 3. It is a type of artificial lung that flows through. Then, in FIG. 2, the outer surface (outer surface 3a', or outer surface 3a' and outer surface layer 3a) of the hollow fiber membrane 3 serving as the blood contact portion is coated with the antithrombotic polymer compound 18. The coating (coating) of the antithrombotic polymer compound 18 is selectively formed on the outer surface 3a'of the hollow fiber membrane 3. FIG. 2 shows a form in which a coating (coating) of the antithrombotic polymer compound 18 is formed on the outer surface 3a'of the hollow fiber membrane used for the extracorporeal blood perfusion type artificial lung. In such a hollow fiber membrane, blood comes into contact with the outer surface 3a'side, and oxygen-containing gas flows to the inner surface 3c' side. In the present invention, as described above, the hollow fiber membrane internal blood perfusion type artificial lung may be used. Therefore, the hollow fiber membrane may have a structure opposite to the above-mentioned form, that is, a form in which a coating (coating) of the antithrombotic polymer compound 18 is formed on the inner surface 3c'.

In addition, "the antithrombotic polymer compound covers the outer surface of the hollow fiber membrane" means that the coating (coating) of the antithrombotic polymer compound is the outer surface (the surface on the side where blood flows) of the hollow fiber membrane, or It is intended to be formed on the outer surface and outer layer. On the other hand, "the antithrombotic polymer compound coats the outer surface of the hollow fiber membrane" means that the coating (coating) of the antithrombotic polymer compound is on the outer surface (the surface on the side where blood flows) of the hollow fiber membrane. Intended to be formed. Further, "the antithrombotic polymer compound coats the outer surface layer of the hollow fiber membrane" means that the antithrombotic polymer compound partially penetrates into the outer surface layer (near the outer surface of the pores) of the hollow fiber membrane. It is intended to form a coating (coating). The coating (coating) of the antithrombotic polymer compound may be formed on at least a part of the blood contact portion (outer surface) of the hollow fiber membrane, but has antithrombotic biocompatibility (adhesion / adhesion of platelets). It is preferable that the hollow fiber membrane is formed on the entire blood contact portion (outer surface) of the hollow fiber membrane from the viewpoint of the effect of suppressing / preventing the activation of platelets and the effect of suppressing / preventing the activation of platelets. That is, it is preferable that the antithrombotic polymer compound covers the entire blood contact portion (outer surface) of the artificial lung.

In the embodiment according to FIG. 2, the antithrombotic polymer compound may be present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane 3, but the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane 3 may be present. It is preferably virtually nonexistent. In the present specification, "the antithrombotic polymer compound is substantially not present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane 3" means that the inner surface of the hollow fiber membrane (the side through which the oxygen-containing gas flows). This means that no penetration of the antithrombotic polymer compound is observed in the vicinity of the surface). In the method for producing an artificial lung according to the present invention, a film is formed by applying a colloidal solution of an antithrombotic polymer, so that the antithrombotic polymer compound is applied to the inner layer 3b or the inner layer 3c of the hollow fiber membrane 3. Can be in a form that is virtually nonexistent.

The hollow fiber membrane type artificial lung 1 according to the present embodiment includes a housing 2 having a blood inlet 6 and a blood outlet 7, and a large number of gas exchange porous hollow fiber membranes 3 housed in the housing 2. It has a hollow fiber membrane bundle and a pair of partition walls 4 and 5 that tightly support both ends of the hollow fiber membrane bundle on the housing 2, and between the partition walls 4 and 5 and the inner surface of the housing 2 and the outer surface of the hollow fiber membrane 3. It has a blood chamber 12 formed in, a gas chamber formed inside the hollow fiber membrane 3, and a gas inlet 8 and a gas outlet 9 communicating with the gas chamber.

Specifically, the hollow fiber membrane type artificial lung 1 of the present embodiment includes a tubular housing 2, an aggregate of gas exchange hollow fiber membranes 3 housed in the tubular housing 2, and a hollow fiber membrane 3. It has partition walls 4 and 5 that hold both ends in the housing 2 in a liquid-tight manner, and the inside of the tubular housing 2 is divided into a blood chamber 12 which is a first fluid chamber and a gas chamber which is a second fluid chamber. The tubular housing 2 is provided with a blood inlet 6 and a blood outlet 7 that communicate with the blood chamber 12.

A cap-shaped gas inflow having a gas inflow port 8 which is a second fluid inflow port communicating with a gas chamber which is an internal space of the hollow fiber membrane 3 is provided above the partition wall 4 which is an end portion of the tubular housing 2. The side header 10 is attached. Therefore, the gas inflow chamber 13 is formed by the outer surface of the partition wall 4 and the inner surface of the gas inflow side header 10. The gas inflow chamber 13 communicates with a gas chamber formed by the internal space of the hollow fiber membrane 3.

Similarly, a cap-shaped gas outflow side header 11 provided below the partition wall 5 and having a gas outflow port 9 which is a second fluid outflow port communicating with the internal space of the hollow fiber membrane 3 is attached. Therefore, the gas outflow chamber 14 is formed by the outer surface of the partition wall 5 and the inner surface of the gas outflow side header 11.

The hollow fiber membrane 3 is a porous membrane made of a hydrophobic polymer material, and is the same as a known hollow fiber membrane used for artificial lungs, and is not particularly limited. Since the hollow fiber membrane (particularly the inner surface of the hollow fiber membrane) is made of a hydrophobic polymer material in this way, leakage of plasma components can be suppressed.

Here, the inner diameter of the hollow fiber membrane is not particularly limited, but is preferably 50 to 300 μm. The outer diameter of the hollow fiber membrane is not particularly limited, but is preferably 100 to 400 μm. The wall thickness (thickness) of the hollow fiber membrane is preferably 20 μm to 100 μm, more preferably 25 to 80 μm, still more preferably 25 to 70 μm, and particularly preferably 25 to 60 μm. In the present specification, the "thickness (thickness) of the hollow fiber membrane" means the wall thickness between the inner surface and the outer surface of the hollow fiber membrane, and the formula: [(outside the hollow fiber membrane). Diameter)-(Inner diameter of hollow fiber membrane)] / 2. Here, by setting the lower limit of the wall thickness of the hollow fiber membrane as described above, the strength of the hollow fiber membrane can be sufficiently ensured. In addition, it is satisfactory in terms of manufacturing labor and cost, and is preferable from the viewpoint of mass 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 (that is, the pore diameter of the opening of the hollow fiber) is preferably 10 nm to 5 μm, more preferably 50 nm to 1 μm, and particularly preferably 50 nm to 100 nm.

In the present specification, the “diameter of the opening of the hollow fiber membrane” refers to the opening (in the present specification, the outer surface side in the present embodiment) coated with the antithrombotic polymer compound. Refers to the average diameter of (sometimes referred to simply as "pores"). Further, the average diameter of the opening (sometimes referred to simply as "pore diameter" or "pore diameter" in the present specification) is measured by the method described below.

First, the side of the hollow fiber membrane coated with the antithrombotic polymer compound (in this embodiment, the outer surface) is photographed with a scanning electron microscope (SEM). Next, image processing is performed on the obtained SEM image, the hole portion (opening) is inverted to white, and the other portion is inverted to black, and the number of pixels in the white portion is measured. The boundary level of binarization is an intermediate value between the difference between the whitest part and the blackest part.

Then, the number of pixels of the hole (opening) displayed in white is measured. The hole area is calculated based on the number of pixels of each hole obtained in this way and the resolution (μm / pixel) of the SEM image. From the obtained hole area, the diameter of each hole is calculated by regarding the holes as circular, and a statistically significant number, for example, the diameter of 500 holes is extracted at random, and the arithmetic mean is calculated as ". The diameter of the opening of the hollow thread ”.

Further, as the material used for the porous membrane, the same material as the hollow fiber membrane used for the known artificial lung can be used. Specific examples thereof include polyolefin resins such as polypropylene and polyethylene, and hydrophobic polymer materials such as polysulfone, polyacrylonitrile, polytetrafluoroethylene and cellulose acetate. Of these, polyolefin resins are preferably used, and polypropylene is more preferred. The method for producing the hollow fiber membrane is not particularly limited, and a known method for producing the hollow fiber membrane can be applied in the same manner or appropriately modified. For example, the hollow fiber membrane is preferably formed with micropores formed on the wall by a stretching method or a solid-liquid phase separation method.

As the material constituting the tubular housing 2, the same material as that used for the housing of a known artificial lung can be used. Specific examples thereof 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 is preferably cylindrical and transparent, for example. By forming it with a transparent body, it is possible to easily check the inside.

The amount of the hollow fiber membrane stored in the present embodiment is not particularly limited, and the same amount as that of a known artificial lung can be applied. For example, about 5,000 to 100,000 porous hollow fiber membranes 3 are housed in the housing 2 in parallel in the axial direction thereof. Further, the hollow fiber membrane 3 is fixed in a liquidtight state by the partition walls 4 and 5 with both ends of the hollow fiber membrane 3 open at both ends of the housing 2. The partition walls 4 and 5 are formed of a potting agent such as polyurethane or silicone rubber. The portion of the housing 2 sandwiched between the partition walls 4 and 5 is partitioned into a gas chamber on the inner side of the hollow fiber membrane 3 and a blood chamber 12 on the outer side of the hollow fiber membrane 3.

In the present embodiment, the gas inflow side header 10 having the gas inflow port 8 and the gas outflow side header 11 having the gas outflow port 9 are liquidtightly attached to the housing 2. These headers may also be made of any material, but may be made of, for example, the hydrophobic synthetic resin used in the housings described above. The header may be attached by any method, for example, the header is fused by ultrasonic waves, high frequencies, induction heating, etc., adhered using an adhesive, or mechanically fitted to the housing 2. Attached to. Alternatively, a tightening ring (not shown) may be used. It is preferable that the blood contact portions (inner surface of the housing 2 and outer surface of the hollow fiber membrane 3) of the hollow fiber membrane type artificial lung 1 are all formed of a hydrophobic material.

As shown in FIG. 2, the outer surface 3a'(and in some cases, the outer surface layer 3a; hereinafter, the same applies) of the hollow fiber membrane 3 which is at least the blood contact portion of the hollow fiber membrane type artificial lung 1 is antithrombotic. The thrombotic polymer compound 18 is coated. As described above, it is preferable that the antithrombotic polymer compound is substantially not present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane. Since the antithrombotic polymer compound is substantially absent, the hydrophobic characteristics of the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane of the membrane base material itself are maintained as they are, and the plasma component leaks (leaks). ) Can be effectively prevented. In particular, it is preferable that the antithrombotic polymer compound is substantially not present in both the inner layer 3b and the inner surface layer 3c of the hollow fiber membrane. Further, the hollow fiber membrane 3 is provided with a passage (lumen) 3d forming a gas chamber in the center. In addition, the hollow fiber membrane 3 has an opening 3e that communicates the outer surface 3a'and the inner surface 3c'. The hollow fiber membrane having such a structure is in a form in which blood comes into contact with the outer surface 3a'side coated with the antithrombotic polymer compound 18, while oxygen-containing gas is circulated on the inner surface 3c' side. used. In a preferred embodiment of the present invention, the hollow fiber membrane 3 has an inner surface 3c'that forms a lumen through which oxygen-containing gas flows, and an outer surface 3a' that comes into contact with blood, and the outer surface 3a'is , A form coated with a membrane containing an antithrombotic polymer compound according to the present invention (that is, an external perfusion type).

In the present embodiment, the coating (coating) of the antithrombotic polymer compound is selectively formed on the outer surface (external perfusion type) of the hollow fiber membrane. Therefore, blood (particularly plasma component) does not easily or does not penetrate into the pores of the hollow fiber membrane. Therefore, leakage of blood (particularly plasma component) from the hollow fiber membrane can be effectively suppressed / prevented. In particular, when the antithrombotic polymer compound is substantially absent in 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 may be formed. Since the hydrophobic state of the material is maintained, leakage of blood (particularly plasma component) can be more effectively suppressed and prevented. Therefore, the artificial lung obtained by the method of the present invention can maintain a high gas exchange capacity for a long period of time.

Further, according to the present invention, by using the colloidal solution, a coating (coating) of the antithrombotic polymer compound can be uniformly formed on the outer surface or the inner surface of the hollow fiber membrane. Therefore, there is little adhesion / adhesion and activation of platelets at the blood contact portion of the hollow fiber membrane. Further, it is possible to suppress / prevent the coating from peeling from the hollow fiber membrane.

The coating of the antithrombotic polymer compound according to the present embodiment is essentially formed on the outer surface of the hollow fiber membrane of the artificial lung, but in addition to the outer surface, other constituent members (for example, the entire blood contact portion). May be formed in. By adopting this configuration, it is possible to more effectively suppress / prevent the adhesion / adhesion and activation of platelets in the entire blood contact portion of the artificial lung. Further, since the contact angle of the blood contact surface is lowered, the priming work becomes easy. In this case, the coating of the antithrombotic polymer compound according to the present invention is preferably formed on other constituent members with which blood comes into contact, but the hollow fiber membrane or hollow fiber membrane other than the blood contact portion. The other portion (for example, the portion buried in the partition wall) may not be coated with the antithrombotic polymer compound. Since such a portion does not come into contact with blood, there is no particular problem even if the antithrombotic polymer compound is not coated.

Further, the artificial lung obtained by the method of the present invention may be of the type shown in FIG. FIG. 3 is a cross-sectional view showing another embodiment of the artificial lung obtained by the method of the present invention. Further, FIG. 4 is a cross-sectional view taken along the line AA of FIG.

In FIG. 3, the artificial lung (hollow fiber membrane external blood perfusion type artificial lung) 20 has an inner tubular member 31 having an opening 32 for blood flow on the side surface and a large number of gases wound around the outer surface of the inner tubular member 31. A tubular hollow fiber membrane bundle 22 made of a replacement porous hollow fiber membrane 3, a housing 23 for accommodating the tubular hollow fiber membrane bundle 22 together with an inner tubular member 31, and a state in which both ends of the hollow fiber membrane 3 are opened. , The partition walls 25 and 26 for fixing both ends of the tubular hollow fiber membrane bundle 22 to the housing, the blood inlet 28 and the blood outlets 29a and 29b communicating with the blood chamber 17 formed in the housing 23, and the hollow fiber. It has a gas inflow port 24 and a gas outflow port 27 that communicate with the inside of the membrane 3.

In the artificial lung 20 of the present embodiment, as shown in FIGS. 3 and 4, the housing 23 includes an outer tubular member 33 for accommodating the inner tubular member 31, and the tubular hollow fiber membrane bundle 22 is an inner cylinder. It is housed between the shape member 31 and the outer tubular member 33, and further, the housing 23 has one of a blood inlet or a blood outlet communicating with the inside of the inner tubular member and blood communicating with the inside of the outer tubular member. It has either an inlet or a blood outlet.

Specifically, in the artificial lung 20 of the present embodiment, the housing 23 is housed in the outer tubular member 33 and the inner tubular member 31, and the inner tubular body 35 whose tip is opened in the inner tubular member 31. Be prepared. A blood inlet 28 is formed at one end (lower end) of the inner cylinder 35, and two outwardly extending blood outlets 29a and 29b are formed on the side surface of the outer tubular member 33. The number of blood outlets may be one or a plurality.

The tubular hollow fiber membrane bundle 22 is wound around the outer surface of the inner tubular member 31. That is, the inner cylindrical member 31 is the core of the tubular hollow fiber membrane bundle 22. The tip of the inner cylinder 35 housed inside the inner cylindrical member 31 is open near the first partition wall 25. Further, a blood inflow port 28 is formed at a lower end portion protruding from the inner cylindrical member 31.

The inner cylindrical member 35, the inner tubular member 31 around which the hollow fiber membrane bundle 22 is wound around the outer surface, and the outer tubular member 33 are arranged substantially concentrically. Then, one end (upper end) of the inner tubular member 31 and one end (upper end) of the outer tubular member 33 around which the hollow fiber membrane bundle 22 is wound are concentrically positioned by the first partition wall 25. While being maintained, the space formed between the inside of the inner cylindrical member and the outer surface of the outer tubular member 33 and the outer surface of the hollow fiber membrane is in a liquid-tight state that does not communicate with the outside.

Further, a portion of the inner cylinder 35 slightly above the blood inlet 28, the other end (lower end) of the inner tubular member 31 around which the hollow fiber membrane bundle 22 is wound around the outer surface, and the other end of the outer tubular member 33 (the other end). At the lower end), the second partition wall 26 maintains a concentric positional relationship between the two, and the space formed between the inner cylinder 35 and the inner tubular member 31 and the outer tubular member 33 and the hollow fiber. The space formed between the outer surface of the membrane and the outer surface is in a liquidtight state that does not communicate with the outside. Further, the partition walls 25 and 26 are formed of a potting agent such as polyurethane or silicone rubber.

Therefore, in the artificial lung 20 of the present embodiment, the blood inflow portion 17a formed inside the inner cylinder 35, and the substantially tubular space formed between the inner cylinder 35 and the inner tubular member 31. The first blood chamber 17b is provided, and the second blood chamber 17c which is a substantially tubular space formed between the hollow fiber membrane bundle 22 and the outer tubular member 33 is provided, whereby blood is provided. A chamber 17 is formed.

Then, the blood flowing in from the blood inflow port 28 flows into the blood inflow portion 17a, rises in the inner cylinder 35 (blood inflow portion 17a), and flows out from the upper end 35a (open end) of the inner cylinder 35. , Flows into the first blood chamber 17b, passes through the opening 32 formed in the inner tubular member 31, comes into contact with the hollow fiber membrane, exchanges gas, and then flows into the second blood chamber 17c. Then, it flows out from the blood outlets 29a and 29b.

Further, a gas inflow member 41 having a gas inflow port 24 is fixed to one end of the outer cylindrical member 33, and similarly, a gas having a gas outlet 27 at the other end of the outer tubular member 33. The outflow member 42 is fixed. The blood inlet 28 of the inner cylinder 35 penetrates the gas outflow member 42 and projects to the outside.

The outer tubular member 33 is not particularly limited, but a cylindrical body, a polygonal cylinder, a member having an elliptical cross section, or the like can be used. It is preferably a cylinder. The inner diameter of the outer tubular member is not particularly limited and may be the same as the inner diameter of the outer tubular member used in a known artificial lung, but is preferably about 32 to 164 mm. Further, the effective length of the outer tubular member (the length of the portion of the total length that is not buried in the partition wall) is also not particularly limited, and is the same as the effective length of the outer tubular member used for a known artificial lung. However, it is preferably about 10 to 730 mm.

The shape of the inner tubular member 31 is not particularly limited, but for example, a cylindrical body, a polygonal cylinder, or an elliptical cross section can be used. It is preferably a cylinder. The outer diameter of the inner tubular member is not particularly limited and may be the same as the outer diameter of the inner tubular member used in a known artificial lung, but is preferably about 20 to 100 mm. Further, the effective length of the inner tubular member (the length of the portion of the total length that is not buried in the partition wall) is also not particularly limited, and is the same as the effective length of the inner tubular member used for a known artificial lung. However, it is preferably about 10 to 730 mm.

The inner tubular member 31 is provided with a large number of blood circulation openings 32 on the side surface. The size of the opening 32 is preferably large in total area as long as the required strength of the tubular member is maintained. Examples of satisfying such conditions are shown in FIG. 5 which is a front view, FIG. 6 which is a central vertical sectional view of FIG. 5, and FIG. 7 which is a sectional view taken along line BB of FIG. In addition, a plurality of openings 32 are provided on the outer peripheral surface of the tubular member at equal intervals (for example, 4 to 24, 8 in the longitudinal direction in the figure), and annular arrangement openings are provided at equal intervals in the axial direction of the tubular member. It is preferable to provide a plurality of sets (8 sets / circumference in the figure). Further, the opening shape may be a circle, a polygon, an ellipse, or the like, but an oval shape as shown in FIG. 5 is preferable.

The shape of the inner cylinder 35 is not particularly limited, but for example, a cylinder, a polygonal cylinder, or an elliptical cross section can be used. It is preferably a cylinder. The distance between the tip opening of the inner cylinder 35 and the first partition wall 25 is not particularly limited, and the same distance as that used for a known artificial lung can be applied, but about 20 to 50 mm is preferable. be. Further, the inner diameter of the inner cylinder 35 is also not particularly limited and may be the same as the inner diameter of the inner cylinder used for a known artificial lung, but about 10 to 30 mm is preferable.

The thickness of the tubular hollow fiber membrane bundle 22 is not particularly limited and may be the same as the thickness of the tubular hollow fiber membrane bundle used in known artificial lungs, but is preferably 5 to 35 mm, particularly 10 mm to 28 mm. Is preferable. Further, the filling rate of the hollow fiber membrane in the tubular space formed between the outer surface and the inner side surface of the tubular hollow fiber membrane bundle 22 is also not particularly limited, and the filling rate in a known artificial lung is similarly applied. Although it is possible, 40 to 85% is preferable, and 45 to 80% is particularly preferable. The outer diameter of the hollow fiber membrane bundle 22 may be the same as the outer diameter of the hollow fiber membrane bundle used in known artificial lungs, but is preferably 30 to 170 mm, and particularly preferably 70 to 130 mm. As the gas exchange membrane, the one described above is used.

Then, the hollow fiber membrane bundle 22 is formed by winding the hollow fiber membrane around the inner tubular member 31, specifically, forming the hollow fiber membrane bobbin with the inner tubular member 31 as the core. Both ends of the bobbin can be formed by fixing both ends with a partition wall and then cutting both ends of the hollow fiber membrane bobbin together with the inner tubular member 31 which is the core. By this cutting, the hollow fiber membrane opens on the outer surface of the partition wall. The method for forming the hollow fiber membrane is not limited to the above method, and other known methods for forming the hollow fiber membrane may be used in the same manner or appropriately modified.

In particular, it is preferable that one or a plurality of hollow fiber membranes are wound around the inner tubular member 31 at the same time so that the hollow fiber membranes that are substantially parallel and adjacent to each other are substantially at regular intervals. Thereby, the drift of blood can be suppressed more effectively. Further, the distance between the hollow fiber membranes and the adjacent hollow fiber membranes is not limited to the following, but it is preferably 1/10 to 1/1 of the outer diameter of the hollow fiber membranes. Further, the hollow fiber membrane preferably has a distance of 30 to 200 μm from the adjacent hollow fiber membrane.

Further, the hollow fiber membrane bundle 22 has one or a plurality of hollow fiber membranes (preferably 2 to 16) at the same time, and all the adjacent hollow fiber membranes are inside at substantially a constant interval. It is formed by being wound around the tubular member 31, and when the hollow fiber membrane is wound on the inner tubular member, a rotating body and a hollow fiber membrane for rotating the inner tubular member 31 are provided. It is preferable that the winder for knitting is formed by being wound around the inner tubular member 31 by moving under the condition of the following formula (1).

By satisfying the above conditions, the formation of blood drift can be reduced. At this time, n, which is the relationship between the rotation speed of the winding rotating body and the reciprocating number of the winder, is not particularly limited, but is usually 1 to 5, preferably 2 to 4.

In the artificial lung according to the other embodiment, blood flows in from the inside of the tubular hollow fiber membrane bundle 22, and the blood that has passed through the hollow fiber membrane bundle 22 flows to the outside of the hollow fiber membrane bundle 22. It is a type that flows out from the artificial lung 20, but is not limited to this. Contrary to the other embodiment, blood flows in from the outside of the tubular hollow fiber membrane bundle 22, blood passing through the hollow fiber membrane bundle 22 flows inside the hollow fiber membrane bundle 22, and then the artificial lung 20 It may be of a more outflow type.

Further, also in the hollow fiber membrane type artificial lung 20, as shown in FIG. 2, the present invention applies to at least the outer surface 3a'(further, the outer surface layer 3a) of the hollow fiber membrane 3 of the hollow fiber membrane type artificial lung 1. It is preferable that the antithrombotic polymer compound 18 is coated. Here, the antithrombotic polymer compound may be present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane 3, but is substantially present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane. It is preferable that there is no such thing. Further, the hollow fiber membrane 3 is provided with a passage (lumen) 3d forming a gas chamber in the center. In addition, the hollow fiber membrane 3 has an opening 3e that communicates the outer surface 3a'and the inner surface 3c'. Here, the preferred form of the hollow fiber membrane (inner diameter, outer diameter, wall thickness, porosity, pore diameter, etc.) is not particularly limited, but a form similar to that described in FIG. 1 can be adopted.

In the artificial lung 20 according to the present embodiment, the hollow fiber membranes 3 are in contact with each other and have a so-called bobbin shape in which they are stacked in multiple layers. In the present embodiment, the coating with the antithrombotic polymer compound is uniformly and selectively formed on the outer surface 3a'of the hollow fiber membrane. With such a configuration, leakage of blood (particularly plasma component) to the inner surface layer 3c of the hollow fiber membrane can be suppressed / prevented. That is, the outer surface 3a'(further, the outer layer 3a) of the hollow fiber membrane 3 which is the blood contact portion is selectively coated with the antithrombotic polymer compound, so that blood (particularly plasma component) leaks (particularly plasma component). Leakage) can be effectively suppressed and prevented. In particular, when the antithrombotic polymer compound according to the present invention is substantially not present in the inner layer 3b and the inner surface layer 3c of the hollow fiber membrane 3, the inner layer 3b and the inner surface layer 3c of the hollow fiber membrane are hydrophobic of the material. Since the sexual state is maintained, leakage of blood (particularly plasma component) can be more effectively suppressed / prevented. In this embodiment, the blood flow path is complicated and has many narrow parts, and the gas exchange ability is excellent. However, in terms of platelet adhesion / adhesion and activation, an extracorporeal blood perfusion type artificial that is not a bobbin type. May be inferior to the lungs. However, as described above, since the coating of the antithrombotic polymer compound is uniform, there is little adhesion / adhesion and activation of platelets at the blood contact portion of the hollow fiber membrane. In addition, it is possible to suppress / prevent the coating (particularly the uneven coating portion) from peeling from the hollow fiber membrane.

Further, the coating of the antithrombotic polymer compound is essentially formed on the outer surface of the hollow fiber membrane of the artificial lung, but is formed on other constituent members (for example, the entire blood contact portion) in addition to the outer surface. You may. By adopting this configuration, it is possible to more effectively suppress / prevent the adhesion / adhesion and activation of platelets in the entire blood contact portion of the artificial lung. Further, since the contact angle of the blood contact surface is lowered, the priming work becomes easy. In this case, the coating of the antithrombotic polymer compound is preferably formed on other constituent members with which blood comes into contact, but the hollow fiber membrane or other part of the hollow fiber membrane other than the blood contact portion ( For example, the portion buried in the partition wall and the contact portion between the hollow fibers) may not be coated with the antithrombotic polymer compound. Since such a portion does not come into contact with blood, there is no particular problem even if the antithrombotic polymer compound is not coated.

The effects of the present invention will be described with reference to the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, "%" and "parts" mean "mass%" and "parts by mass", respectively.

[Synthesis of antithrombotic polymer compounds]
Preparation Example 1: a weight average molecular weight 420,000 Synthesis of 2-methoxyethyl acrylate PMEA a (MEA) 80g (0.61mol) was dissolved in methanol 115 g, placed in a four-necked flask, 1 hour _{N 2} bubbling at 50 ° C. This was done to prepare a monomer solution. Separately, 0.08 g of 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in 5 g of methanol to provide a polymerization initiator solution. Was prepared. Next, this polymerization initiator solution was added to the monomer solution, and the polymerization reaction was carried out at 50 ° C. for 5 hours. After polymerization for a predetermined time, the polymerization solution was added dropwise to ethanol, and the precipitated polymer (PMEA) was recovered. The weight average molecular weight of the recovered polymer was measured and found to be 420,000.

[Preparation of coating liquid]
Example 1-1: Coat solution having a protamine sulfate concentration of 0.005% by mass 1.2 g of PMEA (weight average molecular weight = 420,000) synthesized in Production Example 1 above was dissolved in 20 g of methanol. 380 g of distilled water was added to another container, and the methanol solution of PMEA was added at an addition rate of 20 g / min while stirring with a stirrer. Then, the mixture was stirred at 25 ° C. for 10 minutes to obtain a cloudy coating liquid. The coating liquid was a colloidal liquid in which the colloid of PMEA was dispersed. To this colloidal solution, 2.2 ml of an aqueous solution of protamine sulfate (10 mg / ml aqueous solution; molecular weight of protamine sulfate = about 5,000) was added to obtain a coating solution (1). At this time, the solvent of the coating liquid (1) is a mixing ratio of water: methanol = 17: 1 (mass ratio), and the concentration of PMEA is 0.3% by mass.

Example 1-2: Coat solution having a protamine sulfate concentration of 0.027% by mass In Example 1-1 above, the amount of protamine sulfate used was changed, and 11 ml of a protamine sulfate aqueous solution (10 mg / ml aqueous solution) was added. The coating liquid (2) was obtained in the same manner as in Example 1-1 except for. The coating liquid (2) was also a solution containing a colloid like the coating liquid (1). At this time, the solvent of the coating liquid (2) is a water: methanol mixing ratio = 12: 1 (mass ratio), and the concentration of PMEA is 0.3% by mass.

Comparative Example 1-1: No addition of protamine sulfate A coating liquid (3) was obtained in the same manner as in Example 1-1 except that the aqueous solution of protamine sulfate was not added in Example 1-1. The coating liquid (3) was also a solution containing a colloid like the coating liquid (1).

[Preparation of artificial lung]
Example 2-1
Gas exchange porous hollow made of porous polypropylene with an inner diameter of 195 μm, an outer diameter of 295 μm, a wall thickness of 50 μm, a pore ratio of about 35% by volume, and an outer surface pore diameter (that is, the average diameter of openings) of 80 nm. An extracorporeal blood perfusion type hollow fiber membrane artificial lung (a) having a membrane area (outer surface area of the hollow fiber membrane) of 0.5 m ^{2 around which the membrane was wound was prepared.}

The coating solution (1) prepared in Example 1-1 was filled in the blood flow path of the artificial lung (a), allowed to stand at 25 ° C. for 120 seconds, and then the coating solution was removed to obtain a flow rate of 80 L. The hollow fiber membrane was dried by flowing air from the blood to produce an extracorporeal blood perfusion type hollow fiber membrane artificial lung (1) having a hollow fiber membrane having a coating formed on the outer surface. The extracorporeal blood perfusion type hollow fiber membrane artificial lung (1) thus obtained is also referred to as an artificial lung (1).

Example 2-2
The blood external perfusion type hollow fiber was used in the same manner as in Example 2-1 except that the coating liquid used in Example 2-1 was changed to the coating liquid (2) prepared in Example 1-2. A filamentous membrane artificial lung (2) was manufactured. The extracorporeal blood perfusion type hollow fiber membrane artificial lung (2) thus obtained is also referred to as an artificial lung (2).

Comparative Example 2-1
The blood external perfusion type hollow fiber was used in the same manner as in Example 2-1 except that the coating liquid used in Example 2-1 was changed to the coating liquid (3) prepared in Comparative Example 1-1. A filamentous membrane artificial lung (3) was manufactured. The extracorporeal blood perfusion type hollow fiber membrane artificial lung (3) thus obtained is also referred to as an artificial lung (3).

[Experiment 1. Quantification of coat amount]
With respect to the artificial lungs (1) to (2) of Examples 2-1 to 2-2 and the artificial lungs (3) of Comparative Example 2-1 the coating amount of PMEA was measured by the following method.

The artificial lungs (1) to (3) were disassembled, and the artificial lung membrane was taken out. 3 g of the artificial lung membrane was filled in a glass tube with a screw cap, 25 ml of acetone was added, and the mixture was stirred for 120 minutes to extract the PMEA coated on each artificial lung membrane. The entire amount of the acetone extract was transferred to another glass tube with a screw cap. Acetone was evaporated using a heat block. 10 ml of tetrahydrofuran was added to the glass tube containing the evaporated dry matter to dissolve the evaporated dry matter. A THF solution (standard solution) containing 1 mg / ml PMEA was analyzed using GPC, and the area of the peak corresponding to PMEA was calculated. Subsequently, the evaporated dry solid THF solution (test solution) was analyzed using GPC, and the area of the peak corresponding to PMEA was calculated in the same manner. Then, the amount of PMEA in the test solution was calculated using the following formula 1, and the amount of PMEA coated per ^{1 m 2 of} the artificial lung membrane (area of the outer surface of the hollow fiber membrane 1 m ^{2) was calculated using the formula 2.} The results are shown in Table 1 below.

From the results in Table 1 above, it was confirmed that the artificial lungs (1) and (2) produced by the method according to the present invention dramatically increase the coating amount of PMEA.

[Experiment 2. Antithrombotic test]
The antithrombotic properties of the artificial lung (1) and the artificial lung (3) obtained in Example 2-1 and Comparative Example 2-1 were evaluated according to the following method.

Each artificial lung was incorporated into an extracorporeal circulation circuit and filled with 90 ml of fresh porcine blood supplemented with heparin and 110 ml of saline. The heparin concentration in the circulating blood was 0.5 u / ml. Circulating blood was circulated at room temperature (25 ° C.) at 500 ml / min. Immediately after the start of circulation, 0.7 ml of a solution obtained by diluting protamine sulfate (100 mg / 10 ml) 100-fold with physiological saline was injected into the circulating blood. After 30 minutes, blood was sampled from each blood circulation circuit, the platelet count was measured, the ratio to the platelet count before the start of circulation was calculated, and the platelet count maintenance rate was determined. The higher the retention rate of platelets in the blood, the higher the antithrombotic property. The results are shown in Table 2 below.

From the results in Table 2 above, the artificial lung (1) produced by the method according to the present invention is compared with the artificial lung (3) using a coating solution containing no water-soluble cationic polymer in the coating solution. Therefore, it can be seen that the antithrombotic property is significantly improved.

This application is based on Japanese Patent Application No. 2017-048241 filed on March 14, 2017, the disclosure of which is referenced and incorporated as a whole.

Claims (8)

A method for producing an artificial lung having a plurality of porous hollow fiber membranes for gas exchange having an outer surface, an inner surface forming a lumen, and an opening for communicating the outer surface and the inner surface. hand,
A method for producing an artificial lung, which comprises applying a solution containing a colloid of an antithrombotic polymer compound and a water-soluble cationic polymer to either the outer surface or the inner surface. The hollow fiber membrane has an inner surface that forms the lumen through which oxygen-containing gas flows, and an outer surface that comes into contact with blood.
The method for producing an artificial lung according to claim 1, wherein the solution is applied to the outer surface. The production of an artificial lung according to claim 1 or 2, wherein the water-soluble cationic polymer is selected from the group consisting of protamine sulfate, protamine, polyethyleneimine, polyallylamine, poly-L-lysine, albumin and gelatin. Method. The method for producing an artificial lung according to any one of claims 1 to 3, wherein the solution contains 0.001% by mass or more of the water-soluble cationic polymer. The method for producing an artificial lung according to any one of claims 1 to 4, wherein the solution contains 0.01% by mass or more of the antithrombotic polymer compound. The solution according to any one of claims 1 to 5, wherein the solution contains the antithrombotic polymer compound and the water-soluble cationic polymer in a mass ratio of 1: 0.01 to 0.10. The method for producing an artificial lung according to the description. The antithrombotic polymer compound has the following formula (I):

However, R ³ represents a hydrogen atom or a methyl group, R ¹ represents an alkylene group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms.
The method for producing an artificial lung according to any one of claims 1 to 6, which has a structural unit derived from an alkoxyalkyl (meth) acrylate represented by. The method for producing an artificial lung according to any one of claims 1 to 7, wherein the weight average molecular weight of the antithrombotic polymer compound is more than 200,000 and less than 800,000.

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