WO2018168533A1

WO2018168533A1 - Method for producing artificial lung

Info

Publication number: WO2018168533A1
Application number: PCT/JP2018/008099
Authority: WO
Inventors: 崇王安齊
Original assignee: テルモ株式会社
Priority date: 2017-03-14
Filing date: 2018-03-02
Publication date: 2018-09-20
Also published as: JP6956170B2; JPWO2018168533A1

Abstract

Provided is a method for producing an artificial lung having a plurality of gas-exchange porous hollow-fiber membranes, provided with an outer surface, an inner surface that forms a lumen, and an opening part that communicates between the outer surface and the inner surface, said method including the application of a solution including a colloid of an antithrombotic polymer compound and a water-soluble salt including a metal cation or ammonium cation to either the outer surface or the inner surface. The present invention provides a means with which it is possible to increase the coating quantity of antithrombotic polymer compound relative to the hollow-fiber membranes.

Description

Artificial lung manufacturing method

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 oxygenator, particularly a hollow fiber membrane external blood perfusion oxygenator, for removing carbon dioxide in blood and adding oxygen to blood in extracorporeal blood circulation.

A hollow fiber membrane oxygenator using a porous membrane is generally widely used as an extracorporeal circulation device or a cardiopulmonary device for assisting circulation in open heart surgery. A membrane oxygenator mainly uses a hollow fiber membrane, and performs blood gas exchange through the hollow fiber membrane. As a method for perfusing blood to an artificial lung, blood flows inside the hollow fiber membrane and gas flows outside the hollow fiber membrane, and conversely, blood flows outside the hollow fiber membrane and gas flows into the hollow fiber. There is an external perfusion system that flows inside the membrane.

In the hollow fiber membrane oxygenator, the inner surface or outer surface of the hollow fiber membrane comes into contact with blood, so the inner surface or outer surface of the hollow fiber membrane in contact with blood has an effect on platelet adhesion (adhesion) and activation. There is a risk of giving. In particular, an external perfusion type artificial lung in which the outer surface of the hollow fiber membrane is in contact with blood tends to affect the adhesion (adhesion) and activation of the platelet system because it disturbs the blood flow.

Taking these issues into consideration, using an alkoxyalkyl (meth) acrylate as an antithrombotic material, an external perfusion type, utilizing the effect of inhibiting and preventing the adhesion and activation of platelet-based alkoxyalkyl (meth) acrylate. 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 the main component of alkoxyalkyl (meth) acrylate in a mixed solvent of water, methanol and ethanol. It is described that after coating with a coating solution obtained by dissolving the polymer as follows, drying is performed.

As a technique capable of suppressing leakage of plasma components after blood circulation (plasma leak), International Publication No. 2016/143752 includes a technique for 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 diameter of the colloid so as to be a specific ratio or more 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 controlled automatically is obtained.

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

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

As a result of intensive studies to solve the above problems, the present inventor has found that the above problem can be solved by adding a specific water-soluble salt to the colloidal solution of the antithrombotic polymer compound. We have learned and have completed the present invention.

That is, the object is to provide an artificial gas having a plurality of gas exchange porous hollow fiber membranes having an outer surface, an inner surface that forms a lumen, and an opening that communicates 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 salt containing a metal cation or an ammonium cation to either the outer surface or the inner surface. Can be achieved by a method for producing an artificial lung.

FIG. 1 is a cross-sectional view showing one embodiment of a hollow fiber membrane external blood perfusion oxygenator obtained by the production method of the present invention. In FIG. 1, reference numeral 1 is a hollow fiber membrane external blood perfusion type artificial lung; reference numeral 2 is a housing; reference numeral 3 is a hollow fiber membrane; reference numerals 4 and 5 are partition walls; Reference numeral 7 denotes a blood outlet; reference numeral 8 denotes a gas inlet; reference numeral 9 denotes a gas outlet; reference numeral 10 denotes a gas inlet header; reference numeral 11 denotes a gas outlet 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 a hollow fiber membrane external blood perfusion oxygenator obtained by the production method of the present invention. In FIG. 2, reference numeral 3 indicates a hollow fiber membrane; reference numeral 3a indicates an outer surface layer; reference numeral 3a ′ indicates an outer surface; reference numeral 3b indicates an inner layer; reference numeral 3c indicates an inner surface layer; Reference numeral 3d indicates a passage; reference numeral 3e indicates an opening; and reference numeral 18 indicates an antithrombogenic material. FIG. 3 is a cross-sectional view showing another embodiment of a hollow fiber membrane external blood perfusion oxygenator obtained by the production method of the present invention. In FIG. 3, reference numeral 3 denotes a hollow fiber membrane; reference numeral 17 denotes a blood chamber; reference numeral 17a denotes a blood inflow portion; reference numeral 17b denotes a blood chamber; reference numeral 17c denotes a second blood chamber; 20 is a hollow fiber membrane external blood perfusion type artificial lung; 22 is a cylindrical hollow fiber membrane bundle; 23 is a housing; 24 is a gas inlet; 25 and 26 are partition walls Reference numeral 27 denotes a gas outlet; reference numeral 28 denotes a blood inlet;

reference numerals

29a and 29b denote blood outlets; reference numeral 31 denotes an inner cylindrical member; reference numeral 32 denotes a blood circulation opening; Reference numeral 33 denotes an outer cylindrical member; reference numeral 35 denotes an inner cylindrical body; reference numeral 35a denotes an upper end of the inner cylindrical body 35; and reference numeral 41 denotes a gas inflow member. 4 is a cross-sectional view taken along line AA in FIG. In FIG. 4, reference numeral 3 denotes a hollow fiber membrane; reference numeral 17a denotes a blood inflow portion; reference numeral 17c denotes a second blood chamber; reference numeral 22 denotes a cylindrical hollow fiber membrane bundle;

reference numerals

29a and 29b denote Reference numeral 31 denotes an inner cylindrical member; reference numeral 32 denotes an opening for blood circulation; reference numeral 33 denotes an outer cylindrical member; and reference numeral 35 denotes an inner cylindrical body. FIG. 5 is a front view showing an example of an inner cylindrical member used for a hollow fiber membrane external blood perfusion oxygenator obtained by the production method of the present invention. In FIG. 5, the code | symbol 31 represents an inner cylindrical member; the code | symbol 32 represents the opening for blood circulation, respectively. FIG. 6 is a central longitudinal sectional view of the inner cylindrical member shown in FIG. In FIG. 6, the code | symbol 31 represents an inner cylindrical member; the code | symbol 32 represents the opening for blood circulation, respectively. 7 is a cross-sectional view taken along line BB in FIG. In FIG. 7, reference numeral 31 denotes an inner cylindrical member; reference numeral 32 denotes a blood circulation opening.

The present invention provides an artificial lung having a plurality of gas exchange porous hollow fiber membranes including an outer surface, an inner surface that forms a lumen, and an opening that communicates the outer surface and the inner surface. A production method comprising applying a solution containing a colloid of an antithrombotic polymer compound and a water-soluble salt containing a metal cation or an ammonium cation to either the outer surface or the inner surface And relates to a method for producing an artificial lung. According to the method for producing an artificial lung of the present invention, a means capable of increasing the coating amount of the antithrombotic polymer compound on the hollow fiber membrane is provided.

In the method for producing an artificial lung according to the present invention, a solution containing colloidal particles of an antithrombotic polymer compound further contains a water-soluble salt containing a metal cation or an ammonium cation (hereinafter, also simply referred to as “water-soluble salt”). May be included). Then, the artificial lung is manufactured by coating (applying) the solution on the outer surface or 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 for exerting the above-described effects by 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 International Publication No. 2016/143752, the hollow fiber membrane is coated with a colloidal solution of an antithrombotic polymer compound. At this time, colloidal particles (particle surface) of the antithrombotic polymer compound contained in the colloidal solution are negatively charged, and cations are present around the colloidal particles so as to neutralize this charge. it is conceivable that. That is, the colloidal particles are presumed to be in a state where an electric double layer is formed. And the said cation plays the role which adsorb | sucks a colloid particle with respect to the hollow fiber membrane surface charged to the negative charge.

On the other hand, the cations existing around the colloidal particles repel the cations existing on the surface of the other colloidal particles and have a role of dispersing the colloidal particles. Here, when a water-soluble salt is added to colloidal particles having an electric double layer, cations existing around the colloidal particles are pushed close to the surface of the colloidal particles, and the thickness of the electric double layer is reduced. At this time, the water-soluble salt used in the method according to the present invention includes a metal cation or an ammonium cation charged to a sign opposite to the negative charge of the colloidal particles, and these cations particularly have a thickness of the electric double layer. It is estimated that the effect of decreasing is high. And when the thickness of the electric double layer is reduced in this way, the colloidal particles approach each other within the range in which intermolecular force works between the colloidal particles, and before the repulsion between the cations surrounding the colloidal particles occurs, Tends to aggregate. As a result, the colloidal particles adsorbed on the surface of the hollow fiber membrane are likely to agglomerate, so that the coating amount of the antithrombotic polymer compound is presumed to increase. In addition, it is considered that the amount of coating is also increased by adsorbing colloidal particles in an aggregated state in the colloidal solution on the surface of the hollow fiber membrane. Therefore, the artificial lung manufactured by the method according to the present invention is excellent in antithrombogenicity.

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

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

[Method for producing artificial lung]
In the method for producing an artificial lung according to the present invention, a solution (colloid solution) containing a colloid of an antithrombotic polymer compound and a water-soluble salt containing a metal cation or an ammonium cation on the outer surface or inner surface of the hollow fiber membrane. ) Is applied. Below, the preferable form of the manufacturing method of the oxygenator which concerns on this invention is demonstrated. In addition, this invention is not limited to the following preferable forms except coat | covering the outer surface or inner surface of a hollow fiber membrane with the said solution.

In the method of the present invention, first, a solution (colloid solution) containing a colloid of an antithrombotic polymer compound and a water-soluble salt containing a metal cation or an ammonium cation is prepared, and the colloid solution is removed from the hollow fiber membrane. Apply (cover) to the surface or inner surface. Thereafter, if necessary, the coating formed on the outer surface or inner surface of the hollow fiber membrane may be washed for the purpose of removing the water-soluble salt. Hereinafter, (1) a colloidal solution preparation step, (2) a colloidal solution coating (coating) step, and (3) a cleaning step will be described.

(1) Step of preparing colloidal solution In this step, a colloidal solution to be applied 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 includes an antithrombotic polymer compound and a water-soluble salt containing a metal cation or an ammonium cation. By including the water-soluble salt, the colloidal particles of the antithrombotic polymer compound are likely to aggregate, so that the coating amount of the antithrombotic polymer compound can be increased.

The water-soluble salt contained in the colloidal solution according to the present invention contains a metal cation or an ammonium cation. Here, “water-soluble” means that the solubility in water (25 ° C.) is 0.1 g / 100 mL or more, and “salt” is generated in a form in which a cation and an anion neutralize charges. Means a compound. The water-soluble salt can be removed by washing with water after coating the hollow fiber membrane with an antithrombotic polymer compound. Therefore, it can suppress that these water-soluble salts elute into the blood by performing sufficient water washing at the time of manufacture of an artificial lung.

The water-soluble salt according to the present invention is not particularly limited as long as it contains a metal cation or an ammonium cation.

The metal cation is not particularly limited as long as it is charged positively, but monovalent, divalent or trivalent ions are preferable, and Li, Na, K, Cs, Be, Mg, Ca, Ba, Ag, Examples include ions of metals such as Al, Bi, Cu, Fe, Ga, Mn, Pb, Sn, Ti, V, W, Y, Yb, Zn, and Zr. These metal ions tend to allow cations present around the colloidal particles to approach the surface of the colloidal particles, and as a result, facilitate the aggregation of the colloidal particles. As a result, the coating amount of the antithrombotic polymer compound can be further increased.

Among them, from the viewpoint of increasing the coating amount, the metal cation is selected from the group consisting of cations of alkali metals such as Li, Na, K, and Cs and group 2 elements such as Be, Mg, Ca, and Ba. It is preferably selected, and even more preferably selected from alkali metal cations such as Li, Na, K, and Cs. Furthermore, in addition to the same viewpoint, from the viewpoint of biocompatibility, the metal cation is particularly preferably selected from the group consisting of Li, Na and K, and most preferably Na. Further, when the metal cation is a cation of a Group 2 element, Mg is preferable. In addition, the metal cation in the water-soluble salt may be one kind alone or a combination of two or more kinds.

The ammonium cation is not particularly limited, but is represented by the formula: (R) _a (H) _b N ⁺ (wherein, a is an integer from 0 to 4; b is an integer from 0 to 4; a + b is R is an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an i-butyl group, or a t-butyl group. A cation is preferred. Such an ammonium cation facilitates the aggregation of colloidal particles, and can effectively increase the coating amount. Among them, the ammonium cation is an unsubstituted ammonium cation (NH ₄ ⁺ ; in the above formula, a = 0, b = 4) because the aggregation of colloidal particles is easily promoted and the coating amount is easily increased. And more preferred. In addition, the ammonium cation in the water-soluble salt may be used alone or in combination of two or more.

On the other hand, the anion (counter anion) that forms a salt with the metal cation or ammonium cation is not particularly limited as long as it has a negative charge, but halogen such as fluoride ion, chloride ion, bromide ion, iodide ion, etc. Ion of inorganic acid such as sulfate ion, amidosulfuric acid ion, carbonate ion; organic acid ion such as acetate ion, aliphatic hydroxy acid ion, aromatic hydroxy acid ion, methanesulfonic acid ion, benzenesulfonic acid ion; etc. Is mentioned. Among them, the anion of the water-soluble salt is preferably a halide ion such as fluoride ion, chloride ion, bromide ion or iodide ion because it does not inhibit the aggregation of colloidal particles and easily increases the coating amount. Furthermore, in addition to the same viewpoint, from the viewpoint of biocompatibility, the counter anion is more preferably selected from the group consisting of fluoride ion, chloride ion and bromide ion, and chloride ion is particularly preferable. When the counter anion is an inorganic acid ion, it is preferably a sulfate ion. In addition, the anion in water-soluble salt may be single 1 type, and 2 or more types of combinations may be sufficient as it.

The water-soluble salt according to the present invention is preferably a combination of the metal cation or ammonium cation and an anion. Among these, the water-soluble salt according to the present invention is preferably sodium chloride or magnesium sulfate, and particularly preferably sodium chloride. These water-soluble salts tend to promote the aggregation of the colloid of the antithrombotic polymer compound and easily increase the coating amount. Furthermore, since these water-soluble salts have good biocompatibility, the water washing step can be omitted after the anti-thrombotic polymer compound is coated on the hollow fiber membrane, or the water washing step can be simplified. it can. Therefore, it is also preferable from the viewpoint of productivity. In addition, the said water-soluble salt may be used individually by 1 type, or may mix and use 2 or more types.

The solvent used for the preparation of the solution (colloid solution) containing the antithrombotic polymer compound and the water-soluble salt dissolves the water-soluble salt, and appropriately disperses the antithrombotic polymer compound to form the colloid solution. It is preferable to use what can be prepared. From the viewpoint of more effectively preventing the colloid solution from penetrating to the outer surface or inner surface of the pores of the hollow fiber membrane (the surface on the side where the oxygen-containing gas flows), the solvent preferably contains water. Here, the water is preferably pure water, ion-exchanged water or distilled water, and particularly preferably distilled water.

Further, the solvent other than water used for the preparation of the colloidal solution is not particularly limited, but is preferably methanol or acetone in consideration of ease of control such as dispersibility of the antithrombotic polymer compound. Solvents 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 ease of further control 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 ease of further control of the average particle size of the colloid, the mixing ratio of water: methanol (mass) Ratio) is preferably 6 to 32: 1, and 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 water-soluble salt 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. Subsequently, while stirring separately prepared water, On the other hand, it is preferable to prepare a colloidal solution by a method in which the antithrombotic polymer compound-containing solution is added and a water-soluble salt is further added. According to such a method, it is easy to disperse the antithrombotic polymer compound. Further, according to the above method, a colloid having a uniform particle diameter can be formed, and there is an advantage that a uniform film can be easily formed.

In the above method, the addition rate of 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 the stirring temperature for preparing the colloidal solution are not particularly limited, but from the viewpoint of easily forming a colloid with a uniform particle size and uniformly dispersing the colloid, the solution containing the antithrombotic polymer compound in water. After the addition, stirring for 1 to 30 minutes is preferable, and stirring for 5 to 15 minutes is more preferable. Further, the stirring temperature is preferably 10 to 40 ° C, more preferably 20 to 30 ° C.

In the above method, the water-soluble salt may be mixed as it is with the antithrombotic polymer-containing solution or the solution after the antithrombotic polymer-containing solution is added to water, but is dissolved in another solvent in advance. It may be mixed in the form of a solution. In the latter case, the other solvent is not particularly limited as long as it can dissolve the water-soluble salt, but examples thereof include the same solvents as those used in the colloidal solution. Further, 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 of easy preparation of a uniform solution. Further, the concentration of the water-soluble salt in the other solvent in this case is not particularly limited, but in consideration of ease of mixing, the amount of the water-soluble salt added is preferably relative to 100 parts by mass of the other solvent. Is 0.1 to 30 parts by mass, more preferably 0.5 to 20 parts by mass, and even more preferably 1 to 10 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. Furthermore, from the above viewpoint, the colloid solution preferably contains the antithrombotic polymer compound at a concentration of 0.05% by mass or more, and particularly preferably contains 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 it is preferably 0.3% by mass or less in consideration of the ease of forming a film and the effect of reducing coat unevenness. The content is more preferably 0.2% by mass or less, and particularly preferably 0.15% by mass or less. Moreover, if it is such a range, the fall of the gas exchange capability by the coating film of an antithrombotic polymer compound becoming too thick is also suppressed.

Therefore, the concentration of the antithrombotic polymer compound in the colloidal solution is preferably 0.01 to 0.3% by mass, more preferably 0.05 to 0.2% by mass, and 0.1 to 0%. .15% by mass is particularly preferable.

Further, the concentration of the water-soluble salt in the colloidal solution is not particularly limited, but is preferably 0.01% by mass or more from the viewpoint of facilitating the aggregation of the colloid and easily increasing the coating amount. The higher the concentration of the water-soluble salt, the more the coating amount can be increased. Furthermore, from the above viewpoint, the colloidal solution preferably contains a water-soluble salt at a concentration of 0.05% by mass or more, and particularly preferably contains a water-soluble salt at a concentration of 0.1% by mass or more. On the other hand, the upper limit of the concentration of the water-soluble salt in the colloidal solution is not particularly limited, but considering the ease of removal of the water-soluble salt, it is preferably 0.5% by mass or less, and 0.3% by mass or less. Is more preferable, and is particularly preferably 0.25% by mass or less. Moreover, if it is such a range, the fall of the gas exchange capability by the coating film of an antithrombotic polymer compound becoming too thick is also suppressed.

Accordingly, the concentration of the water-soluble salt in the colloidal solution is preferably 0.01 to 0.5% by mass, more preferably 0.05 to 0.3% by mass, and 0.1 to 0.25% by mass. % Is particularly preferred.

Furthermore, the mixing ratio of the anti-thrombotic polymer compound contained in the colloid solution and the water-soluble salt is not particularly limited, but the colloid of the anti-thrombotic polymer compound can be more easily aggregated, effectively increasing the coating amount. From the viewpoint of easy formation, the mixing ratio (molar ratio) of the antithrombotic polymer compound to the water-soluble salt is preferably 1: 3,000 to 30,000, preferably 1: 5,000 to 25,000. More preferably, it is particularly preferably 1: 10,000 to 20,000. Moreover, if it is such a range, the fall of the gas exchange capability by the coating film of an antithrombotic polymer compound becoming too thick is also suppressed.

Furthermore, the mixing ratio of the antithrombotic polymer compound contained in the colloid solution and the water-soluble salt may be in the following range. That is, the mixing ratio (mass ratio) of the antithrombotic polymer compound: water-soluble salt is preferably 1: 0.1 to 5, more preferably 1: 0.3 to 3, and 1: It is particularly preferably 1 to 2.8, and most preferably 1: 1.5 to 2.5. Moreover, if it is such a range, the fall of the gas exchange capability by the coating film of an antithrombotic polymer compound becoming too thick is also suppressed.

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

(Antithrombogenic polymer compound and method for producing the same)
The antithrombotic polymer compound used in the present invention is a compound that imparts antithrombogenicity to an artificial lung by being applied to a hollow fiber membrane.

Here, the weight average molecular weight of the antithrombotic polymer compound is not particularly limited, but is preferably 80,000 or more. In the artificial lung production method 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, from the viewpoint of easy preparation of a desired colloidal solution, the weight average molecular weight of the antithrombotic polymer compound is preferably less than 800,000. By setting it as the said range, it can suppress that the said compound aggregates or precipitates in the solution containing an antithrombotic polymer compound, and can prepare the stable colloidal solution. 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. Even more preferably, it is more preferably 230,000-450,000.

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 film) can be reduced. 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, elution of the coating (particularly a low molecular weight polymer) into the blood can be more effectively suppressed / prevented. Moreover, it is preferable also from the point of antithrombogenicity and biocompatibility. In the present specification, the “low molecular weight polymer” means a polymer having a weight average molecular weight of less than 60,000.

In this specification, “weight average molecular weight” is a value measured by gel permeation chromatography (Gel permeation chromatography, GPC) using polystyrene as a standard substance and tetrahydrofuran (THF) as a mobile phase. . Specifically, a polymer to be analyzed is dissolved in THF to prepare a 10 mg / ml solution. For the polymer solution thus prepared, GPC system LC-20 manufactured by Shimadzu Corporation was attached with GPC column LF-804 manufactured by Shodex, THF was flowed as a mobile phase, and polystyrene was used as a standard substance. The GPC of the resulting polymer is measured. After preparing a calibration curve with standard polystyrene, the weight average molecular weight of the polymer to be analyzed is calculated based on this curve.

The antithrombotic polymer compound can be used without particular limitation as long as it has antithrombogenicity and biocompatibility. Among these, from the viewpoint of excellent properties, the antithrombotic polymer compound is represented by the following formula (I):

Wherein 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 (meth) acrylate. The compound having the structural unit represented by the above formula (I) has antithrombotic biocompatibility (platelet adhesion / adhesion suppression / prevention effect and platelet activation suppression / prevention effect), particularly platelet adhesion. / Excellent anti-adhesion effect. Therefore, by using a compound having the above structural unit, antithrombotic biocompatibility (platelet adhesion / adhesion suppression / prevention effect and platelet activation suppression / prevention effect), particularly platelet adhesion / adhesion It is possible to produce an artificial lung that is excellent in suppressing and preventing effects.

In the present specification, “(meth) acrylate” means “acrylate and / or methacrylate”. That is, “alkoxyalkyl (meth) acrylate” includes all alkoxyalkyl acrylates, only alkoxyalkyl methacrylates, and all alkoxyalkyl acrylates and alkoxyalkyl methacrylates.

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 methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and a propylene group linear or branched alkylene group. Among these, an ethylene group and a propylene group are preferable, and an ethylene group is particularly preferable in consideration of further improvement effects of antithrombogenicity 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 is a straight chain of methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group or There are branched alkyl groups. Among these, a methyl group and an ethyl group are preferable, and a methyl group is particularly preferable in view of further improving effects of antithrombogenicity and biocompatibility. R ³ represents a hydrogen atom or a methyl group. In addition, when the antithrombotic polymer compound according to the present invention has two or more kinds of structural units derived from alkoxyalkyl (meth) acrylate, 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, butoxyethyl acrylate, Examples include methoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, and butoxyethyl methacrylate. Of these, methoxyethyl (meth) acrylate and methoxybutyl acrylate are preferred, and methoxyethyl acrylate (MEA) is particularly preferred from the viewpoint of further improving the antithrombogenicity and biocompatibility. That is, the antithrombotic polymer compound according to the present invention is preferably polymethoxyethyl acrylate (PMEA). The above alkoxyalkyl (meth) acrylates may be used alone or in admixture 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, from the viewpoint of easy preparation of a desired colloidal solution, the weight average molecular weight of PMEA is preferably less than 800,000. By setting it as the said range, it can suppress that the said compound aggregates or precipitates in the solution containing PMEA, and can prepare the stable colloidal solution. Furthermore, 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 constituent unit derived from alkoxyalkyl (meth) acrylate, and is composed of one or more constituent units derived from alkoxyalkyl (meth) acrylate. 1 or 2 or more types of constituent units derived from one or more alkoxyalkyl (meth) acrylates and one or more types copolymerizable with the alkoxyalkyl (meth) acrylates. The polymer (copolymer) comprised from the structural unit (other structural units) derived from a monomer may be sufficient. In addition, when the antithrombotic polymer compound according to the present invention is composed of two or more structural units, the structure of the polymer (copolymer) is not particularly limited, and a random copolymer, alternating copolymer Any of a coalescence, a periodic copolymer, and a block copolymer may be sufficient. In addition, the terminal 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 that can be copolymerized with an 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 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, methacrylamide, N, N-dimethylmethacrylamide, N, N -Diethylmethacrylamide, aminomethylmeta Relate, aminoethyl methacrylate, diaminomethyl methacrylate, di-aminoethyl methacrylate. Among these, as the copolymerizable monomer, those having no hydroxyl group or cationic group in the molecule are preferable. The copolymer may be any of a random copolymer, a block copolymer, and 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 structural unit derived from the copolymerizable monomer in all the structural units of the copolymer is not particularly limited, but in consideration of antithrombogenicity and biocompatibility, the copolymerizable monomer It is preferable that the structural unit derived from (other structural unit) is more than 0 mol% and 50 mol% or less in all the structural units of the copolymer. If it exceeds 50 mol%, the effect of alkoxyalkyl (meth) acrylate may be reduced.

Moreover, the antithrombotic polymer compound containing the 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):

And one or more monomers (copolymerizable monomers) that can be copolymerized with the alkoxyalkyl (meth) acrylate added as necessary. By stirring together with a polymerization initiator in a polymerization solvent to prepare a monomer solution and heating the monomer solution, alkoxyalkyl (meth) acrylate, or alkoxyalkyl (meth) acrylate and, if necessary, 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 those defined in the above formula (I), and thus the description thereof is omitted here.

The polymerization solvent that can be used in the preparation of the monomer solution is not particularly limited as long as it can dissolve the alkoxyalkyl (meth) acrylate of the formula (II) used and the copolymerizable monomer added as necessary. Not limited. For example, water, alcohols such as methanol, ethanol, propanol and isopropanol, aqueous solvents such as polyethylene glycols; aromatic solvents such as toluene, xylene and tetralin; and halogens such as chloroform, dichloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene System solvents and the like. Among these, methanol is preferable in consideration of ease of dissolution of the alkoxyalkyl (meth) acrylate, ease of obtaining the polymer having the weight average molecular weight as described above, and the like.

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 relatively high. For this reason, 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. More than 50% by mass. Furthermore, 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. In addition, the said monomer density | concentration means the total density | concentration of these monomers, when using 2 or more types of monomers.

The polymerization initiator is not particularly limited, and a known one may be used. Preferably, it is a radical polymerization initiator from the viewpoint of excellent polymerization stability. Specifically, it is a persulfate such as potassium persulfate (KPS), sodium persulfate, ammonium persulfate; hydrogen peroxide, t-butyl persulfate. Peroxides such as oxide and methyl ethyl ketone peroxide; 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-methylpropionamidine) dihydrochloride, 2,2′-azobis [N- (2- Ruboxyethyl) -2-methylpropionamidine)] hydrate, 3-hydroxy-1,1-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, 1,1,3,3-tetrabutyl Peroxyneodecanoate, t-butylperoxyneodecanoate, t-butylperoxyneoheptanoate, t-butylperoxypivalate, t-amylperoxyneodecanoate, t-amylperoxy Examples thereof include azo compounds such as pivalate, di (2-ethylhexyl) peroxydicarbonate, di (secondary butyl) peroxydicarbonate, azobiscyanovaleric acid and the like. Further, for example, a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or ascorbic acid may be combined with the radical polymerization initiator and used as a redox initiator. The blending amount of the polymerization initiator is 0.0001 to 1 mol with respect to the total amount of monomers (alkoxyalkyl (meth) acrylate and copolymerizable monomer added if necessary; hereinafter the same). % 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, more preferably 100 parts by mass of monomer (the whole when plural types of monomers are used). Is 0.05 to 0.5 parts by mass. With such a blending amount of the polymerization initiator, a polymer having a desired weight average molecular weight can be produced more efficiently.

The polymerization initiator may be mixed as it is with the monomer and the polymerization solvent, or may be mixed as it is with the monomer and the polymerization solvent 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, and examples thereof include the same solvents as the polymerization solvent. Further, the other solvent may be the same as or different from the polymerization solvent, but considering the ease of controlling the polymerization, it is preferable to use the same solvent as the polymerization solvent. In this case, the concentration of the polymerization initiator in the other solvent is not particularly limited. However, in consideration of ease of mixing, the addition amount of the polymerization initiator is preferably relative to 100 parts by mass of the other solvent. Is 0.1 to 10 parts by mass, more preferably 0.15 to 5 parts by mass, and still more preferably 0.2 to 1.8 parts by mass.

Next, the monomer solution is heated to (co) polymerize alkoxyalkyl (meth) acrylate or alkoxyalkyl (meth) acrylate and another monomer. Here, as the polymerization method, for example, known polymerization methods such as radical polymerization, anionic polymerization, and cationic polymerization can be employed, and preferably radical polymerization that is easy to manufacture is used.

Polymerization conditions are not particularly limited as long as the above 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, and 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 process can be effectively suppressed and 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 in the polymerization.

The atmosphere in which the polymerization reaction is performed is not particularly limited, and may be performed in an air atmosphere or an inert gas atmosphere 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, it is preferable to perform purification by a reprecipitation method because a (co) polymer suitable for the preparation of a colloidal solution can be obtained. At this time, ethanol is preferably used as the poor solvent used for reprecipitation.

The polymer after purification can be dried by any method such as freeze drying, reduced pressure drying, spray drying, or heat drying. However, from the viewpoint of little influence on the physical properties of the polymer, freeze drying or reduced pressure drying is performed. Is preferred.

(2) Colloidal solution coating (coating) step Next, the colloidal solution prepared as described above is coated (coated) on the outer surface or inner surface of the hollow fiber membrane. Specifically, after assembling an artificial lung (for example, a structure as shown in FIG. 1 or FIG. 3 described later), the colloidal solution prepared in the above step (1) is contacted (or distributed), The outer surface or inner surface (that is, the blood contact portion) of the hollow fiber membrane is coated with an antithrombotic polymer compound. The colloidal solution may be applied to the hollow fiber membrane before the artificial lung is assembled.

In the present invention, the outer surface or inner surface of the hollow fiber membrane is brought into contact with the colloid solution (the colloid solution is circulated to the blood circulation side of the artificial lung), and the anti-thrombogenic property is increased on the outer surface or inner surface of the hollow fiber membrane. Form a coating film of molecular compounds. Here, the coating amount of the colloid solution on the outer surface or inner surface of the hollow fiber membrane is not particularly limited.

A preferred embodiment of the oxygenator manufactured by the method according to the present invention is an external perfusion oxygenator, in which the outer surface of the hollow fiber membrane is coated with an antithrombotic polymer compound. Therefore, in this step, it is preferable to apply a colloidal solution to the outer surface of the hollow fiber membrane in order to produce an artificial lung having the above configuration. That is, in the manufacturing method according to the present invention, the hollow fiber membrane has the inner surface that forms the lumen through which an oxygen-containing gas flows, and the outer surface that comes into contact with blood. A method of applying the colloidal solution is preferable.

Further, the coating method of the antithrombotic polymer compound is not particularly limited, but filling, dip coating (dipping method), spraying, spin coating, dripping, blade coating, brush coating, roll coating, air knife coating, curtain coating, 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 (dipping method) are preferred in order to increase the coating amount of the antithrombotic polymer compound.

Also, 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) takes into account the coating amount, the ease of forming the coating film, the effect of reducing coat unevenness, etc. 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 distribution temperature of the colloidal solution to the blood circulation side of the artificial lung) takes into account the coating amount, the ease of forming a coating film, the effect of reducing coat unevenness, etc. 5 to 40 ° C is preferable, and 15 to 30 ° C is more preferable. The colloidal solution is preferably allowed to stand at the time of contact between the colloidal solution and the hollow fiber membrane. By allowing the colloid solution to stand, a sufficient amount of the antithrombotic polymer compound can be coated.

After contact with the colloidal solution, the coating film is dried to form a coating (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 conditions are such that the coating (coating) with the antithrombotic polymer compound according to the present invention can be formed on the outer surface (and further the outer layer) or the inner surface (and the inner layer) of the hollow fiber membrane. If 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 allowing a gas of preferably 5 to 40 ° C., more preferably 15 to 30 ° C. to flow through the hollow fiber membrane continuously or stepwise. 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 include air and inert gases such as nitrogen gas and argon gas. Further, the amount of gas flow 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) Washing step This step is a step of washing the coating with the antithrombotic polymer compound, and is optionally provided. In this step, the water-soluble salt present in the coating can be removed by washing the coating with the antithrombotic polymer compound. On the other hand, if the water-soluble salt 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 a cleaning solvent, or a combination thereof may be used. The washing solvent used at this time is not particularly limited as long as it does not dissolve the coating film made of the antithrombotic polymer compound and can remove impurities including water-soluble salts, but water or hot water is preferable. Used. The temperature of the washing water is not particularly limited, but is preferably 20 ° C to 100 ° C, more preferably 25 to 80 ° C. Further, the washing time (time for bringing the washing solvent into contact with the coating) is not particularly limited, but is preferably 1 to 10 minutes, more preferably 2 to 5 minutes. According to the said conditions, water-soluble salt can fully be removed.

Furthermore, 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 an 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 10 mg / m ² or more, and 20 mg / m ^2. The above is more preferable. With such a coating amount, an artificial lung excellent in antithrombogenicity 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 excellent in gas exchange ability can be obtained. In addition, the said coating amount employ | adopts the value measured by the method as described in the following Example. In the present specification, the “membrane area” of the hollow fiber membrane refers to the area of the outer surface or 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 a blood external perfusion type hollow fiber membrane artificial lung), the “membrane area” is the outside of the hollow fiber membrane. It refers to the surface area, and is calculated from the product of the outer diameter, the circumferential ratio, the number and the 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 oxygenator is a blood internal perfusion type hollow fiber membrane oxygenator), the “membrane area” It refers to the area of the inner surface of the membrane, and is calculated from the product of the inner diameter, the circumferential ratio, the number and the effective length of the hollow fiber membrane.

In addition, since the artificial lung produced by the method of the present invention is coated with a sufficient amount of the antithrombotic polymer material as described above, the antithrombogenicity of the surface side or inner surface side of the hollow fiber membrane is low. improves. Therefore, when the artificial lung is incorporated into the extracorporeal 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 65% or more, more preferably 80% or more, and particularly preferably 90% or more (upper limit: 100% ). In addition, the said platelet number maintenance rate employ | adopts the value measured by the method as described in the following Example.

In the artificial lung produced by the method according to the present invention, the antithrombotic polymer compound (polymer) coats the outer surface or inner surface by applying a colloidal solution to the outer surface or inner surface of the hollow fiber membrane. It has a configuration. At this time, the water-soluble salt contained in the colloidal solution may remain in the coating with the antithrombotic polymer compound. In such a case, it is determined that the oxygenator was manufactured by the method according to the present invention. The presence or absence of a water-soluble salt in such a coating can be confirmed by any analytical means. For example, it can be confirmed by methods such as ion chromatography, electrical conductivity, ICP, elemental analysis, and atomic absorption spectrum. The present invention also applies to the case where the coating amount of the antithrombotic polymer compound is within the above coating amount range even when no water-soluble salt remains in the coating with the antithrombotic polymer compound. It is judged that it was manufactured by the method concerning.

Details of the oxygenator manufactured by the method of the present invention will be described below with reference to the drawings.

FIG. 1 is a cross-sectional view of one embodiment of a hollow fiber membrane external blood perfusion oxygenator 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 a hollow fiber membrane external blood perfusion oxygenator obtained by the production method of the present invention. FIG. 3 is a cross-sectional view of another embodiment of the oxygenator obtained by the production method of the present invention.

In FIG. 1, an artificial lung 1 houses a number of porous hollow fiber membranes 3 for gas exchange in a housing 2, blood flows on the outer surface side of the hollow fiber membrane 3, and an oxygen-containing gas is contained inside the hollow fiber membrane 3. Is a type of artificial lung. In FIG. 2, the antithrombotic polymer compound 18 is coated on the outer surface (the outer surface 3a ', or the outer surface 3a' and the outer surface layer 3a) of the hollow fiber membrane 3 serving as a blood contact portion. The coating (coating) of the antithrombotic polymer compound 18 is selectively formed on the outer surface 3 a ′ 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 3 a ′ of the hollow fiber membrane used in the hollow fiber membrane external blood perfusion type artificial lung. In such a hollow fiber membrane, blood contacts the outer surface 3a 'side, and an oxygen-containing gas flows through the inner surface 3c' side. In the present invention, as described above, a hollow fiber membrane internal blood perfusion oxygenator may be used. Therefore, the hollow fiber membrane may have a configuration opposite to the above configuration, that is, a configuration in which a coating (coating) of the antithrombotic polymer compound 18 is formed on the inner surface 3c ′.

“An 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 of the hollow fiber membrane (the surface on the blood flow side), 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 of the hollow fiber membrane (the surface on the blood flow side). Intended to be formed. “An antithrombotic polymer compound covers the outer surface layer of the hollow fiber membrane” means that the antithrombotic polymer compound partially penetrates into the outer surface layer of the hollow fiber membrane (near the outer surface of the pores). It is intended to form a coating. The anti-thrombotic polymer compound coating (coating) may be formed on at least a part of the blood contact portion (outer surface) of the hollow fiber membrane, but the antithrombotic biocompatibility (platelet adhesion / adhesion) From the viewpoints of the suppression / prevention effect and the suppression / prevention effect of platelet activation, it is preferably formed on the entire blood contact portion (outer surface) of the hollow fiber membrane. That is, the antithrombotic polymer compound preferably 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 3 b or the inner surface layer 3 c of the hollow fiber membrane 3, but in the inner layer 3 b or the inner surface layer 3 c of the hollow fiber membrane 3. It is preferable that it does not exist substantially. In this specification, “the antithrombotic polymer compound is not substantially 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 on 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 coating 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 surface layer 3c of the hollow fiber membrane 3. Can be in a substantially non-existent form.

A hollow fiber membrane type artificial lung 1 according to this embodiment includes a housing 2 having a blood inlet 6 and a blood outlet 7 and a number of gas exchange porous hollow fiber membranes 3 housed in the housing 2. A hollow fiber membrane bundle and a pair of partition walls 4 and 5 that support both ends of the hollow fiber membrane bundle in a liquid-tight manner on the housing 2. The blood chamber 12 is formed in the inside, the gas chamber formed inside the hollow fiber membrane 3, and the gas inlet 8 and the gas outlet 9 communicating with the gas chamber.

Specifically, the hollow fiber membrane oxygenator 1 of the present embodiment includes a cylindrical housing 2, an aggregate of gas exchange hollow fiber membranes 3 housed in the cylindrical housing 2, and a hollow fiber membrane 3. Both ends of the housing 2 are liquid-tightly held in the housing 2, and the inside of the cylindrical housing 2 is partitioned into a blood chamber 12 as a first fluid chamber and a gas chamber as a second fluid chamber. The cylindrical housing 2 is provided with a blood inlet 6 and a blood outlet 7 that communicate with the blood chamber 12.

A cap-like gas inflow having a gas inlet 8 that is a second fluid inlet that communicates with a gas chamber that is an internal space of the hollow fiber membrane 3 is provided above the partition wall 4 that is an end of the cylindrical housing 2. A 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-like gas outflow side header 11 having a gas outflow port 9 provided as a second fluid outflow port provided below the partition wall 5 and 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 the same hollow fiber membrane used for known artificial lungs is used and is not particularly limited. As described above, the hollow fiber membrane (particularly the inner surface of the hollow fiber membrane) is made of a hydrophobic polymer material, so that 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 thickness (film 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 (film thickness) of the hollow fiber membrane” means the thickness between the inner surface and the outer surface of the hollow fiber membrane, and the formula: [(outside of the hollow fiber membrane (Diameter) − (inner diameter of hollow fiber membrane)] / 2. Here, by setting the lower limit of the thickness of the hollow fiber membrane as described above, sufficient strength of the hollow fiber membrane can be secured. Moreover, it is satisfactory in terms of manufacturing effort and cost, which 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” means the opening (in the present embodiment, the outer surface side) of the side coated with the antithrombotic polymer compound (in the present specification, The average diameter of the material may be simply referred to as “pore”. Further, the average diameter of the openings (in the present specification, sometimes simply referred to as “pore diameter” or “pore diameter”) is measured by the method described below.

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

Subsequently, 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 thus determined and the resolution (μm / pixel) of the SEM image. From the obtained hole area, the diameter of each hole is calculated by regarding the hole as a circle, and a statistically significant number, for example, the diameter of 500 holes is randomly extracted, and the arithmetic average is expressed as “ The diameter of the opening of the hollow fiber ”.

Also, as the material used for the porous membrane, the same material as the hollow fiber membrane used for known artificial lungs can be used. Specific examples 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 preferable. The method for producing the hollow fiber membrane is not particularly limited, and a known method for producing a hollow fiber membrane can be applied in the same manner or appropriately modified. For example, the hollow fiber membrane is preferably formed by forming micropores in the wall by a stretching method or a solid-liquid phase separation method.

The material constituting the cylindrical housing 2 can also be the same material as that used for a known artificial lung housing. Specific examples include hydrophobic synthetic resins such as polycarbonate, acrylic / styrene copolymer, and acrylic / butylene / styrene copolymer. The shape of the housing 2 is not particularly limited, but is preferably, for example, a cylindrical shape and a transparent body. By forming it with a transparent body, the inside can be easily confirmed.

The accommodation amount of the hollow fiber membrane 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 accommodated in the housing 2 in parallel in the axial direction. Further, the hollow fiber membrane 3 is fixed in a liquid-tight state by the partition walls 4 and 5 with both ends of the hollow fiber membrane 3 being opened at both ends of the housing 2. The partition walls 4 and 5 are made of a potting agent such as polyurethane or silicone rubber. A portion sandwiched between the partition walls 4 and 5 in the housing 2 is partitioned into a gas chamber inside the hollow fiber membrane 3 and a blood chamber 12 outside the hollow fiber membrane 3.

In this embodiment, a gas inflow side header 10 having a gas inflow port 8 and a gas outflow side header 11 having a gas outflow port 9 are liquid-tightly attached to the housing 2. These headers may be formed of any material, but may be formed of, for example, a hydrophobic synthetic resin used for the housing described above. The header may be attached by any method. For example, the header 2 may be bonded to the housing 2 by fusing using ultrasonic waves, high frequency, induction heating or the like, bonding using an adhesive, or mechanically fitting. Attached to. Further, a tightening ring (not shown) may be used. It is preferable that all the blood contact portions (the inner surface of the housing 2 and the outer surface of the hollow fiber membrane 3) of the hollow fiber membrane-type artificial lung 1 are made of a hydrophobic material.

As shown in FIG. 2, the outer surface 3a ′ of the hollow fiber membrane 3 serving as at least a blood contact portion of the hollow fiber membrane oxygenator 1 (or the outer surface layer 3a in some cases; the same shall apply hereinafter) The thrombotic polymer compound 18 is coated. As described above, it is preferable that the antithrombogenic polymer compound is not substantially present in the inner layer 3b or the inner surface layer 3c of the hollow fiber membrane. Since the antithrombotic polymer compound is not substantially present, the hydrophobic property of the inner layer 3b or inner surface layer 3c of the hollow fiber membrane itself is maintained as it is, and leakage of plasma components (leakage) ) Can be effectively prevented. In particular, it is preferable that the antithrombogenic polymer compound is not substantially present in both the inner layer 3b and the inner surface layer 3c of the hollow fiber membrane. The hollow fiber membrane 3 includes a passage (inner lumen) 3d that forms a gas chamber at 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 configuration is such that blood is in contact with the outer surface 3a ′ side coated with the antithrombotic polymer compound 18, and 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 an oxygen-containing gas flows, and an outer surface 3a ′ that contacts blood, and the outer surface 3a ′ A form coated with a film containing the antithrombotic polymer compound according to the present invention (ie, external perfusion type).

In this embodiment, the coating (coating) of the antithrombotic polymer compound is selectively formed on the outer surface (external perfusion type) of the hollow fiber membrane. For this reason, blood (particularly plasma components) does not easily penetrate into the pores of the hollow fiber membrane or does not penetrate. Therefore, leakage of blood (particularly plasma components) from the hollow fiber membrane can be effectively suppressed / prevented. In particular, when the antithrombotic polymer compound is substantially not present in the inner layer 3b of the hollow fiber membrane and the inner layer 3c of the hollow fiber membrane, the inner layer 3b of the hollow fiber membrane and the inner layer 3c of the hollow fiber membrane are: Since the hydrophobic state of the material is maintained, leakage (leakage) of blood (particularly plasma components) can be more effectively suppressed / prevented. Therefore, the artificial lung obtained by the method of the present invention can maintain a high gas exchange capacity over a long period of time.

Further, according to the present invention, by using a colloidal solution, a coating (coating) of the antithrombotic polymer compound can be uniformly formed on the outer surface or inner surface of the hollow fiber membrane. For this reason, there is little adhesion / adhesion and activation of platelets at the blood contact portion of the hollow fiber membrane. It is also 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 formed on the outer surface of the hollow fiber membrane of the artificial lung, but in addition to the outer surface, other components (for example, the entire blood contact portion) May be formed. With this configuration, platelet adhesion / adhesion and activation can be more effectively suppressed / prevented in the entire blood contact portion of the artificial lung. Moreover, since the contact angle of the blood contact surface is lowered, the priming operation is facilitated. In this case, the coating of the antithrombotic polymer compound according to the present invention is preferably formed on another constituent member that comes into contact with blood, but the hollow fiber membrane or hollow fiber membrane other than the blood contact portion is formed. The other part (for example, the part 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 oxygenator obtained by the method of the present invention. 4 is a cross-sectional view taken along line AA in FIG.

In FIG. 3, an artificial lung (hollow fiber membrane external blood perfusion type artificial lung) 20 includes an inner cylindrical member 31 having a blood circulation opening 32 on its side surface, and a number of gases wound around the outer surface of the inner cylindrical member 31. In the state which opened the both ends of the cylindrical hollow fiber membrane bundle 22 which consists of the porous hollow fiber membrane 3 for replacement | exchange, the housing 23 which accommodates the cylindrical hollow fiber membrane bundle 22 with the inner side cylindrical member 31, and the hollow fiber membrane 3 , Partition

walls

25 and 26 for fixing both ends of the cylindrical hollow fiber membrane bundle 22 to the housing, a blood inlet 28 and

blood outlets

29a and 29b communicating with the blood chamber 17 formed in the housing 23, and a hollow fiber A gas inlet 24 and a gas outlet 27 communicating with the inside of the membrane 3 are provided.

As shown in FIGS. 3 and 4, the oxygenator 20 of the present embodiment includes an outer cylindrical member 33 that houses an inner cylindrical member 31, and the cylindrical hollow fiber membrane bundle 22 is an inner cylinder. The housing 23 is housed between the outer cylindrical member 33 and the outer cylindrical member 33, and the housing 23 is blood connected to one of the blood inlet or the blood outlet communicating with the inside of the inner cylindrical member and the inside of the outer cylindrical member. The other of the inlet or the blood outlet.

Specifically, in the oxygenator 20 of the present embodiment, the housing 23 is housed in the outer cylindrical member 33 and the inner cylindrical member 31, and the inner cylindrical body 35 whose front end opens in the inner cylindrical member 31. Prepare. A blood inlet 28 is formed at one end (lower end) of the inner cylinder 35, and two

blood outlets

29 a and 29 b extending outward are formed on the side surface of the outer cylindrical member 33. There may be one or more blood outlets.

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

The inner cylindrical member 35, the inner cylindrical member 31 with the hollow fiber membrane bundle 22 wound around the outer surface, and the outer cylindrical member 33 are arranged substantially concentrically. Then, one end (upper end) of the inner cylindrical member 31 and the one end (upper end) of the outer cylindrical member 33 around which the hollow fiber membrane bundle 22 is wound on the outer surface 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 cylindrical 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 slightly above the blood inlet 28 of the inner cylinder 35, the other end (lower end) of the inner cylindrical member 31 around which the hollow fiber membrane bundle 22 is wound around the outer surface, and the other end (outer end of the outer cylindrical member 33 ( The lower end) maintains the concentric positional relationship between the second partition wall 26 and the space formed between the inner cylindrical body 35 and the inner cylindrical member 31 and the outer cylindrical member 33 and the hollow fiber. The space formed between the outer surface of the membrane is in a liquid-tight state that does not communicate with the outside. Moreover, the

partition walls

25 and 26 are formed of a potting agent such as polyurethane or silicone rubber.

Therefore, in the oxygenator 20 of this embodiment, the blood inflow part 17a formed by the inside of the inner cylinder 35, the substantially cylindrical space formed between the inner cylinder 35 and the inner cylinder member 31, and The first blood chamber 17b is formed, and the second blood chamber 17c is formed between the hollow fiber membrane bundle 22 and the outer cylindrical member 33 and has a substantially cylindrical space. A chamber 17 is formed.

The blood flowing in from the blood inlet 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 cylindrical member 31, contacts the hollow fiber membrane, and after gas exchange, flows into the second blood chamber 17c. The blood flows out from the

blood outlets

29a and 29b.

A gas inflow member 41 having a gas inlet 24 is fixed to one end of the outer cylindrical member 33, and similarly, a gas having a gas outlet 27 is provided to the other end of the outer cylindrical member 33. An outflow member 42 is fixed. The blood inlet 28 of the inner cylindrical body 35 protrudes outside through the gas outflow member 42.

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

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

The inner cylindrical member 31 includes 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 necessary strength of the tubular member is maintained. For example, FIG. 5 is a front view, FIG. 6 is a central longitudinal sectional view of FIG. 5, and FIG. 7 is a sectional view taken along the line BB of FIG. In addition, an annular arrangement opening in which a plurality of openings 32 (for example, 4 to 24 pieces, 8 pieces in the longitudinal direction in the figure) are provided on the outer peripheral surface of the cylindrical member at equal angular intervals is provided at equal intervals in the axial direction of the cylindrical member A plurality of sets (8 sets / circumference in the figure) are preferable. 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.

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

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

The hollow fiber membrane bundle 22 is formed by winding a hollow fiber membrane around the inner cylindrical member 31, specifically, by forming a hollow fiber membrane bobbin with the inner cylindrical member 31 as a core, and forming the hollow fiber membrane. Both ends of the bobbin can be formed by cutting both ends of the hollow fiber membrane bobbin together with the inner cylindrical member 31 as the core after fixing with the partition walls. In addition, by this cutting | disconnection, a hollow fiber membrane opens in the outer surface of a partition. In addition, the formation method of a hollow fiber membrane is not limited to the said method, You may use the formation method of other well-known hollow fiber membranes similarly or suitably modified.

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

Furthermore, the hollow fiber membrane bundle 22 has one or more (preferably 2 to 16) hollow fiber membranes at the same time, and all the adjacent hollow fiber membranes have a substantially constant interval. A rotator and a hollow fiber membrane for rotating the inner cylindrical member 31 when the hollow fiber membrane is wound on the inner cylindrical member while being formed by being wound around the cylindrical member 31. It is preferable that the winder for weaving is formed by being wound around the inner cylindrical member 31 by moving under the condition of the following formula (1).

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

In the oxygenator according to the other embodiment, after blood flows from the inside of the cylindrical 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, Although it is of the type that flows out from the oxygenator 20, it is not limited to this. Contrary to the other embodiments described above, blood flows from the outside of the cylindrical hollow fiber membrane bundle 22, and after the blood passing through the hollow fiber membrane bundle 22 flows inside the hollow fiber membrane bundle 22, the oxygenator 20 It may be of a more outflow type.

Also in the hollow fiber membrane type artificial lung 20, as shown in FIG. 2, at least the outer surface 3a ′ (and further the outer layer 3a) of the hollow fiber membrane 3 of the hollow fiber membrane type artificial lung 1 is applied to the present invention. The antithrombotic polymer compound 18 is preferably 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. Preferably not. The hollow fiber membrane 3 includes a passage (inner lumen) 3d that forms a gas chamber at 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, preferred forms of the hollow fiber membrane (inner diameter, outer diameter, wall thickness, porosity, pore diameter, etc.) are not particularly limited, but the same form as described in FIG. 1 can be adopted.

In the oxygenator 20 according to the present embodiment, the hollow fiber membranes 3 are in the form of a so-called bobbin that is in contact with each other and stacked in layers. In the present embodiment, the coating with the antithrombotic polymer compound is selectively formed uniformly on the outer surface 3a 'of the hollow fiber membrane. By adopting such a configuration, leakage of blood (particularly plasma components) to the inner surface layer 3c of the hollow fiber membrane can be suppressed / prevented. That is, leakage of blood (especially plasma components) can be achieved by selectively covering the outer surface 3a ′ (and further the outer surface layer 3a) of the hollow fiber membrane 3 which is a blood contact portion with an antithrombotic polymer compound ( Leakage) can be effectively suppressed / prevented. In particular, when the antithrombotic polymer compound according to the present invention is substantially absent from 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 made of a hydrophobic material. Since the sex state is maintained, leakage (leakage) of blood (particularly plasma components) can be more effectively suppressed / prevented. In this embodiment, the blood flow path is complicated and has many narrow portions, and is excellent in gas exchange ability. However, in terms of adhesion / adhesion and activation of platelets, an external blood perfusion type artificial body that is not a bobbin type is used. May be inferior to lungs. However, as described above, since the coating of the antithrombotic polymer compound is uniform, platelet adhesion / adhesion and activation at the blood contact portion of the hollow fiber membrane are small. Further, it is possible to suppress / prevent peeling of the coating (particularly the coating uneven portion) from the hollow fiber membrane.

In addition, the coating of the antithrombotic polymer compound is essentially formed on the outer surface of the hollow fiber membrane of the artificial lung, but in addition to the outer surface, it is formed on other components (for example, the entire blood contact portion). May be. With this configuration, platelet adhesion / adhesion and activation can be more effectively suppressed / prevented in the entire blood contact portion of the artificial lung. Moreover, since the contact angle of the blood contact surface is lowered, the priming operation is facilitated. In this case, it is preferable that the coating of the antithrombotic polymer compound is formed on another component that comes into contact with blood, but the hollow fiber membrane other than the blood contact portion or other part of the hollow fiber membrane ( 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 effect of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, “%” and “part” mean “% by mass” and “part by mass”, respectively.

[Synthesis of antithrombotic polymer compounds]
Production Example 1: Synthesis of PMEA with a weight average molecular weight of 420,000 2-methoxyethyl acrylate (MEA) 80 g (0.61 mol) was dissolved in 115 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour. And a monomer solution was prepared. Separately, 0.08 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 5 g of methanol to obtain a polymerization initiator solution. Was prepared. Next, this polymerization initiator solution was added to the monomer solution, and a polymerization reaction was performed at 50 ° C. for 5 hours. After polymerization for a predetermined time, the polymerization solution was dropped into ethanol, and the precipitated polymer (PMEA) was recovered. In addition, it was 420,000 when the weight average molecular weight of the collect | recovered polymer was measured.

[Preparation of coating solution]
Example 1-1: Coating solution having a sodium chloride concentration of 0.2 mass% 0.4 g of PMEA (weight average molecular weight = 420,000) synthesized in Production Example 1 was dissolved in 20 g of methanol. 370 g of distilled water was added to another container, and the above PMEA methanol solution was added at an addition rate of 20 g / min while stirring with a stirrer. Then, it stirred at 25 degreeC for 10 minute (s), and the coating liquid which became cloudy was obtained. The coating liquid was a colloid liquid in which PMEA colloid was dispersed. 10 g of an aqueous solution containing sodium chloride at a concentration of 8% by mass was added to the colloidal solution to obtain a coating solution (1). At this time, the solvent of the coating liquid (1) has a water: methanol mixing ratio = 19: 1 (mass ratio) and a PMEA concentration of 0.1 mass%.

Example 1-2: Coating solution having a sodium chloride concentration of 0.05% by mass Example 1 except that the aqueous sodium chloride solution used in Example 1-1 was changed to an aqueous solution having a concentration of 2% by mass. The coating liquid (2) was obtained in the same manner as -1. The coating liquid (2) was also a solution containing a colloid, like the coating liquid (1).

Comparative Example 1-1: Sodium chloride not added A coating liquid (3) was obtained in the same manner as in Example 1-1 except that the sodium chloride aqueous solution was not added. The coating liquid (3) was also a solution containing a colloid, like the coating liquid (1).

[Production of artificial lung]
Example 2-1
Porous hollow for gas exchange made of porous polypropylene having an inner diameter of 195 μm, an outer diameter of 295 μm, a wall thickness of 50 μm, a porosity of about 35% by volume, and an outer surface pore diameter (ie, average diameter of openings) of 80 nm A blood external 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 wound with a yarn membrane was produced.

The coating liquid (1) prepared in Example 1-1 above is filled into the blood flow path of the artificial lung (a) and left standing at 25 ° C. for 120 seconds, and then the coating liquid is removed to obtain a flow rate of 80 L. The hollow fiber membrane was dried to produce a blood external perfusion type hollow fiber membrane artificial lung (1) having a hollow fiber membrane having a coating formed on the outer surface. The blood external perfusion type hollow fiber artificial lung (1) thus obtained is also referred to as an artificial lung (1).

Example 2-2
In Example 2-1 above, except that the coating solution used was changed to the coating solution (2) prepared in Example 1-2 above, blood external perfusion type hollow was obtained in the same manner as in Example 2-1. A thread membrane oxygenator (2) was produced. The blood external perfusion type hollow fiber artificial lung (2) thus obtained is also referred to as an artificial lung (2).

Comparative Example 2-1
In Example 2-1 above, except that the coating liquid used was changed to the coating liquid (3) prepared in Comparative Example 1-1, the blood external perfusion type hollow was the same as in Example 2-1 above. A thread membrane oxygenator (3) was produced. The blood external perfusion type hollow fiber artificial lung (2) thus obtained is also referred to as an artificial lung (3).

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

The artificial lungs (1) to (3) were disassembled and the artificial lung membrane was taken out. Among them, 3 g of the artificial lung membrane was filled into a glass tube with a screw cap, 25 ml of acetone was added, and the mixture was stirred for 120 minutes to extract PMEA coated on each artificial lung membrane. The whole amount of the acetone extract was transferred to another glass tube with a screw cap. Acetone was evaporated using a heat block. Ten ml of tetrahydrofuran was added to the glass tube containing the evaporated dry matter to dissolve the evaporated dry matter. The 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. Thereafter, the amount of PMEA in the test solution was calculated using the following formula 1, and the amount of PMEA coating per 1 m ^{2 of} artificial lung membrane (the area 1 m ² of the outer surface of the hollow fiber membrane) was calculated using 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 drastically increased the PMEA coating amount.

[Experiment 2. Antithrombogenicity test]
The anti-thrombogenicity of the artificial lung (1) and the artificial lung (3) obtained in Example 2-1 and Comparative Example 2-1 was evaluated according to the following method.

Each artificial lung was incorporated into an extracorporeal circuit and filled with 90 ml of fresh pig blood with heparin added and 110 ml of physiological 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) with physiological saline 100 times 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 platelet count maintenance rate in the blood, the higher the antithrombogenicity. The results are shown in Table 2 below.

From the results of 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 that does not contain a salt containing a metal cation or an ammonium cation in the coating solution. Thus, it can be seen that the antithrombogenicity is significantly improved.

This application is based on Japanese Patent Application No. 2017-048248 filed on March 14, 2017, the disclosure of which is referenced and incorporated as a whole.

Claims

A method for producing an artificial lung having a plurality of gas exchange porous hollow fiber membranes comprising an outer surface, an inner surface that forms a lumen, and an opening that communicates the outer surface and the inner surface. And
A method for producing an artificial lung, which comprises applying a solution containing a colloid of an antithrombotic polymer compound and a water-soluble salt containing a metal cation or an ammonium cation to either the outer surface or the inner surface. .
The hollow fiber membrane has the inner surface forming the lumen through which oxygen-containing gas flows, and the outer surface in contact with blood;
The method for producing an artificial lung according to claim 1, wherein the solution is applied to the outer surface.
The method for producing an artificial lung according to claim 1 or 2, wherein the water-soluble salt is sodium chloride or magnesium sulfate.
The method for producing an artificial lung according to any one of claims 1 to 3, wherein the solution contains 0.01% by mass or more of the water-soluble salt.
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 artificial lung according to any one of claims 1 to 5, wherein the solution contains the antithrombotic polymer compound and the water-soluble salt in a molar ratio of 1: 3,000 to 30,000. Manufacturing method.
The antithrombotic polymer compound has the following formula (I):

Where 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 comprises a structural unit derived from an alkoxyalkyl (meth) acrylate represented by the formula:
The method for producing an artificial lung according to any one of claims 1 to 7, wherein a weight average molecular weight of the antithrombotic polymer compound is more than 200,000 and less than 800,000.